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<!doctype html> <html data-n-head-ssr lang="en" data-n-head="%7B%22lang%22:%7B%22ssr%22:%22en%22%7D%7D"> <head > <link data-n-head="ssr" rel="icon" type="image/png" sizes="16x16" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_16-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="icon" type="image/png" sizes="32x32" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_32-tenantFavicon-Frontiers.png"> <link data-n-head="ssr" rel="apple-touch-icon" type="image/png" sizes="180x180" href="https://brand.frontiersin.org/m/ed3f9ce840a03d7/favicon_180-tenantFavicon-Frontiers.png"> <title>Frontiers | Current Perspectives on “Off-The-Shelf” Allogeneic NK and CAR-NK Cell Therapies</title><meta data-n-head="ssr" charset="utf-8"><meta data-n-head="ssr" name="viewport" content="width=device-width, initial-scale=1"><meta data-n-head="ssr" data-hid="charset" charset="utf-8"><meta data-n-head="ssr" data-hid="mobile-web-app-capable" name="mobile-web-app-capable" content="yes"><meta data-n-head="ssr" data-hid="apple-mobile-web-app-title" name="apple-mobile-web-app-title" content="Frontiers | Articles"><meta data-n-head="ssr" data-hid="theme-color" name="theme-color" content="#0C4DED"><meta data-n-head="ssr" data-hid="description" property="description" name="description" content="Natural killer cells (NK cells) are the first line of the innate immune defense system, primarily located in peripheral circulation and lymphoid tissues. The..."><meta data-n-head="ssr" data-hid="og:title" property="og:title" name="title" content="Frontiers | Current Perspectives on “Off-The-Shelf” Allogeneic NK and CAR-NK Cell Therapies"><meta data-n-head="ssr" data-hid="og:description" property="og:description" name="description" content="Natural killer cells (NK cells) are the first line of the innate immune defense system, primarily located in peripheral circulation and lymphoid tissues. The..."><meta data-n-head="ssr" data-hid="keywords" name="keywords" content="Natural Killer cells,CAR-NK cells,Immunotherapy,NK cell expansion,lentiviral delivery,AAV delivery,Killer immune receptors,GMP manufacturing"><meta data-n-head="ssr" data-hid="og:site_name" property="og:site_name" name="site_name" content="Frontiers"><meta data-n-head="ssr" data-hid="og:image" property="og:image" name="image" content="https://images-provider.frontiersin.org/api/ipx/w=1200&f=png/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g001.jpg"><meta data-n-head="ssr" data-hid="og:type" property="og:type" name="type" content="article"><meta data-n-head="ssr" data-hid="og:url" property="og:url" name="url" content="https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.732135/full"><meta data-n-head="ssr" data-hid="twitter:card" name="twitter:card" content="summary_large_image"><meta data-n-head="ssr" data-hid="citation_volume" name="citation_volume" content="12"><meta data-n-head="ssr" data-hid="citation_journal_title" name="citation_journal_title" content="Frontiers in Immunology"><meta data-n-head="ssr" data-hid="citation_publisher" name="citation_publisher" content="Frontiers"><meta data-n-head="ssr" data-hid="citation_journal_abbrev" name="citation_journal_abbrev" content="Front. Immunol."><meta data-n-head="ssr" data-hid="citation_issn" name="citation_issn" content="1664-3224"><meta data-n-head="ssr" data-hid="citation_doi" name="citation_doi" content="10.3389/fimmu.2021.732135"><meta data-n-head="ssr" data-hid="citation_firstpage" name="citation_firstpage" content="732135"><meta data-n-head="ssr" data-hid="citation_language" name="citation_language" content="English"><meta data-n-head="ssr" data-hid="citation_title" name="citation_title" content="Current Perspectives on “Off-The-Shelf” Allogeneic NK and CAR-NK Cell Therapies"><meta data-n-head="ssr" data-hid="citation_keywords" name="citation_keywords" content="Natural Killer cells; CAR-NK cells; Immunotherapy; NK cell expansion; lentiviral delivery; AAV delivery; Killer immune receptors; GMP manufacturing"><meta data-n-head="ssr" data-hid="citation_abstract" name="citation_abstract" content="<p>Natural killer cells (NK cells) are the first line of the innate immune defense system, primarily located in peripheral circulation and lymphoid tissues. They kill virally infected and malignant cells through a balancing play of inhibitory and stimulatory receptors. In pre-clinical investigational studies, NK cells show promising anti-tumor effects and are used in adoptive transfer of activated and expanded cells, <italic>ex-vivo</italic>. NK cells express co-stimulatory molecules that are attractive targets for the immunotherapy of cancers. Recent clinical trials are investigating the use of CAR-NK for different cancers to determine the efficiency. Herein, we review NK cell therapy approaches (NK cell preparation from tissue sources, ways of expansion <italic>ex-vivo</italic> for “off-the-shelf” allogeneic cell-doses for therapies, and how different vector delivery systems are used to engineer NK cells with CARs) for cancer immunotherapy.</p>"><meta data-n-head="ssr" data-hid="citation_pdf_url" name="citation_pdf_url" content="https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.732135/pdf"><meta data-n-head="ssr" data-hid="citation_online_date" name="citation_online_date" content="2021/11/01"><meta data-n-head="ssr" data-hid="citation_publication_date" name="citation_publication_date" content="2021/12/01"><meta data-n-head="ssr" data-hid="citation_author_0" name="citation_author" content="Heipertz, Erica L."><meta data-n-head="ssr" data-hid="citation_author_institution_0" name="citation_author_institution" content="Cell & Gene Therapy, Thermo Fisher Scientific, United States"><meta data-n-head="ssr" data-hid="citation_author_1" name="citation_author" content="Zynda, Evan R."><meta data-n-head="ssr" data-hid="citation_author_institution_1" name="citation_author_institution" content="BioProduction, Thermo Fisher Scientific, United States"><meta data-n-head="ssr" data-hid="citation_author_2" name="citation_author" content="Stav-Noraas, Tor Espen"><meta data-n-head="ssr" data-hid="citation_author_institution_2" name="citation_author_institution" content="BioProduction, Thermo Fisher Scientific, Norway"><meta data-n-head="ssr" data-hid="citation_author_3" name="citation_author" content="Hungler, Andrew D."><meta data-n-head="ssr" data-hid="citation_author_institution_3" name="citation_author_institution" content="Cell & Gene Therapy, Thermo Fisher Scientific, United States"><meta data-n-head="ssr" data-hid="citation_author_4" name="citation_author" content="Boucher, Shayne E."><meta data-n-head="ssr" data-hid="citation_author_institution_4" name="citation_author_institution" content="Cell & Gene Therapy, Thermo Fisher Scientific, United States"><meta data-n-head="ssr" data-hid="citation_author_5" name="citation_author" content="Kaur, Navjot"><meta data-n-head="ssr" data-hid="citation_author_institution_5" name="citation_author_institution" content="Cell & Gene Therapy, Thermo Fisher Scientific, United States"><meta data-n-head="ssr" data-hid="citation_author_6" name="citation_author" content="Vemuri, Mohan C."><meta data-n-head="ssr" data-hid="citation_author_institution_6" name="citation_author_institution" content="Cell & Gene Therapy, Thermo Fisher Scientific, United States"><meta data-n-head="ssr" data-hid="dc.identifier" name="dc.identifier" content="doi:10.3389/fimmu.2021.732135"><link data-n-head="ssr" rel="manifest" href="/article-pages/_nuxt/manifest.c499fc0a.json" data-hid="manifest"><link data-n-head="ssr" rel="canonical" href="https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.732135/full"><script data-n-head="ssr" data-hid="newrelic-browser-script" type="text/javascript">window.NREUM||(NREUM={});NREUM.info = {"agent":"","beacon":"bam.nr-data.net","errorBeacon":"bam.nr-data.net","licenseKey":"598a124f17","applicationID":"588603994","agentToken":null,"applicationTime":2.067407,"transactionName":"MQcDMkECCkNSW0YMWghNIgldDQFTRxd1IGFJTQ==","queueTime":0,"ttGuid":"95326b9da6b31447"}; (window.NREUM||(NREUM={})).init={privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]},distributed_tracing:{enabled:true}};(window.NREUM||(NREUM={})).loader_config={agentID:"594400880",accountID:"230385",trustKey:"230385",xpid:"VgUHUl5WGwYIXFdSBAgOUg==",licenseKey:"598a124f17",applicationID:"588603994"};;/*! 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aria-label="Search" data-event="iBar-a-search" class="Ibar__icon Ibar__icon--search"><span>Search</span></a>    <div class="Ibar__userArea"></div></div></div></nav> <div class="ArticlePage"><div><div class="Layout Layout--withAside Layout--withIbarMix ArticleDetails"> <main class="Layout__main"> <div class="ArticleDetails__main"><div class="ArticleLayoutHeader"><div class="ArticleLayoutHeader__info"><p class="ArticleLayoutHeader__info__title"> REVIEW article </p> <p class="ArticleLayoutHeader__info__journalDate"><span>Front. Immunol.</span> <span>, 01 December 2021</span></p> <p class="ArticleLayoutHeader__info__journalDate"> Sec. Cancer Immunity and Immunotherapy </p> <p class="ArticleLayoutHeader__info__doiVolume"><span> Volume 12 - 2021 | </span> <a href="https://doi.org/10.3389/fimmu.2021.732135" class="ArticleLayoutHeader__info__doi"> https://doi.org/10.3389/fimmu.2021.732135 </a></p> </div>  <p class="ArticleLayoutHeader__isPartOfRT"><span class="ArticleLayoutHeader__isPartOfRT__label">This article is part of the Research Topic</span> <span class="ArticleLayoutHeader__isPartOfRT__title">NK cell modifications to advance their anti-tumor activities</span> <span class="Link__wrapper"><a aria-label="View all 13 articles" href="https://www.frontiersin.org/research-topics/45264/nk-cell-modifications-to-advance-their-anti-tumor-activities/magazine" target="_self" data-event="customLink-link-a_viewAll13Articles" class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right"><span>View all 13 articles</span></a></span></p></div> <div class="ArticleDetails__main__content"><div class="ArticleDetails__main__content__main ArticleDetails__main__content__main--fullArticle"><div class="JournalAbstract"><div class="JournalAbstract__titleWrapper"><h1>Current Perspectives on “Off-The-Shelf” Allogeneic NK and CAR-NK Cell Therapies</h1> </div> </div> <div class="JournalFullText"><div class="JournalAbstract"><a id="h1" name="h1"></a><div class="authors"><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/1446932" class="user-id-1446932"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1446932/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Erica L. Heipertz">Erica L. Heipertz</a><sup>1</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Evan R. Zynda" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Evan R. Zynda<sup>2</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Tor Espen Stav-Noraas" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Tor Espen Stav-Noraas<sup>3</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Andrew D. Hungler" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Andrew D. Hungler<sup>1</sup></span><span class="author-wrapper notranslate"><img class="pr5" src="https://loop.frontiersin.org/cdn/images/profile/default_32.jpg" alt="Shayne E. Boucher" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';">Shayne E. Boucher<sup>1</sup></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/1534933" class="user-id-1534933"><img class="pr5" src="https://loop.frontiersin.org/images/profile/1534933/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Navjot Kaur">Navjot Kaur</a><sup>1</sup></span><span class="author-wrapper notranslate"><a href="https://loop.frontiersin.org/people/675032" class="user-id-675032"><img class="pr5" src="https://loop.frontiersin.org/images/profile/675032/74" onerror="this.onerror=null;this.src='https://loop.frontiersin.org/cdn/images/profile/default_32.jpg';" alt="Mohan C. Vemuri*">Mohan C. Vemuri</a><sup>1*</sup></span></div><ul class="notes"><li><span><sup>1</sup></span>Cell & Gene Therapy, Thermo Fisher Scientific, Frederick, MD, United States</li><li><span><sup>2</sup></span>BioProduction, Thermo Fisher Scientific, Grand Island, NY, United States</li><li><span><sup>3</sup></span>BioProduction, Thermo Fisher Scientific, Oslo, Norway</li></ul><p>Natural killer cells (NK cells) are the first line of the innate immune defense system, primarily located in peripheral circulation and lymphoid tissues. They kill virally infected and malignant cells through a balancing play of inhibitory and stimulatory receptors. In pre-clinical investigational studies, NK cells show promising anti-tumor effects and are used in adoptive transfer of activated and expanded cells, <i>ex-vivo</i>. NK cells express co-stimulatory molecules that are attractive targets for the immunotherapy of cancers. Recent clinical trials are investigating the use of CAR-NK for different cancers to determine the efficiency. Herein, we review NK cell therapy approaches (NK cell preparation from tissue sources, ways of expansion <i>ex-vivo</i> for “off-the-shelf” allogeneic cell-doses for therapies, and how different vector delivery systems are used to engineer NK cells with CARs) for cancer immunotherapy.</p><div class="clear"></div></div><div class="JournalFullText"><a id="h2" name="h2"></a><h2>Natural Killer Cell Biology</h2><p class="mb15">Human natural killer (NK) cells are innate cytotoxic lymphoid cells derived from CD34+ precursors originating from hematopoietic stem cells (<a href="#B1">1</a>, <a href="#B2">2</a>) and play an essential role in tumor surveillance. Unlike T cells, NK cells can kill malignant cells in an antigen-independent manner and have shown promise in a number of clinical trials involving both solid and hematological cancers (<a href="#B3">3</a>). NK cells do not require HLA matching. Their ability to act in an antigen-independent manner makes them a viable option for an “off the shelf” therapy that can be manufactured on a large scale and easily distributed to cancer patients.</p><p class="mb15">NK cells are subdivided into two populations based on their relative expression of CD56 (neural cell adhesion molecule; NCAM) and CD16: immature CD56<sup>bright</sup> CD16<sup>neg</sup> NK cells, and mature CD56<sup>dim</sup> CD16<sup>pos</sup> NK cells (<a href="#B4">4</a>). The CD56<sup>bright</sup> population accounts for 10% of NK cells circulating in the blood and are located primarily in lymph nodes. Immature CD56<sup>bright</sup> NK cells have an immunoregulatory function and produce cytokines, such as interferon-gamma (IFN-γ), TNFα, TNF-β, IL-10, and GM-CSF (<a href="#B5">5</a>). In contrast, the mature CD56<sup>dim</sup> CD16<sup>pos</sup> population accounts for up to 90% of the circulating NK cells (<a href="#B6">6</a>). The key function of mature CD56<sup>dim</sup> CD16<sup>pos</sup> NK cells is natural and Ab-mediated cell cytotoxicity. Mature CD56<sup>dim</sup> NK cells express high amounts of killer cell immunoglobulin receptors (KIRs) (<a href="#B7">7</a>).</p><p class="mb15">The mechanism for the transition from CD56<sup>bright</sup> to CD56<sup>dim</sup> is still widely unknown, but the change in surface markers is a major indicator for transitioning to maturity (<a href="#B2">2</a>, <a href="#B7">7</a>). CD16, CD27, CD56, CD57, and perforin are all markers for NK cell maturation (<a href="#B7">7</a>, <a href="#B8">8</a>). CD27 is a marker of immature NK cells, associated with the TNFα receptor group and found on three times as many immature CD56<sup>bright</sup> as mature CD56<sup>dim</sup> (<a href="#B7">7</a>). Inversely CD57 and perforin are markers for terminal maturity and are highly expressed on mature NK cells (<a href="#B7">7</a>, <a href="#B9">9</a>).</p><p class="mb15">Located throughout the body, NK cells represent 5-20% of all lymphocytes in the blood and organs with high concentrations in the bone marrow, spleen, liver, lungs, skin, kidneys, uterus, and secondary lymphoid tissue (<a href="#B8">8</a>, <a href="#B10">10</a>). The tissue-specific location has been shown to have a significant impact on NK cell functionality and cytokine production. Mature NK cells in the lung are shown to produce higher amounts of granzyme B, a serine protease associated with cytotoxicity, than those NK cells found in the lymph nodes or gut (<a href="#B8">8</a>).</p><p class="mb15">NK cells secrete a number of pro-inflammatory cytokines, such as TNF and IFN-γ that stimulate an adaptive immune response and prevent tumor angiogenesis (<a href="#B5">5</a>). The production levels of IFN-γ and TNFα from NK cells can be stimulated through various cytokines such as IL-12, IL-15, and IL-18 (<a href="#B8">8</a>).</p><p class="mb0">NK cells function by killing virally infected, stressed, and cancerous cells in an antigen-independent manner (<a href="#B1">1</a>, <a href="#B2">2</a>, <a href="#B8">8</a>). Additionally, NK cells work to activate other immune cells using co-stimulatory signals (<a href="#B2">2</a>). NK cell’s cytolytic function is based on an array of activation and inhibitory signals (<a href="#f1">Figure 1</a>) as well as self-major histocompatibility complexes (MHC) class I molecules (<a href="#B1">1</a>, <a href="#B2">2</a>). NK cells recognize target cell MHC class I molecules which bind to the NK cell KIRs allowing the NK to identify “self.” This self-identification inhibits the cytotoxic activity against normal cells (<a href="#B1">1</a>, <a href="#B2">2</a>, <a href="#B7">7</a>). In addition to preventing cytotoxic function, this binding also prevents inflammation and helps with the “licensing” of the immature NK cells (<a href="#B7">7</a>). Tumor cells often downregulate MHC class I expression to avoid lysis by cytotoxic T cells. Additionally, DNA damage and cellular stress upregulates tumor ligands’ expression on malignant cells, which are recognized by NK cell-activating receptors (<a href="#f2">Figure 2</a>). NK cells will trigger cell-mediated lysis (<a href="#B1">1</a>) if a cell down-regulates its MHC class I molecules and upregulates activation ligands.</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 1</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g001.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g001.jpg" alt="www.frontiersin.org" id="f1" loading="lazy"> </picture> </a><p><strong>Figure 1</strong> NK cell surface receptors and ligands on tumor cells are involved in tumor recognition. NK cells express a set of stimulatory (or activation) receptors as well as inhibitory receptors to recognize healthy cells and aberrant cells such as virus-infected or a potential tumorigenic cell through MHC-1 receptor appearance.</p></div><div class="DottedLine"></div><div class="Imageheaders">FIGURE 2</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g002.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g002.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g002.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g002.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g002.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g002.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g002.jpg" alt="www.frontiersin.org" id="f2" loading="lazy"> </picture> </a><p><strong>Figure 2</strong> Phenotypic and functional properties of immature (left) and mature (right) NK cells. Immature NK cells express CD56<sup>bright</sup>, absent, or CD16<sup>dim</sup>, low KIR, and CD27 and are also known as NK<sup>regulatory</sup> that exhibit low cytotoxicity, but high cytokine production. Mature NK cells, in contrast, express CD56<sup>dim</sup>, high CD16, high KIRs, and CD57 and are also knows as NK<sup>cytotoxic</sup> that exhibit high cytotoxicity and low cytokine production.</p></div><div class="DottedLine"></div><p class="mb15 w100pc float_left mt15">Once a cell is designated as infected, stressed, or cancerous, NK cells work to kill it through a direct release of cytolytic granules containing perforin and granzyme B. The contents of cytolytic granules are released from the cell <i>via</i> degranulation (<a href="#f2">Figure 2</a>). The granules from the NK cell form a synapse with the target cell, releasing the cytolytic contents. Perforin and granzyme B are key components of cytolytic granules and trigger apoptosis through caspase-dependent and independent mechanisms. Perforin aids in the entry of the granzyme B into the target cell, which ultimately leads to target cell death (<a href="#B11">11</a>).</p><p class="mb0">In addition to direct lysis of malignant or virally infected cells, CD56<sup>dim</sup> CD16<sup>pos</sup> NK cells mediate antibody-dependent cellular cytotoxicity (ADCC). ADCC is triggered when NK cells recognize an antibody opsonized target cell. The binding of CD16 with the Fc portion of IgG antibodies trigger the release of perforin and granzyme B which lyse the target cell (<a href="#B11">11</a>). ADCC is provoked by several therapeutic monoclonal antibodies (mAbs) and may enhance the homing and efficacy of NK cell therapy (<a href="#B12">12</a>).</p><a id="h3" name="h3"></a><h2>NK Cell-Based Strategies in Clinical Trials Targeting Different Indications</h2><p class="mb0">Autologous and allogeneic NK cell therapies have shown great potential in preclinical studies and clinical trials. Different strategies are considered in clinical trials using NK cells for cancer therapies, including utilizing an agonist to NK cell activation receptors (mABs; transtuzumab, rituximab, etc., + IL-2 and anti PD1) or by blocking NK cells inhibitory receptor signals with mABs to KIR (NKG2A-CD94 or with CTLA-4 and PD-1 checkpoint inhibitor) (<a href="#B13">13</a>). Recent findings demonstrate the potential of allogeneic NK cells for hematological malignancies and solid tumors (<a href="#B14">14</a>). Unlike T cells, NK cells do not induce graft-<i>versus</i>-host-disease (GVHD) and their alloreactivity is enhanced under KIR mismatch with HLA ligands on cancer cells (<a href="#B15">15</a>). Several clinical trials have highlighted the safety of the allogeneic transfer of NK cells (<a href="#B16">16</a>). Allogeneic NK cells were used to target different cancers including hematological malignancies, lymphoma, leukemia, and solid tumors such as melanoma, neuroblastoma, gastric cancers, ovarian and breast tumors (<a href="#T1">Table 1</a>).</p><div class="DottedLine"></div><div class="Imageheaders">TABLE 1</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t001.jpg" name="table 1" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t001.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t001.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t001.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t001.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t001.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t001.jpg" alt="www.frontiersin.org" id="T1" loading="lazy"> </picture> </a><p><strong>Table 1</strong> Completed allogeneic NK cell clinical trials.</p></div><div class="DottedLine"></div><p class="mb0">An “off the shelf” NK cell therapy solves the one-donor, one-patient limitation that makes -autologous cell therapy processes labor-intensive. A critical step to enable allogeneic NK cell-based therapies would require a healthy donor source for NK cells and expanding to clinically relevant doses. Most clinical trials of NK cells require large numbers of cells for infusion, ranging from 5×10<sup>6</sup> to 1×10<sup>8</sup> CD3<sup>neg</sup>CD56<sup>pos</sup> NK cells per kilogram body weight (<a href="#B5">5</a>).</p><a id="h4" name="h4"></a><h2>Sources of Natural Killer Cells for Immunotherapy</h2><p class="mb0">NK cells for therapy can be acquired from various sources such as umbilical cord blood (UCB) (<a href="#B17">17</a>), peripheral blood (PB) (<a href="#B18">18</a>, <a href="#B19">19</a>), human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) (<a href="#B20">20</a>) as well as cells lines such as NK-92 (<a href="#B21">21</a>). To date, most of the NK cell clinical trials are based on UCB-NK cells, PB-NK cells, and the lymphoma-derived NK cell line NK-92. There are critical challenges in the manufacturing process of the final therapeutic cell doses. For example, isolation and expansion of PB-NK cells and UCB-NK cells result in a mixed composition (<a href="#B22">22</a>). The cell line NK-92 is derived from a cancer patient with non-Hodgkin lymphoma; thus, the cells need to be irradiated before infusion, limiting the NK cell persistence (<a href="#B23">23</a>). In contrast to these limitations, hESC-NK cells and iPSC-NK cells are more homogenous and can be generated in sufficient cell numbers for allogeneic clinical use (<a href="#B24">24</a>). Pluripotent (hESC/iPSC) derived NK cells can result in allogeneic therapy providing a standard cell-based treatment option for different diseases (<a href="#B24">24</a>–<a href="#B26">26</a>). Processing workflow of NK cell isolation from different donor sources through expansion for adaptive transfer is described (<a href="#f3">Figure 3</a>).</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 3</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g003.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g003.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g003.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g003.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g003.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g003.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g003.jpg" alt="www.frontiersin.org" id="f3" loading="lazy"> </picture> </a><p><strong>Figure 3</strong> Sources of Natural killer cells for immunotherapy. NK cells for cell therapy applications can originate from different sources: Peripheral blood NK cells (PB NK cells) <strong>(A)</strong>, allogeneic umbilical cord blood NK cells (CB-NK Cells) <strong>(B)</strong>, NK cell cancer cell lines (NK-92) <strong>(C)</strong>, human embryonic stem cells (hESC) and inducible pluripotent stem cells (iPSCs) <strong>(D)</strong>. Advantages and limitations with the different NK cell sources vary as described in the NK cell isolation section.</p></div><div class="DottedLine"></div><h3>Umbilical Cord Blood</h3><p class="mb0">The umbilical cord is an abundant source of cytotoxic CD56<sup>pos</sup>CD16<sup>pos</sup> NK cells, with high lytic potential of cancer cells (<a href="#B27">27</a>). UCB-NK cells are isolated from cord blood after birth, <i>via</i> venipuncture of the umbilical cord, and purification by density gradient centrifugation (<a href="#B28">28</a>). Alternatively, CD34 hematopoietic stem cells can be isolated from UCB and differentiated to NK cells (<a href="#B19">19</a>, <a href="#B29">29</a>). NK cells generated from CD34 cells from HLA matched umbilical cord blood units showed good tolerance, no GVHD or toxicity (<a href="#B30">30</a>). UCB is a readily available source with the potential to manufacture multiple doses from a single frozen vial of NK cells isolated from a healthy donor (<a href="#B21">21</a>, <a href="#B31">31</a>). In addition, UCB NK cells are of a younger and more proliferative phenotype relative to PB NK cells (<a href="#B32">32</a>, <a href="#B33">33</a>).</p><h3>Peripheral Blood</h3><p class="mb0">Peripheral blood contains NK cells and is a reliable source of CD34 progenitor cells from individuals undergoing GCS-F mobilization (<a href="#B34">34</a>). Isolating large numbers of PB NK cells and hematopoietic stem cells is difficult as the percentage derived from leukapheresis can be low and highly variable (<a href="#B22">22</a>, <a href="#B35">35</a>, <a href="#B36">36</a>). Further, cryopreservation of PB NK cells lowers the cytotoxic ability (<a href="#B35">35</a>, <a href="#B37">37</a>). Allogeneic NK cells can be isolated from PBMCs by either CD3/CD19 depletion (<a href="#B38">38</a>) or CD3 depletion and subsequent CD56 enrichment (<a href="#B39">39</a>). The second round of purification based on CD3 depletion can also be implemented post-expansion (<a href="#B39">39</a>) to increase NK cell purity. An evaluation of 94 samples with CD3/CD19 depletion and 13 samples with CD3 depletion/CD56 enrichments for NK cell isolations in support of 8 clinical trials demonstrated limitations and benefits with NK cell isolation strategies (<a href="#B34">34</a>). CD3/CD19 depletion resulted in a mean NK cell recovery of 74% and viability of 96%. However, CD3 depletion/CD56 enrichment resulted in a high NK cell purity (90%), with 5% CD14 monocytes (<a href="#B38">38</a>).</p><h3>iPSC or hESC Derived NK Cells</h3><p class="mb15">Pluripotent stem cells (iPSC or hESC) are an unlimited source for the derivation of human NK cells for therapy. NK cells derived from iPSC/hESC result in a homogenous population, which can be expanded on a large scale and can be genetically modified (<a href="#B40">40</a>). NK cells are generated from different iPSC cell lines (<a href="#B41">41</a>–<a href="#B43">43</a>) on stromal feeders using IL-3, IL-7, IL-5, Stem cell factor (SCF), fms-like tyrosine kinase receptor-3 ligand (FLT3L) (<a href="#B24">24</a>). NK cells derived this way are homogenous and express CD56, KIR, CD16, NKp44, NKp46, and are capable of killing tumor cells (<a href="#B24">24</a>). Similar to iPSCs, hESCs can also be differentiated to NK cells based on stromal cell-mediated differentiation, involving CD34+CD45+ cell sorting and NK cell differentiation with IL-3, IL-5, IL-7, fms-like tyrosine kinase receptor 3 ligand (FLT3L), and Stem cell factor (SCF) (<a href="#B26">26</a>).</p><p class="mb0">Recently a stromal-free process for iPSC NK cell generation has been established based on embryoid bodies (EB) as self-stromal cells are formed inside the EB (<a href="#B40">40</a>). Feeder-dependent hESC/iPSC was adapted to a feeder independent system before EB generation (<a href="#B44">44</a>). To generate EBs, hESC/iPSC are seeded in APEL media containing SCF, BMP4, VEGF, Rocki (rho kinase inhibitor). In the second and final step, NK cells are generated by transferring EBs to gelatin-coated wells containing NK cell differentiation media with IL-3, SCF, IL-7, and IL-15. After four weeks of culture, differentiated NK cells stained positive for CD45 and CD56 markers were harvested (<a href="#B40">40</a>).</p><h3>NK Cancer Cell Lines</h3><p class="mb0">Among the available NK cancer cell lines, only NK-92 cell line has shown antitumor activity in a variety of tumors and has worked well in pre-clinical studies (<a href="#B21">21</a>, <a href="#B45">45</a>). Furthermore, NK-92 cancer cell line has received FDA approval for clinical phase patient trials (<a href="#B46">46</a>, <a href="#B47">47</a>). The NK-92 cancer cell line is well characterized and robust clinical protocols are available for cGMP manufacturing (<a href="#B48">48</a>). These cells can be genetically engineered, but with a variable efficiency of 4% - 95% (<a href="#B49">49</a>) and expanded to substantial numbers. However, NK-92 cancer cell line requires irradiation prior to infusion, as it is cytogenetically abnormal. Select advantages and disadvantages with NK cells derived from different tissue sources are shown in <a href="#T2">Table 2</a>.</p><div class="DottedLine"></div><div class="Imageheaders">TABLE 2</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t002.jpg" name="table 2" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t002.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t002.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t002.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t002.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t002.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t002.jpg" alt="www.frontiersin.org" id="T2" loading="lazy"> </picture> </a><p><strong>Table 2</strong> Advantages and drawbacks of NK Cells from different sources.</p></div><div class="DottedLine"></div><a id="h5" name="h5"></a><h2>NK Cell Expansion for the Creation of Allogeneic Doses</h2><p class="mb15">Regardless of how the NK cells are sourced, every method of NK cell expansion can be classified as either a feeder-cell-based system or a feeder-free system. A multitude of cells and cell lines are used as feeders to stimulate allogeneic NK cell expansion. K562 leukemia cells have been successfully used in this regard for several decades (<a href="#B50">50</a>) and are the most used and well-characterized example. Other examples including EBV transformed lymphoblastoid (EBV-LCL) (<a href="#B51">51</a>), HEK293 (<a href="#B52">52</a>), autologous irradiated PBMCs (<a href="#B53">53</a>), Jurkat cells (<a href="#B54">54</a>), the Wilms tumor cell line, HFWT (la5), RPMI1866 (<a href="#B55">55</a>), MM170 (<a href="#B56">56</a>), and Daudi (<a href="#B57">57</a>) have also been applied with varying degrees of success. Strategies to prime and propagate NK cells using EBV-transformed lymphoblastoid cells and irradiated PBMCs continue to show promise, but protocols employing K562 cells remain superior in terms of both the magnitude and speed of expansion. Still, many groups attempt to improve the outcome even more by supplementing the culture with antibodies, such as OKT-3 (<a href="#B58">58</a>, <a href="#B59">59</a>) and other cyto-stimulants, such as PHA, ionomycin (<a href="#B53">53</a>), and concanavalin A (<a href="#B60">60</a>). One group has even claimed an extremely robust average of 50,000-fold expansion in 21 days (about 3 weeks) using a modified K562 line that expresses membrane-bound IL-21 (<a href="#B61">61</a>). A potential pitfall of employing feeder cells is that they are associated with a multitude of regulatory concerns. These cells must be stringently qualified using cumbersome assays and viral testing to ensure that they are free of microbial contaminants, such as mycoplasma (<a href="#B62">62</a>). Moreover, additional actions need to be taken to ensure that the final product is free from the feeder cells. This has encouraged researchers to develop and employ several feeder-free systems in the cultivation of NK cells.</p><p class="mb15">To date, there has been a clear trade-off in that feeder-free systems alleviate many regulatory concerns but result in much lower yields. Several cell-free methods can be explored to activate and stimulate NK cells, including cytokines, and antibodies. Cytokines represent the most widely studied and earliest feeder-free method for activating NK cells. IL-2 is the most potent NK cell stimulant and elicits immunostimulatory signaling, increases cytokine release (<a href="#B63">63</a>), promotes cell motility (<a href="#B63">63</a>), and enhances cytotoxicity (<a href="#B64">64</a>). More recently, many alternative immunogenic cytokines have garnered attention for NK stimulation, including interleukins-15, -21, -12, -18, and -27. Much like IL-2, IL-15 stimulates NK cell proliferation, immunostimulatory receptor expression, and cytotoxicity (<a href="#B65">65</a>, <a href="#B66">66</a>), which makes it a great candidate to be used as an NK stimulant in a stand-alone fashion. In addition, it boasts several benefits over IL-2. Marks-Konczalik and colleagues reported that IL-15 inhibited activation-induced cell death that results from continuous IL-2 stimulation (<a href="#B67">67</a>)and unlike IL-2, IL-15 does not induce activation and proliferation of Tregs (<a href="#B68">68</a>), which results in peripheral tolerance and potentially leads to a more robust anti-tumor response. However, there is a tradeoff, research conducted by Felices et al. recently demonstrated that sustained IL-15 signaling results in exhausted NK cells and a loss of <i>in vitro</i> and <i>in vivo</i> efficacy (<a href="#B69">69</a>). Several groups have tried to stimulate NK cells with lower doses of IL-2 or IL-15 in combination with some of the other cytokines or they have developed cytokine schedules to alleviate some of the drawbacks associated with persistent stimulation with the one cytokine over the entire expansion protocol (<a href="#B70">70</a>). IL-21 alone is not sufficient to stimulate significant NK-cell expansion (<a href="#B71">71</a>, <a href="#B72">72</a>), however, there is a synergistic proliferative effect when IL-21 is combined with other immunostimulatory cytokines like IL-2 and IL-15 (<a href="#B71">71</a>, <a href="#B72">72</a>). Furthermore, the addition of IL-21 to NK cell culture has been associated with increased immunostimulatory cytokine production (<a href="#B73">73</a>) and upregulation of perforin and granzyme A and B (<a href="#B74">74</a>), leading to enhanced NK cell cytotoxicity (<a href="#B75">75</a>, <a href="#B76">76</a>). IL-12, IL-18, and IL-27 are slightly less characterized but have also displayed the ability to positively contribute to NK cell expansion, especially when used in conjunction with the IL-2 or IL-15. Research demonstrates that IL-12 can have a synergistic effect with IL-2, which results in enhanced NK cell cytokine secretion, proliferation, and cytotoxic capacity (<a href="#B77">77</a>, <a href="#B78">78</a>). IL-18 and IL-27 have recently been combined with IL-15 to boost NK cell fold expansion (<a href="#B79">79</a>). Another advantage of combining the cytokines can result in a lower dose of the individual cytokines, which can lead to a higher percentage of memory NK cells (<a href="#B19">19</a>). The combination of IL-12, IL-15, and IL-18 drives preferential expansion of memory-like NK cells, which exhibit heightened responses when they encounter tumor cells (<a href="#B79">79</a>–<a href="#B81">81</a>) and longer lifespans following engraftment (<a href="#B79">79</a>–<a href="#B81">81</a>). An additional benefit of these cells is an increased capacity to produce immunostimulatory cytokines upon secondary challenge. This memory response is an intrinsic quality that is passed on to all cellular progeny (<a href="#B79">79</a>–<a href="#B81">81</a>).</p><p class="mb15">Apart from these most common feeder-cell and feeder-free cytokine systems, several groups have moved towards strategies that are a hybrid of the two. Several groups have engineered feeder cells that express immunostimulatory signaling molecules, such as 41BB, IL-15 (<a href="#B82">82</a>, <a href="#B83">83</a>), and IL-21 (<a href="#B63">63</a>, <a href="#B84">84</a>–<a href="#B86">86</a>) on their cell surfaces. These strategies have resulted in highly cytotoxic NK cells that display both extremely high proliferative capacities (up 50,000-fold expansion) (<a href="#B61">61</a>), extended survival, and the ability to secrete immunogenic cytokines, leading many groups to adopt these methods into their clinical protocols. This approach has recently been taken one step further to avoid safety concerns by stimulating NK cells with K562-mb21-41BBL cell lysates (<a href="#B87">87</a>).</p><p class="mb0">Most of the experiments and trials discussed in this review have utilized small-scale, open methods for NK cell activation and expansion, such as flasks and G-Rex vessels. However, these methods are hampered by logistical hurdles, inconsistencies, and safety concerns. To reach the desired cell numbers for allogeneic manufacturing and clear all regulatory and safety hurdles associated with drug approval, it will be necessary to develop closed, and automated systems with large-scale capabilities. Hence, clinical scale NK cell manufacturing development suitable for effective allogeneic therapy production is a priority. Several options have been explored, including a G-Rex-based method that was developed under good manufacturing practice (GMP) conditions and required little to no manual intervention for the 8- to 10-day expansion and yielded 19 billion functional NK cells (<a href="#B88">88</a>). Another example of static culture is the use of large, gas-permeable culture bags, which were successfully applied in combination with feeder cells, antibodies, and cytokines to yield an NK cell fold expansion of 15,000 (<a href="#B89">89</a>). A more recent trend for achieving clinical scale NK cell expansion has been the use of bioreactors. In addition to large cell capacity, these devices are highly adaptable for closed and automated manufacturing processes (<a href="#f4">Figure 4</a>). Robust NK cell expansion with the Xuri Cell Expansion System W25 (Cytiva) has been demonstrated by several groups (<a href="#B90">90</a>–<a href="#B92">92</a>). The most common approach is to expand the isolated NK cells in static culture before transferring them to rocking bioreactors, which effectively nourish high cell densities (<a href="#B90">90</a>–<a href="#B92">92</a>). These workflows were able to generate 50 billion highly cytotoxic NK cells (<a href="#B91">91</a>). Stirred tanks are another type of dynamic culture bioreactor that has gained favor in the NK cell therapy community. Pierson and colleagues first demonstrated that the cultivation of NK cells in a 750ml-stirred tank significantly outperforms that in a comparable static vessel (<a href="#B93">93</a>). Moreover, it was recently shown that NK cell propagation in 2L stirred tanks scaled up exceptionally well to 50L stir tanks (<a href="#B94">94</a>) making this platform an excellent fit for allogeneic manufacturing workflows. Aside from the well-known wave motion reactors and stirred tank reactors, there has also been success using lesser-characterized reactors, such as the ZRP Bioreactor 50M, which was able to grow massive amounts of highly pure and functional NK cells (<a href="#B95">95</a>).</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 4</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g004.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g004.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g004.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g004.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g004.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g004.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g004.jpg" alt="www.frontiersin.org" id="f4" loading="lazy"> </picture> </a><p><strong>Figure 4</strong> Bioreactors offer several advantages to the clinical manufacturing of cell therapies. The shift from static vessels on the left toward dynamic bioreactors on the right allows for several process improvements, such as scalability, automated and closed operation, digital integration, and intimate control of liquids. These capabilities result in increased safety and consistency, reduced labor requirement and cost, and improved quality of cellular output.</p></div><div class="DottedLine"></div><a id="h6" name="h6"></a><h2>NK Cell Therapy Packaging and Release Testing</h2><p class="mb15">Once the desired expansion is achieved, a major challenge is the downstream processing of these cells and preparing the allogeneic doses. Manufacturing and storing these “off-the-shelf” doses remotely, requires cryopreservation, which is often problematic in the case of NK cells. In addition to a loss in cell viability, it is common to see a significant drop in cytotoxicity after thawing. This functional loss routinely corresponds to a reduction in the expression of CD16 on NK cell surfaces (<a href="#B63">63</a>). However, many groups are attempting to mitigate these issues with different strategies. A few more promising examples are to expose thawed cells to IL-2 immediately, thereby restoring their cytotoxic capacity (<a href="#B60">60</a>), using twice as many cells in the dose to compensate for the reduced function per cell (<a href="#B96">96</a>), and inoculating the NK cells immediately after thawing them (<a href="#B37">37</a>, <a href="#B96">96</a>). A separate, but related concern, is a 6-fold decrease in motile NK cells following cryopreservation (<a href="#B37">37</a>). Efforts to develop effective cryopreservation solutions that preserve NK cell numbers and functionality are currently a priority to carry this field forward.</p><p class="mb0">Beyond viability and cytotoxicity issues following the cryopreservation and recovery cycle, there is a multitude of other criteria that should be considered before confidently releasing the NK cells for administration as a therapeutic dose. Safety is the overarching theme for most of these considerations. Several of these requirements are focused on confirming that there are no undesirable trespassers in the dose, such as endotoxins, mycoplasma, bacteria, or feeder cells if they were used for expansion. Confirmation that the dose consists of the desired cellular population is also highly important in preventing the onset of adverse effects that these cellular contaminants can cause. This can be done by setting a minimum requirement for the percent of CD56<sup>pos</sup>/CD3<sup>neg</sup> cells and a maximum allowed amount of CD3<sup>pos</sup> T cells, CD19<sup>pos</sup> B cells, and CD14<sup>pos</sup> monocytes that can safely be released in a dose. These are the key regulatory principles that agencies across different geographical locations will require for cell therapies. Several additional ideas could be incorporated to further ensure therapeutic efficacy. An example of this could be flow cytometric characterization of activating receptors, such as NCRs, NKG2D, NKG2C, NKG2E, 2B4 and the inhibitory receptors NKG2A and KIRs. In addition, indicators of cytotoxic capabilities, CD16 and CD25, markers of differentiation status, CD62L, CD45, HLA-DR, CD69, and CD57, and functional analysis of IFNγ or TGF-β can be included (<a href="#B20">20</a>) (<a href="#f5">Figure 5</a>). It may also be beneficial to modify the cellular requirement based on the characteristics of the disease state. The tumors and surrounding microenvironments pose significant obstacles that are directly opposed to the proper function of adoptive cell therapies, such as NK cell therapies (<a href="#B97">97</a>). While many of the escape mechanisms are identified, there is often no way to identify which ones a particular tumor is employing. Thus, understanding the individual challenges associated with each tumor through a standardized molecular imprint could go a long way in cultivating the most effective cell therapy or combination therapy.</p><div class="DottedLine"></div><div class="Imageheaders">FIGURE 5</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g005.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g005.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g005.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g005.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g005.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g005.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g005.jpg" alt="www.frontiersin.org" id="f5" loading="lazy"> </picture> </a><p><strong>Figure 5</strong> Natural killer cell-specific strategies for NK cell therapy release criteria. In addition to verifying that cell therapies are free from endotoxins, mycoplasma, bacteria, and feeder cells, there is a multitude of cell markers that can be selected to ensure that the therapeutic population possesses desired phenotypic and functional qualities. T cells, monocytes, and B cells must be removed for safety. Receptors and cytokines can then be evaluated to confirm that the outgoing cell population is responsive, cytotoxic, and safe.</p></div><div class="DottedLine"></div><a id="h7" name="h7"></a><h2>CAR-NK Engineering</h2><p class="mb15">When NK cells are engineered with a tumor-specific chimeric antigen receptor (CAR), superior NK cell elicited cytotoxicity and improved cell infiltration into the tumor microenvironment are noticed. Genetic modification of NK cells by transducing with CAR receptors directed against tumor specific antigens may enhance both NK cell tumor specificity and NK cell persistence. CARs are engineered receptor proteins that recognize a target antigen on tumor cells and are successfully used in T cell therapy for lymphoid leukemias. Most of the CAR-T trials are restricted to autologous therapies, which are cumbersome, although strikingly efficient in targeted tumor cell killing (<a href="#B98">98</a>). The development of allogeneic CAR-T cells is challenging, as these treatments must be specifically tailored to avoid graft <i>versus</i> host diseases (GVHD) and elimination by the host immune system (<a href="#B99">99</a>). In contrast, several advantages are recognized with CAR-NK cell therapy over CAR-T cell therapy clinical approaches. First, there are less side effects such as low/no GVHD (<a href="#B100">100</a>), cytokine release syndrome (<a href="#B101">101</a>) and neurotoxicity (<a href="#B102">102</a>). Second, CAR-NK cells can also eliminate tumor cells efficiently in a CAR-independent manner through their stimulatory and inhibitory receptors and CD16-mediated ADCC (<a href="#B103">103</a>). Therefore, several researchers are exploring different approaches to genetically engineer NK cells with CARs to augment the efficiency of NK cells to kill tumors (<a href="#B104">104</a>).</p><p class="mb0">NK cells are successfully engineered to express CARs against several tumor-specific antigen targets and are shown to be efficient for <i>in vitro</i> and <i>in vivo</i> killing of tumor cells in experimental investigational studies. Human iPSC-derived NK cells engineered with specific CAR constructs demonstrated significantly enhanced targeted anti-tumor activity in an ovarian cancer xenograft model (<a href="#B105">105</a>). Although autologous NK cells can be generated <i>in vitro</i>, they have limited efficiency against own patient’s tumor cells. There are currently 72 clinical trials using CAR-NK cell lines and 35 primary CAR-NK preclinical studies based on PubMed and Global data (<a href="http://www.carnkreview.com">www.carnkreview.com</a>) targeting different tumors (<a href="#B106">106</a>). However, only 5 studies are ongoing in phase I & II clinical trials at <a href="http://www.clincaltrials.gov">www.clincaltrials.gov</a> (<a href="#T3">Table 3</a>). CAR constructs for NK cells consist of three domains: an extracellular antigen recognition domain, a transmembrane domain, and an intracellular cytoplasmic signaling domain (<a href="#f6">Figure 6</a>). The ectodomain contains a single-chain variable fragment (scFv) derived from an antibody recognizing the tumor antigen. The transmembrane domain anchors the CAR structure to the effector cell membrane. CAR recognition of specific antigen triggers intracellular activation domain that results in the killing of the target cells. From the limited number of CAR-NK trials so far, no significant adverse events are noted, and the CAR-NKs showed robust cytolytic activity. In the CAR-NK trials that fit the allogeneic and off-the-shelf approach, CAR-NK cells from a single healthy donor were expanded in cell culture for appropriate dosing. The infused CAR-NKs persisted and expanded at a low level, based on PCR results, for a year within the tumor microenvironment in an ablative conditioning regimen. Most engineered CAR-NK cells are directed against blood-related malignancies, such as CD19 for B cell lymphomas, CD22 for refractory B-cell lymphomas and solid tumors, NKG2D-ligand for pancreatic cancers, and CD33 and ROBO1 specific BiCAR-NK/T for malignant and metastatic solid tumors (<a href="#B107">107</a>). Barriers to a successful implementation of CAR-NK in solid tumors are recently reviewed, including off-tumor effects, impaired antigen recognition, poor cell trafficking, harsh tumor environment, and immune evasion (<a href="#B108">108</a>).</p><div class="DottedLine"></div><div class="Imageheaders">TABLE 3</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t003.jpg" name="table 3" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t003.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t003.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t003.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t003.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t003.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t003.jpg" alt="www.frontiersin.org" id="T3" loading="lazy"> </picture> </a><p><strong>Table 3</strong> On-going CAR-NK Clinical Trials.</p></div><div class="DottedLine"></div><div class="Imageheaders">FIGURE 6</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g006.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g006.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g006.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g006.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g006.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g006.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g006.jpg" alt="www.frontiersin.org" id="f6" loading="lazy"> </picture> </a><p><strong>Figure 6</strong> CAR-NK Molecule Delivery of genetic cargo into NK cells with CAR encoding retro (RV), lenti (LV), or adeno-associated (AAV) vectors. CAR molecule is shown on the right side with single-chain variable fragment (scFv including V<sub>H</sub> and V<sub>L</sub> chains), hinge, transmembrane (TM), and signaling domain. Co-stimulatory signaling domains are indicated in different colors.</p></div><div class="DottedLine"></div><a id="h8" name="h8"></a><h2>Delivery Systems to Engineer NK Cells</h2><p class="mb0">A critical aspect of CAR-NK generation is the introduction of genetic elements into NK cells, referred to as CAR-NK engineering. Once the genetic element is introduced into NK cells, the subsequent expansion of the CAR-NK cells with the cytotoxic killing of the target tumor cell will be another important consideration. The introduction of genetic material into NK cells is carried out using either viral vectors (retrovirus, lentivirus, and Adeno associated virus) or non-viral methods (mRNA and DNA). Examples of the viral and non-viral vector delivery systems with select pros and cons are shown in <a href="#T4">Table 4</a> and <a href="#f7">Figure 7</a>.</p><div class="DottedLine"></div><div class="Imageheaders">TABLE 4</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t004.jpg" name="table 4" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t004.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t004.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t004.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t004.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t004.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-t004.jpg" alt="www.frontiersin.org" id="T4" loading="lazy"> </picture> </a><p><strong>Table 4</strong> Advantages and disadvantages with different gene delivery vectors.</p></div><div class="DottedLine"></div><div class="Imageheaders">FIGURE 7</div><div class="FigureDesc"><a href="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g007.jpg" name="" target="_blank"> <picture> <source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=480&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g007.jpg" media="(max-width: 563px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=370&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g007.jpg" media="(max-width: 1024px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=290&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g007.jpg" media="(max-width: 1441px)"><source type="image/webp" srcset="https://images-provider.frontiersin.org/api/ipx/w=410&f=webp/https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g007.jpg" media=""><source type="image/jpg" srcset="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g007.jpg" media=""> <img src="https://www.frontiersin.org/files/Articles/732135/fimmu-12-732135-HTML/image_m/fimmu-12-732135-g007.jpg" alt="www.frontiersin.org" id="f7" loading="lazy"> </picture> </a><p><strong>Figure 7</strong> Delivery technologies to engineer Natural killer cells. Modes of genetic cargo delivery into NK Cells by viral transduction and non-viral electroporation for gene engineering of NK Cells. Specific advantages and limitations are noted below the arrows.</p></div><div class="DottedLine"></div><h3>Retroviral Vector Systems</h3><p class="mb0">Recent studies from the Rezvani laboratory at MDACC used retroviral vectors to deliver anti-CD19 CAR into NK cells along with IL-15 and inducible caspase 9. The CAR NK cells were used to treat CD19 positive tumors; 7 of 11 patients (64%) had a complete response (4 of 5 patients with CLL and 4 of 6 with non-Hodgkin’s lymphoma). All 8 patients had an objective response (73%) at 13.8 month follow-up (<a href="#B109">109</a>). Gene transfer did not change the function or phenotype of NK cells, nor did it change the proliferative or cytotoxic ability post engineering. Another recent study used retroviral vector systems that ectopically expressed iC9/CAR.19/IL15 to generate CAR-CD19-NK cells from cord blood that persisted for a long time in the tumor microenvironment (<a href="#B110">110</a>, <a href="#B111">111</a>). In both studies, the retroviral vector ectopically produced IL15 that is crucial for NK cell survival and conditionally expressed a caspase 9 (iC9)- an inducible suicide gene that could be activated to shut off the system by eliminating transduced cells when needed. Though retroviral vector systems have high transfection efficiency, the cDNA can integrate into the NK cell genome causing insertional mutagenesis and sometimes an induction of immune response (<a href="#B112">112</a>).</p><h3>Lentiviral Vector Systems</h3><p class="mb15">Lentiviral transduction is the preferred choice to modify NK cells. The lentiviral method allows transduction of primary and non-activated NK cells, and unlike the retroviral vector system, does not require dividing cells (<a href="#B113">113</a>). Single lentiviral transduction usually results in lower transduction efficiencies, PB NK (<10%) or CB NK (<30%) (<a href="#B114">114</a>). In Japan, a study led by Dr. Ueda used a lentiviral system to express CAR-NK-GPC3 for solid tumors of hepatocellular carcinoma (HCC) and ovarian cancers that are treated in <i>in vivo</i> animal models with good success (<a href="#B115">115</a>). Recent studies have improved the efficiencies of lentiviral delivery, by using statins to upregulate the low-density lipoprotein (LDL) receptor on NK cells enhancing the transduction efficiency by 30-50% (<a href="#B116">116</a>).</p><p class="mb0">Pseudotyped lentiviral particles are glycoproteins derived from other enveloped viruses that enable the tropism of the lentiviral. The ability to generate CAR-NK cells depends on the envelope protein lentivirals express. Vesicular stomatitis virus G glycoprotein (VSV-G) pseudotype particles showed the highest transduction efficiency of primary NK cells compared to retroviral vectors (<a href="#B117">117</a>). Feline endogenous retrovirus envelope protein RD114-TR was similar to VSV-G pseudotype particles for primary human NK cells (<a href="#B118">118</a>). Further, a Baboon envelope pseudotyped lentiviral vector BaEV-LV was significantly better than both the RD-114-TR and VSV-G pseudotyped lentiviral vector (<a href="#B119">119</a>). Choosing which LV pseudotypes VSV-G <i>versus</i> RD114-TR <i>versus</i> BaEV-LV has the best transduction efficiency should be an essential consideration for CAR-NK generation. The advantages and disadvantages of different LV pseudotypes have been recently reviewed (<a href="#B120">120</a>, <a href="#B121">121</a>).</p><h3>Adeno Associated Viral Delivery</h3><p class="mb0">Alternative viral vectors with a better safety profile are adenovirus-associated virus (AAV) vectors. One way to improve the efficiency of NK cell cytotoxicity is by blocking their inhibitory receptors. Using CRISPR/cas9 driven delivery by recombinant adeno-associated virus serotype6 (rAAV6), highly efficient knockout of A Disintegrin and Metalloproteinase-17 (ADAM17) and programmed cell death 1 (PDCD1) genes in NK cells was accomplished (<a href="#B121">121</a>). KO of ADAM17 and PDCD1 improved NK activity, cytokine production and cancer cell cytotoxicity. These approaches demonstrate an easy-to-use strategy for efficient gene editing and delivery with AAV vector systems for NK cell therapies (<a href="#B121">121</a>). However, one limitation with AAV is its packaging capacity (~5kb) that limits a large gene transfer. NK cells in general have a low propensity for viral transduction, and higher cell death. Hence, commercially available viral transduction enhancers such as LentiBOOST, PGE2, PS, Vectofusin-1, ViraDuctin, Retronectin, Stauro and 7-hydroxy stauro are sometimes employed to improve vector transduction.</p><h3>Non-Viral DNA Transfection and mRNA-Electroporation</h3><p class="mb15">Successful electroporation of DNA into the NK-92 cancer cell line was shown, but not in primary NK cells from PBMCs or cord blood (<a href="#B33">33</a>). Recently, an improved method with NK cells expanded with IL-2 was reported with 40% efficiency of DNA plasmid transfer (<a href="#B122">122</a>). Following DNA transfer by electroporation, the viability of NK cells was lower, due to harsh electroporation conditions, and the DNA transfection efficiency was less compared to resting NK cells. The real advantage of this approach is complex constructs can also be transferred efficiently into the cells. Plasmid DNA of small (~3.5Kb) and large sizes (~12.5Kb) are transferred with a substantial increase of transfection up to 5-fold compared to the standard electroporation approach (<a href="#B123">123</a>).</p><p class="mb15">Some researchers are exploring electroporation to express CAR molecules on NK cells (<a href="#B124">124</a>, <a href="#B125">125</a>). Unlike DNA electroporation, mRNA electroporation of NK cells may be an efficient alternative, but it induces only transient expression of the transferred gene. mRNA electroporation efficiencies are usually high (80-90%) for PBMCs or cord blood cells and require cytokine stimulation such as IL-2 for post-transduction expansion or the use of feeder cells that are engineered to secrete IL2 for better viability of cells (<a href="#B126">126</a>). Transfection efficiency with mRNA by electroporation depends on the dose of mRNA (25-200 ug/ml) (<a href="#B127">127</a>). High dose of mRNA results in poor viability of cells following transfection. In general, post electroporation expansion is contraindicated with mRNA approaches as it leads to dilution of the mRNA.</p><p class="mb0">Recently another charge-based chemical method has been tried successfully to deliver CAR mRNA into non-dividing NK cells using a nucleofection approach that showed high efficiency (<a href="#B128">128</a>). A specific advantage of using mRNA delivery system is the transient expression of protein by mRNA, thus avoids the risk of genome integration, least expensive to manufacture and savings of time (<a href="#B129">129</a>). Another strategy that has been less frequently used for stable non-viral gene delivery is employing DNA transposons to transduce NK cells which is cost effective, has large cargo (ex: CAR in combination with activating receptors or cytokines) deliver capacity with stable integration. Their disadvantages include potential insertional mutagenesis and the transposon must be delivered as DNA (<a href="#B130">130</a>, <a href="#B131">131</a>). Despite the limitations described above, the most successful non-viral gene delivery for primary NK cells is still rapid transient expression by electroporation.</p><h3>Engineering NK Cell Receptors</h3><p class="mb15">For CAR-engineered cells to act, identifying specific tumor antigens as targets is a challenge, whether for T cells or NK cells. Human NK cells have innate inhibitory receptors such as KIRs and NKG2A molecules that recognize MHC class I and evoke response through immunoreceptors tyrosine-based inhibitory motif (ITIM). T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on T and NK cells and is a promising emerging target for cancer immunotherapy. TIGIT interacts with ligands CD115 and CD112 expressed on tumor cells. There is evidence that TIGIT blockade can help tumor regression (<a href="#B132">132</a>).</p><p class="mb15">In contrast, activating receptors on NK cells such as NKG2D and DNAX accessory molecule 1 (DNAM-1) play a crucial role in tumor surveillance since this receptor has a wide range of ligands that provide target specificity (<a href="#B133">133</a>). Preclinical study data using CAR-NKG2D is promising in colorectal cancer patients (<a href="#B124">124</a>) and multiple myeloma patients (<a href="#B134">134</a>). Natural cytotoxicity receptors (NCRs) like NKp30, NKp44, and NKp46, can recognize multiple stress ligands in infection and oncogenic transformation. Harnessing these receptors on NK cells and their ligands on tumor cells is another new strategy to create CAR-NK cells that can induce anti-tumor immunity.</p><p class="mb0">With the advances made in viral and non-viral gene delivery approaches to generate better CAR-NK molecules, there will be a heightened focus on how these cells perform in clinical trials over the next few years. These results will help determine whether CAR-NKs can effectively target and kill tumor cells (<a href="#B135">135</a>). The viability of CAR-NK cells in the tumor microenvironment is central to the success of therapy, in addition to the repeated dosing of the cells. CAR engineering of NK cells primarily resides between two choices of stable high expression by viral vectors or rapid transient expression of non-viral delivery systems using electroporation.</p><a id="h9" name="h9"></a><h2>Conclusions and Perspectives</h2><p class="mb0">NK cells are critical in immune surveillance of invading viruses and kill tumor cells without the need of tumor specific antigen presentation. Pre-clinical data from early phase clinical trials has significantly increased our knowledge for the use of allogeneic donor NK cells across a wide range of hematological malignancies and solid tumors. Recent advances include developing NK cell expansion protocols without the use of feeders, serum, activation technologies, validation of NK cells from different tissue sources, ability to selectively use donor NK cells with minimal HLA matching, genetic modification to create CAR-NK constructs, and transfer of genetic material using viral and nonviral delivery technologies. These advances point towards a true “off-the-shelf” NK cell therapy. Despite impressive advances, there are multiple outstanding challenges with NK cell therapies. Methods following good manufacturing practices to generate large clinical doses from a single healthy donor and selective expansion appropriate NK cell subsets with best predictive KIR/HLA are needed. Additionally, tumor immune evasion remains a large barrier. Once the NK or CAR-NK cells are infused into the patient, the long-term persistence of these cells <i>in-vivo</i> in the tumor microenvironment needs to be ensured and monitored. Another limitation with NK and CAR-NK cells is the memory property <i>in vivo</i>, which is not fully understood as in the case of memory T cells in adaptive immunity. Identifying novel CAR targets and generation of NK specific CAR constructs will enable CAR-NK cell homing and persistence in solid tumors contributing to breakthrough approaches driving allogeneic NK therapies towards the next frontier of cancer immunotherapy.</p><a id="h10" name="h10"></a><h2>Author Contributions</h2><p class="mb0">EH, EZ, TS, AH, NK and MCV wrote the manuscript and, SB prepared figures. All authors contributed to the article and approved the submitted version.</p><a id="h11" name="h11"></a><h2>Conflict of Interest</h2><p class="mb0">EH, EZ, TS-N, AH, SB, NK, and MV had compensated employment at Thermo Fisher Scientific.</p><a id="h12" name="h12"></a><h2>Publisher’s Note</h2><p class="mb15">All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p><a id="h13" name="h13"></a><h2>Acknowledgments</h2><p class="mb15">The authors thank Dr. Jonathan Chesnut for the support, review and Dr. Premkumar Jayaraman for proofreading the manuscript. Further, the authors acknowledge BioRender (<a href="https://BioRender.com">BioRender.com</a>) for the software to create figures.</p><a id="h14" name="h14"></a><h2>References</h2><div class="References" style="margin-bottom:0.5em; margin-left:2em;"><p class="ReferencesCopy1" style="margin-left:0.7em; text-indent:-1.1em;"><a name="B1" id="B1"></a> 1. Bryceson YT, March ME, Barber DF, Ljunggren HG, Long EO. 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Immunol.</i> 12:732135. doi: 10.3389/fimmu.2021.732135</p><p id="timestamps"><span>Received:</span> 28 June 2021; <span>Accepted:</span> 01 November 2021;<br><span>Published:</span> 01 December 2021.</p><div><p>Edited by:</p><a href="https://loop.frontiersin.org/people/469526">John - Maher</a>, King’s College London, United Kingdom</div><div><p>Reviewed by:</p><a href="https://loop.frontiersin.org/people/1389556">Caroline Hull</a>, Leucid Bio, United Kingdom<br><a href="https://loop.frontiersin.org/people/31783">Dean Anthony Lee</a>, The Research Institute at Nationwide Children’s Hospital, United States<br><a href="https://loop.frontiersin.org/people/332261">Robert J. Canter</a>, University of California, Davis, United States</div><p><span>Copyright</span> © 2021 Heipertz, Zynda, Stav-Noraas, Hungler, Boucher, Kaur and Vemuri. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p><p><span>*Correspondence:</span> Mohan C. Vemuri, <a id="encmail">bW9oYW4udmVtdXJpQHRoZXJtb2Zpc2hlci5jb20=</a></p><div class="clear"></div></div></div></div> <p class="AbstractSummary__disclaimer"><span>Disclaimer: </span> All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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src="https://loop.frontiersin.org/images/profile/469526/32" alt="John - Maher" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> John - Maher </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> King's College London, United Kingdom </div></div></a></div></div> <div class="ArticleDetailsEditors"><div class="ArticleDetailsEditors__editors"><div class="ArticleDetailsEditors__title">Reviewed by</div> <a href="https://loop.frontiersin.org/people/332261/overview" data-event="editorInfo-a-robertJCanter" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/332261/32" alt="Robert J. Canter" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Robert J. Canter </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> University of California, Davis, United States </div></div></a><a href="https://loop.frontiersin.org/people/31783/overview" data-event="editorInfo-a-deanAnthonyLee" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/31783/32" alt="Dean Anthony Lee" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Dean Anthony Lee </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> The Research Institute at Nationwide Children's Hospital, United States </div></div></a><a href="https://loop.frontiersin.org/people/1389556/overview" data-event="editorInfo-a-carolineHull" class="ArticleDetailsEditors__ediorInfo"><figure class="Avatar Avatar--size-32"><img src="https://loop.frontiersin.org/images/profile/1389556/32" alt="Caroline Hull" class="Avatar__img is-inside-mask"></figure> <div class="ArticleDetailsEditors__ediorInfo__info"><div class="ArticleDetailsEditors__ediorInfo__name notranslate"> Caroline Hull </div> <div class="ArticleDetailsEditors__ediorInfo__affiliation notranslate"> Leucid Bio, United Kingdom </div></div></a></div></div> <div class="ArticleDetailsGlossary ArticleDetailsGlossary--open"><button class="ArticleDetailsGlossary__header"><div class="ArticleDetailsGlossary__header__title">Table of contents</div> <div class="ArticleDetailsGlossary__header__arrow"></div></button> <div class="ArticleDetailsGlossary__content"><ul class="flyoutJournal"><li><a href="#h1">Abstract</a></li><li><a href="#h2">Natural Killer Cell Biology</a></li><li><a href="#h3">NK Cell-Based Strategies in Clinical Trials Targeting Different Indications</a></li><li><a href="#h4">Sources of Natural Killer Cells for Immunotherapy</a></li><li><a href="#h5">NK Cell Expansion for the Creation of Allogeneic Doses</a></li><li><a href="#h6">NK Cell Therapy Packaging and Release Testing</a></li><li><a href="#h7">CAR-NK Engineering</a></li><li><a href="#h8">Delivery Systems to Engineer NK Cells</a></li><li><a href="#h9">Conclusions and Perspectives</a></li><li><a href="#h10">Author Contributions</a></li><li><a href="#h11">Conflict of Interest</a></li><li><a href="#h12">Publisher’s Note</a></li><li><a href="#h13">Acknowledgments</a></li><li><a href="#h14">References</a></li></ul></div></div>  <div class="ActionsDropDown"><button aria-label="Open dropdown" data-event="actionsDropDown-button-toggle" class="ActionsDropDown__button ActionsDropDown__button--typeOutline ActionsDropDown__button--iconQuote"><span class="ActionsDropDown__button__label">Export citation</span></button> <div class="ActionsDropDown__menuWrapper"> <ul class="ActionsDropDown__menu"><li><a href="/journals/immunology/articles/10.3389/fimmu.2021.732135/endNote" 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The journal aims to showcase advances and novel approaches to diagnosing and treating immune disorders in both animal and cellular models, as well as in humans. Indexed in MEDLINE, PubMed Central, Scopus and the SCIE Frontiers in Immunology is the official Journal of the \u003Ca href=\"http:\u002F\u002Fwww.iuisonline.org\u002F\" target=\"_blank\" rel=\"noopener\"\u003EInternational Union of Immunological Societies (IUIS)\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\n\n\u003Cp\u003ELed by Field Chief Editor Pietro Ghezzi (Emeritus Professor at Brighton and Sussex Medical School), Frontiers in Immunology welcomes contributions that investigate the basic mechanisms of immune system development and function, with a particular emphasis on describing the clinical and immunological phenotype of human immune disorders and defining their molecular basis. Topics include:\u003C\u002Fp\u003E\n\u003Cul\u003E\n \u003Cli\u003Eadvances in biological drugs\u003C\u002Fli\u003E\n \u003Cli\u003Eimmune system development and function\u003C\u002Fli\u003E\n \u003Cli\u003Emolecular basis of human immune disorders\u003C\u002Fli\u003E\n \u003Cli\u003Enovel approaches to diagnosis and treatment of immune disorders\u003C\u002Fli\u003E\n \u003Cli\u003Eprecision medicine for immunological disorders\u003C\u002Fli\u003E\n \u003Cli\u003Estudies on animal and cellular models and in humans\u003C\u002Fli\u003E\n \u003Cli\u003Estudies on systems immunology with relevant experimental validation.\u003C\u002Fli\u003E\n\u003C\u002Ful\u003E\n\n\u003Cp\u003EFrontiers in Immunology particularly welcomes news ideas and approaches which supports and advances the UN’s Sustainable Development Goal (SDGs), specifically SDG 3: good health and well-being. The research published in this journal could lead to the development of new treatments and therapies for various immunological disorders, thereby promoting well-being for all.\u003C\u002Fp\u003E\n\n\u003Cp\u003EManuscripts that focus on clinical studies, medical treatments, or human diseases without a clear connection to immunology are not suitable for publication in this journal. Additionally, studies that use analytical molecular biology techniques without a clear immunological context or contribution to the field of immunology are also not within the scope of this journal.\u003C\u002Fp\u003E\n\n\u003Cp\u003EFrontiers in Immunology is dedicated to propelling advancements in the field of Immunology by providing unrestricted access to articles and disseminating scientific knowledge to researchers and the public. This enables future scientific breakthroughs.\u003C\u002Fp\u003E\n\n\u003Cp\u003EEthics Statement\u003C\u002Fp\u003E\n\n\u003Cp\u003EAll manuscripts submitted to Frontiers in Immunology that have been conducted in human subjects must conform with current regulations and the Declaration of Helsinki. Ethics committee approval and informed patient consent are required for studies involving human subjects. Institutional animal care and use committee (IACUC) approval is needed for studies involving animals. Phase I - Phase IV clinical trials submitted for publication in Frontiers in Immunology must have been registered with an appropriate public trials registry at the time or before the first patient enrolment. The information on the clinical trial registration (Unique Identifier and URL) must be included in the abstract. Authors are required to disclose all apparent or potential conflicts of interest according to the ICMJE guidelines and those of Frontiers.\u003C\u002Fp\u003E",palette:"red",impactFactor:"7.3",citeScore:"9.4",citations:"824000",showTagline:e,twitter:"@FrontImmunol",__typename:"Journal"},currentFrontiersJournal:{id:u,name:r,slug:v,printISSN:e,shortName:J,electronicISSN:K,abbreviation:_,specialtyId:e,publicationDate:e,isOnline:h,isOpenForSubmissions:h,spaceId:c,field:{id:$,domainId:o,__typename:"journal_field"},__typename:a},articleHubSlug:f,articleHubPage:L,currentArticle:{id:732135,doi:aa,title:ab,acceptanceDate:new Date(1635757078000),receptionDate:new Date(1624893703000),publicationDate:new Date(1638316800000),isPublished:h,abstract:ac,researchTopic:{id:45264,title:"NK cell modifications to advance their anti-tumor activities",articlesCount:M,isMagazinePage:h,slug:"nk-cell-modifications-to-advance-their-anti-tumor-activities",isOpenForSubmission:k},articleType:{id:27,name:"Review"},stage:{id:N,name:f},keywords:["Natural Killer cells","CAR-NK cells","Immunotherapy","NK cell expansion","lentiviral delivery","AAV delivery","Killer immune receptors","GMP manufacturing"],authors:[{id:ad,firstName:ae,lastName:"Heipertz",givenNames:ae,isCorresponding:k,isProfilePublic:h,userId:ad,affiliations:[{organizationName:w,countryName:n,cityName:f,stateName:f,zipCode:f}]},{id:l,firstName:af,lastName:"Zynda",givenNames:af,isCorresponding:k,isProfilePublic:k,userId:l,affiliations:[{organizationName:ag,countryName:n,cityName:f,stateName:f,zipCode:f}]},{id:l,firstName:ah,lastName:"Stav-Noraas",givenNames:ah,isCorresponding:k,isProfilePublic:k,userId:l,affiliations:[{organizationName:ag,countryName:"Norway",cityName:f,stateName:f,zipCode:f}]},{id:l,firstName:ai,lastName:"Hungler",givenNames:ai,isCorresponding:k,isProfilePublic:k,userId:l,affiliations:[{organizationName:w,countryName:n,cityName:f,stateName:f,zipCode:f}]},{id:l,firstName:aj,lastName:"Boucher",givenNames:aj,isCorresponding:k,isProfilePublic:k,userId:l,affiliations:[{organizationName:w,countryName:n,cityName:f,stateName:f,zipCode:f}]},{id:ak,firstName:al,lastName:"Kaur",givenNames:al,isCorresponding:k,isProfilePublic:h,userId:ak,affiliations:[{organizationName:w,countryName:n,cityName:f,stateName:f,zipCode:f}]},{id:am,firstName:an,lastName:"Vemuri",givenNames:an,isCorresponding:h,isProfilePublic:h,userId:am,affiliations:[{organizationName:w,countryName:n,cityName:f,stateName:f,zipCode:f}]}],editors:[{id:ao,firstName:"John",lastName:"Maher",givenNames:"John -",isCorresponding:k,isProfilePublic:h,userId:ao,affiliations:[{organizationName:"King's College London",countryName:ap,cityName:f,stateName:f,zipCode:f}]}],reviewers:[{id:aq,firstName:"Robert",lastName:"Canter",givenNames:"Robert J.",isCorresponding:k,isProfilePublic:h,userId:aq,affiliations:[{organizationName:"University of California, Davis",countryName:n,cityName:f,stateName:f,zipCode:f}]},{id:ar,firstName:"Dean",lastName:"Lee",givenNames:"Dean Anthony",isCorresponding:k,isProfilePublic:h,userId:ar,affiliations:[{organizationName:"The Research Institute at Nationwide Children's Hospital",countryName:n,cityName:f,stateName:f,zipCode:f}]},{id:as,firstName:at,lastName:"Hull",givenNames:at,isCorresponding:k,isProfilePublic:h,userId:as,affiliations:[{organizationName:"Leucid Bio",countryName:ap,cityName:f,stateName:f,zipCode:f}]}],journal:{id:u,slug:v,name:r,shortName:J,electronicISSN:K,field:{id:$,domainId:o},specialtyId:e,journalSectionPaths:[{section:au}]},section:au,impactMetrics:{views:27208,downloads:11797,citations:101},volume:O,articleVolume:"Volume 12 - 2021",relatedArticles:[],isPublishedV2:k,contents:{titleHtml:"Current Perspectives on “Off-The-Shelf” Allogeneic NK and CAR-NK Cell Therapies",fullTextHtml:"\u003Cdiv class=\"JournalAbstract\"\u003E\u003Ca id=\"h1\" name=\"h1\"\u003E\u003C\u002Fa\u003E\u003Cdiv class=\"authors\"\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F1446932\" class=\"user-id-1446932\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1446932\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Erica L. Heipertz\"\u003EErica L. Heipertz\u003C\u002Fa\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Evan R. Zynda\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EEvan R. Zynda\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Tor Espen Stav-Noraas\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003ETor Espen Stav-Noraas\u003Csup\u003E3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Andrew D. Hungler\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EAndrew D. Hungler\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg\" alt=\"Shayne E. Boucher\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\"\u003EShayne E. Boucher\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F1534933\" class=\"user-id-1534933\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F1534933\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Navjot Kaur\"\u003ENavjot Kaur\u003C\u002Fa\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003Cspan class=\"author-wrapper notranslate\"\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F675032\" class=\"user-id-675032\"\u003E\u003Cimg class=\"pr5\" src=\"https:\u002F\u002Floop.frontiersin.org\u002Fimages\u002Fprofile\u002F675032\u002F74\" onerror=\"this.onerror=null;this.src='https:\u002F\u002Floop.frontiersin.org\u002Fcdn\u002Fimages\u002Fprofile\u002Fdefault_32.jpg';\" alt=\"Mohan C. Vemuri*\"\u003EMohan C. Vemuri\u003C\u002Fa\u003E\u003Csup\u003E1*\u003C\u002Fsup\u003E\u003C\u002Fspan\u003E\u003C\u002Fdiv\u003E\u003Cul class=\"notes\"\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E1\u003C\u002Fsup\u003E\u003C\u002Fspan\u003ECell & Gene Therapy, Thermo Fisher Scientific, Frederick, MD, United States\u003C\u002Fli\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E2\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EBioProduction, Thermo Fisher Scientific, Grand Island, NY, United States\u003C\u002Fli\u003E\u003Cli\u003E\u003Cspan\u003E\u003Csup\u003E3\u003C\u002Fsup\u003E\u003C\u002Fspan\u003EBioProduction, Thermo Fisher Scientific, Oslo, Norway\u003C\u002Fli\u003E\u003C\u002Ful\u003E\u003Cp\u003ENatural killer cells (NK cells) are the first line of the innate immune defense system, primarily located in peripheral circulation and lymphoid tissues. They kill virally infected and malignant cells through a balancing play of inhibitory and stimulatory receptors. In pre-clinical investigational studies, NK cells show promising anti-tumor effects and are used in adoptive transfer of activated and expanded cells, \u003Ci\u003Eex-vivo\u003C\u002Fi\u003E. NK cells express co-stimulatory molecules that are attractive targets for the immunotherapy of cancers. Recent clinical trials are investigating the use of CAR-NK for different cancers to determine the efficiency. Herein, we review NK cell therapy approaches (NK cell preparation from tissue sources, ways of expansion \u003Ci\u003Eex-vivo\u003C\u002Fi\u003E for “off-the-shelf” allogeneic cell-doses for therapies, and how different vector delivery systems are used to engineer NK cells with CARs) for cancer immunotherapy.\u003C\u002Fp\u003E\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"JournalFullText\"\u003E\u003Ca id=\"h2\" name=\"h2\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003ENatural Killer Cell Biology\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EHuman natural killer (NK) cells are innate cytotoxic lymphoid cells derived from CD34+ precursors originating from hematopoietic stem cells (\u003Ca href=\"#B1\"\u003E1\u003C\u002Fa\u003E, \u003Ca href=\"#B2\"\u003E2\u003C\u002Fa\u003E) and play an essential role in tumor surveillance. Unlike T cells, NK cells can kill malignant cells in an antigen-independent manner and have shown promise in a number of clinical trials involving both solid and hematological cancers (\u003Ca href=\"#B3\"\u003E3\u003C\u002Fa\u003E). NK cells do not require HLA matching. Their ability to act in an antigen-independent manner makes them a viable option for an “off the shelf” therapy that can be manufactured on a large scale and easily distributed to cancer patients.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003ENK cells are subdivided into two populations based on their relative expression of CD56 (neural cell adhesion molecule; NCAM) and CD16: immature CD56\u003Csup\u003Ebright\u003C\u002Fsup\u003E CD16\u003Csup\u003Eneg\u003C\u002Fsup\u003E NK cells, and mature CD56\u003Csup\u003Edim\u003C\u002Fsup\u003E CD16\u003Csup\u003Epos\u003C\u002Fsup\u003E NK cells (\u003Ca href=\"#B4\"\u003E4\u003C\u002Fa\u003E). The CD56\u003Csup\u003Ebright\u003C\u002Fsup\u003E population accounts for 10% of NK cells circulating in the blood and are located primarily in lymph nodes. Immature CD56\u003Csup\u003Ebright\u003C\u002Fsup\u003E NK cells have an immunoregulatory function and produce cytokines, such as interferon-gamma (IFN-γ), TNFα, TNF-β, IL-10, and GM-CSF (\u003Ca href=\"#B5\"\u003E5\u003C\u002Fa\u003E). In contrast, the mature CD56\u003Csup\u003Edim\u003C\u002Fsup\u003E CD16\u003Csup\u003Epos\u003C\u002Fsup\u003E population accounts for up to 90% of the circulating NK cells (\u003Ca href=\"#B6\"\u003E6\u003C\u002Fa\u003E). The key function of mature CD56\u003Csup\u003Edim\u003C\u002Fsup\u003E CD16\u003Csup\u003Epos\u003C\u002Fsup\u003E NK cells is natural and Ab-mediated cell cytotoxicity. Mature CD56\u003Csup\u003Edim\u003C\u002Fsup\u003E NK cells express high amounts of killer cell immunoglobulin receptors (KIRs) (\u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EThe mechanism for the transition from CD56\u003Csup\u003Ebright\u003C\u002Fsup\u003E to CD56\u003Csup\u003Edim\u003C\u002Fsup\u003E is still widely unknown, but the change in surface markers is a major indicator for transitioning to maturity (\u003Ca href=\"#B2\"\u003E2\u003C\u002Fa\u003E, \u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E). CD16, CD27, CD56, CD57, and perforin are all markers for NK cell maturation (\u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E, \u003Ca href=\"#B8\"\u003E8\u003C\u002Fa\u003E). CD27 is a marker of immature NK cells, associated with the TNFα receptor group and found on three times as many immature CD56\u003Csup\u003Ebright\u003C\u002Fsup\u003E as mature CD56\u003Csup\u003Edim\u003C\u002Fsup\u003E (\u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E). Inversely CD57 and perforin are markers for terminal maturity and are highly expressed on mature NK cells (\u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E, \u003Ca href=\"#B9\"\u003E9\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003ELocated throughout the body, NK cells represent 5-20% of all lymphocytes in the blood and organs with high concentrations in the bone marrow, spleen, liver, lungs, skin, kidneys, uterus, and secondary lymphoid tissue (\u003Ca href=\"#B8\"\u003E8\u003C\u002Fa\u003E, \u003Ca href=\"#B10\"\u003E10\u003C\u002Fa\u003E). The tissue-specific location has been shown to have a significant impact on NK cell functionality and cytokine production. Mature NK cells in the lung are shown to produce higher amounts of granzyme B, a serine protease associated with cytotoxicity, than those NK cells found in the lymph nodes or gut (\u003Ca href=\"#B8\"\u003E8\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003ENK cells secrete a number of pro-inflammatory cytokines, such as TNF and IFN-γ that stimulate an adaptive immune response and prevent tumor angiogenesis (\u003Ca href=\"#B5\"\u003E5\u003C\u002Fa\u003E). The production levels of IFN-γ and TNFα from NK cells can be stimulated through various cytokines such as IL-12, IL-15, and IL-18 (\u003Ca href=\"#B8\"\u003E8\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003ENK cells function by killing virally infected, stressed, and cancerous cells in an antigen-independent manner (\u003Ca href=\"#B1\"\u003E1\u003C\u002Fa\u003E, \u003Ca href=\"#B2\"\u003E2\u003C\u002Fa\u003E, \u003Ca href=\"#B8\"\u003E8\u003C\u002Fa\u003E). Additionally, NK cells work to activate other immune cells using co-stimulatory signals (\u003Ca href=\"#B2\"\u003E2\u003C\u002Fa\u003E). NK cell’s cytolytic function is based on an array of activation and inhibitory signals (\u003Ca href=\"#f1\"\u003EFigure 1\u003C\u002Fa\u003E) as well as self-major histocompatibility complexes (MHC) class I molecules (\u003Ca href=\"#B1\"\u003E1\u003C\u002Fa\u003E, \u003Ca href=\"#B2\"\u003E2\u003C\u002Fa\u003E). NK cells recognize target cell MHC class I molecules which bind to the NK cell KIRs allowing the NK to identify “self.” This self-identification inhibits the cytotoxic activity against normal cells (\u003Ca href=\"#B1\"\u003E1\u003C\u002Fa\u003E, \u003Ca href=\"#B2\"\u003E2\u003C\u002Fa\u003E, \u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E). In addition to preventing cytotoxic function, this binding also prevents inflammation and helps with the “licensing” of the immature NK cells (\u003Ca href=\"#B7\"\u003E7\u003C\u002Fa\u003E). Tumor cells often downregulate MHC class I expression to avoid lysis by cytotoxic T cells. Additionally, DNA damage and cellular stress upregulates tumor ligands’ expression on malignant cells, which are recognized by NK cell-activating receptors (\u003Ca href=\"#f2\"\u003EFigure 2\u003C\u002Fa\u003E). NK cells will trigger cell-mediated lysis (\u003Ca href=\"#B1\"\u003E1\u003C\u002Fa\u003E) if a cell down-regulates its MHC class I molecules and upregulates activation ligands.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 1\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g001.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g001.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g001.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g001.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g001.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g001.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g001.jpg\" alt=\"www.frontiersin.org\" id=\"f1\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 1\u003C\u002Fstrong\u003E NK cell surface receptors and ligands on tumor cells are involved in tumor recognition. NK cells express a set of stimulatory (or activation) receptors as well as inhibitory receptors to recognize healthy cells and aberrant cells such as virus-infected or a potential tumorigenic cell through MHC-1 receptor appearance.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 2\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g002.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g002.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g002.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g002.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g002.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g002.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g002.jpg\" alt=\"www.frontiersin.org\" id=\"f2\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 2\u003C\u002Fstrong\u003E Phenotypic and functional properties of immature (left) and mature (right) NK cells. Immature NK cells express CD56\u003Csup\u003Ebright\u003C\u002Fsup\u003E, absent, or CD16\u003Csup\u003Edim\u003C\u002Fsup\u003E, low KIR, and CD27 and are also known as NK\u003Csup\u003Eregulatory\u003C\u002Fsup\u003E that exhibit low cytotoxicity, but high cytokine production. Mature NK cells, in contrast, express CD56\u003Csup\u003Edim\u003C\u002Fsup\u003E, high CD16, high KIRs, and CD57 and are also knows as NK\u003Csup\u003Ecytotoxic\u003C\u002Fsup\u003E that exhibit high cytotoxicity and low cytokine production.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cp class=\"mb15 w100pc float_left mt15\"\u003EOnce a cell is designated as infected, stressed, or cancerous, NK cells work to kill it through a direct release of cytolytic granules containing perforin and granzyme B. The contents of cytolytic granules are released from the cell \u003Ci\u003Evia\u003C\u002Fi\u003E degranulation (\u003Ca href=\"#f2\"\u003EFigure 2\u003C\u002Fa\u003E). The granules from the NK cell form a synapse with the target cell, releasing the cytolytic contents. Perforin and granzyme B are key components of cytolytic granules and trigger apoptosis through caspase-dependent and independent mechanisms. Perforin aids in the entry of the granzyme B into the target cell, which ultimately leads to target cell death (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003EIn addition to direct lysis of malignant or virally infected cells, CD56\u003Csup\u003Edim\u003C\u002Fsup\u003E CD16\u003Csup\u003Epos\u003C\u002Fsup\u003E NK cells mediate antibody-dependent cellular cytotoxicity (ADCC). ADCC is triggered when NK cells recognize an antibody opsonized target cell. The binding of CD16 with the Fc portion of IgG antibodies trigger the release of perforin and granzyme B which lyse the target cell (\u003Ca href=\"#B11\"\u003E11\u003C\u002Fa\u003E). ADCC is provoked by several therapeutic monoclonal antibodies (mAbs) and may enhance the homing and efficacy of NK cell therapy (\u003Ca href=\"#B12\"\u003E12\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Ca id=\"h3\" name=\"h3\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003ENK Cell-Based Strategies in Clinical Trials Targeting Different Indications\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003EAutologous and allogeneic NK cell therapies have shown great potential in preclinical studies and clinical trials. Different strategies are considered in clinical trials using NK cells for cancer therapies, including utilizing an agonist to NK cell activation receptors (mABs; transtuzumab, rituximab, etc., + IL-2 and anti PD1) or by blocking NK cells inhibitory receptor signals with mABs to KIR (NKG2A-CD94 or with CTLA-4 and PD-1 checkpoint inhibitor) (\u003Ca href=\"#B13\"\u003E13\u003C\u002Fa\u003E). Recent findings demonstrate the potential of allogeneic NK cells for hematological malignancies and solid tumors (\u003Ca href=\"#B14\"\u003E14\u003C\u002Fa\u003E). Unlike T cells, NK cells do not induce graft-\u003Ci\u003Eversus\u003C\u002Fi\u003E-host-disease (GVHD) and their alloreactivity is enhanced under KIR mismatch with HLA ligands on cancer cells (\u003Ca href=\"#B15\"\u003E15\u003C\u002Fa\u003E). Several clinical trials have highlighted the safety of the allogeneic transfer of NK cells (\u003Ca href=\"#B16\"\u003E16\u003C\u002Fa\u003E). Allogeneic NK cells were used to target different cancers including hematological malignancies, lymphoma, leukemia, and solid tumors such as melanoma, neuroblastoma, gastric cancers, ovarian and breast tumors (\u003Ca href=\"#T1\"\u003ETable 1\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003ETABLE 1\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t001.jpg\" name=\"table 1\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t001.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t001.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t001.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t001.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t001.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t001.jpg\" alt=\"www.frontiersin.org\" id=\"T1\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003ETable 1\u003C\u002Fstrong\u003E Completed allogeneic NK cell clinical trials.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cp class=\"mb0\"\u003EAn “off the shelf” NK cell therapy solves the one-donor, one-patient limitation that makes -autologous cell therapy processes labor-intensive. A critical step to enable allogeneic NK cell-based therapies would require a healthy donor source for NK cells and expanding to clinically relevant doses. Most clinical trials of NK cells require large numbers of cells for infusion, ranging from 5×10\u003Csup\u003E6\u003C\u002Fsup\u003E to 1×10\u003Csup\u003E8\u003C\u002Fsup\u003E CD3\u003Csup\u003Eneg\u003C\u002Fsup\u003ECD56\u003Csup\u003Epos\u003C\u002Fsup\u003E NK cells per kilogram body weight (\u003Ca href=\"#B5\"\u003E5\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Ca id=\"h4\" name=\"h4\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003ESources of Natural Killer Cells for Immunotherapy\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003ENK cells for therapy can be acquired from various sources such as umbilical cord blood (UCB) (\u003Ca href=\"#B17\"\u003E17\u003C\u002Fa\u003E), peripheral blood (PB) (\u003Ca href=\"#B18\"\u003E18\u003C\u002Fa\u003E, \u003Ca href=\"#B19\"\u003E19\u003C\u002Fa\u003E), human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) (\u003Ca href=\"#B20\"\u003E20\u003C\u002Fa\u003E) as well as cells lines such as NK-92 (\u003Ca href=\"#B21\"\u003E21\u003C\u002Fa\u003E). To date, most of the NK cell clinical trials are based on UCB-NK cells, PB-NK cells, and the lymphoma-derived NK cell line NK-92. There are critical challenges in the manufacturing process of the final therapeutic cell doses. For example, isolation and expansion of PB-NK cells and UCB-NK cells result in a mixed composition (\u003Ca href=\"#B22\"\u003E22\u003C\u002Fa\u003E). The cell line NK-92 is derived from a cancer patient with non-Hodgkin lymphoma; thus, the cells need to be irradiated before infusion, limiting the NK cell persistence (\u003Ca href=\"#B23\"\u003E23\u003C\u002Fa\u003E). In contrast to these limitations, hESC-NK cells and iPSC-NK cells are more homogenous and can be generated in sufficient cell numbers for allogeneic clinical use (\u003Ca href=\"#B24\"\u003E24\u003C\u002Fa\u003E). Pluripotent (hESC\u002FiPSC) derived NK cells can result in allogeneic therapy providing a standard cell-based treatment option for different diseases (\u003Ca href=\"#B24\"\u003E24\u003C\u002Fa\u003E–\u003Ca href=\"#B26\"\u003E26\u003C\u002Fa\u003E). Processing workflow of NK cell isolation from different donor sources through expansion for adaptive transfer is described (\u003Ca href=\"#f3\"\u003EFigure 3\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 3\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g003.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g003.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g003.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g003.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g003.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g003.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g003.jpg\" alt=\"www.frontiersin.org\" id=\"f3\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 3\u003C\u002Fstrong\u003E Sources of Natural killer cells for immunotherapy. NK cells for cell therapy applications can originate from different sources: Peripheral blood NK cells (PB NK cells) \u003Cstrong\u003E(A)\u003C\u002Fstrong\u003E, allogeneic umbilical cord blood NK cells (CB-NK Cells) \u003Cstrong\u003E(B)\u003C\u002Fstrong\u003E, NK cell cancer cell lines (NK-92) \u003Cstrong\u003E(C)\u003C\u002Fstrong\u003E, human embryonic stem cells (hESC) and inducible pluripotent stem cells (iPSCs) \u003Cstrong\u003E(D)\u003C\u002Fstrong\u003E. Advantages and limitations with the different NK cell sources vary as described in the NK cell isolation section.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ch3\u003EUmbilical Cord Blood\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EThe umbilical cord is an abundant source of cytotoxic CD56\u003Csup\u003Epos\u003C\u002Fsup\u003ECD16\u003Csup\u003Epos\u003C\u002Fsup\u003E NK cells, with high lytic potential of cancer cells (\u003Ca href=\"#B27\"\u003E27\u003C\u002Fa\u003E). UCB-NK cells are isolated from cord blood after birth, \u003Ci\u003Evia\u003C\u002Fi\u003E venipuncture of the umbilical cord, and purification by density gradient centrifugation (\u003Ca href=\"#B28\"\u003E28\u003C\u002Fa\u003E). Alternatively, CD34 hematopoietic stem cells can be isolated from UCB and differentiated to NK cells (\u003Ca href=\"#B19\"\u003E19\u003C\u002Fa\u003E, \u003Ca href=\"#B29\"\u003E29\u003C\u002Fa\u003E). NK cells generated from CD34 cells from HLA matched umbilical cord blood units showed good tolerance, no GVHD or toxicity (\u003Ca href=\"#B30\"\u003E30\u003C\u002Fa\u003E). UCB is a readily available source with the potential to manufacture multiple doses from a single frozen vial of NK cells isolated from a healthy donor (\u003Ca href=\"#B21\"\u003E21\u003C\u002Fa\u003E, \u003Ca href=\"#B31\"\u003E31\u003C\u002Fa\u003E). In addition, UCB NK cells are of a younger and more proliferative phenotype relative to PB NK cells (\u003Ca href=\"#B32\"\u003E32\u003C\u002Fa\u003E, \u003Ca href=\"#B33\"\u003E33\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Ch3\u003EPeripheral Blood\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EPeripheral blood contains NK cells and is a reliable source of CD34 progenitor cells from individuals undergoing GCS-F mobilization (\u003Ca href=\"#B34\"\u003E34\u003C\u002Fa\u003E). Isolating large numbers of PB NK cells and hematopoietic stem cells is difficult as the percentage derived from leukapheresis can be low and highly variable (\u003Ca href=\"#B22\"\u003E22\u003C\u002Fa\u003E, \u003Ca href=\"#B35\"\u003E35\u003C\u002Fa\u003E, \u003Ca href=\"#B36\"\u003E36\u003C\u002Fa\u003E). Further, cryopreservation of PB NK cells lowers the cytotoxic ability (\u003Ca href=\"#B35\"\u003E35\u003C\u002Fa\u003E, \u003Ca href=\"#B37\"\u003E37\u003C\u002Fa\u003E). Allogeneic NK cells can be isolated from PBMCs by either CD3\u002FCD19 depletion (\u003Ca href=\"#B38\"\u003E38\u003C\u002Fa\u003E) or CD3 depletion and subsequent CD56 enrichment (\u003Ca href=\"#B39\"\u003E39\u003C\u002Fa\u003E). The second round of purification based on CD3 depletion can also be implemented post-expansion (\u003Ca href=\"#B39\"\u003E39\u003C\u002Fa\u003E) to increase NK cell purity. An evaluation of 94 samples with CD3\u002FCD19 depletion and 13 samples with CD3 depletion\u002FCD56 enrichments for NK cell isolations in support of 8 clinical trials demonstrated limitations and benefits with NK cell isolation strategies (\u003Ca href=\"#B34\"\u003E34\u003C\u002Fa\u003E). CD3\u002FCD19 depletion resulted in a mean NK cell recovery of 74% and viability of 96%. However, CD3 depletion\u002FCD56 enrichment resulted in a high NK cell purity (90%), with 5% CD14 monocytes (\u003Ca href=\"#B38\"\u003E38\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Ch3\u003EiPSC or hESC Derived NK Cells\u003C\u002Fh3\u003E\u003Cp class=\"mb15\"\u003EPluripotent stem cells (iPSC or hESC) are an unlimited source for the derivation of human NK cells for therapy. NK cells derived from iPSC\u002FhESC result in a homogenous population, which can be expanded on a large scale and can be genetically modified (\u003Ca href=\"#B40\"\u003E40\u003C\u002Fa\u003E). NK cells are generated from different iPSC cell lines (\u003Ca href=\"#B41\"\u003E41\u003C\u002Fa\u003E–\u003Ca href=\"#B43\"\u003E43\u003C\u002Fa\u003E) on stromal feeders using IL-3, IL-7, IL-5, Stem cell factor (SCF), fms-like tyrosine kinase receptor-3 ligand (FLT3L) (\u003Ca href=\"#B24\"\u003E24\u003C\u002Fa\u003E). NK cells derived this way are homogenous and express CD56, KIR, CD16, NKp44, NKp46, and are capable of killing tumor cells (\u003Ca href=\"#B24\"\u003E24\u003C\u002Fa\u003E). Similar to iPSCs, hESCs can also be differentiated to NK cells based on stromal cell-mediated differentiation, involving CD34+CD45+ cell sorting and NK cell differentiation with IL-3, IL-5, IL-7, fms-like tyrosine kinase receptor 3 ligand (FLT3L), and Stem cell factor (SCF) (\u003Ca href=\"#B26\"\u003E26\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003ERecently a stromal-free process for iPSC NK cell generation has been established based on embryoid bodies (EB) as self-stromal cells are formed inside the EB (\u003Ca href=\"#B40\"\u003E40\u003C\u002Fa\u003E). Feeder-dependent hESC\u002FiPSC was adapted to a feeder independent system before EB generation (\u003Ca href=\"#B44\"\u003E44\u003C\u002Fa\u003E). To generate EBs, hESC\u002FiPSC are seeded in APEL media containing SCF, BMP4, VEGF, Rocki (rho kinase inhibitor). In the second and final step, NK cells are generated by transferring EBs to gelatin-coated wells containing NK cell differentiation media with IL-3, SCF, IL-7, and IL-15. After four weeks of culture, differentiated NK cells stained positive for CD45 and CD56 markers were harvested (\u003Ca href=\"#B40\"\u003E40\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Ch3\u003ENK Cancer Cell Lines\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EAmong the available NK cancer cell lines, only NK-92 cell line has shown antitumor activity in a variety of tumors and has worked well in pre-clinical studies (\u003Ca href=\"#B21\"\u003E21\u003C\u002Fa\u003E, \u003Ca href=\"#B45\"\u003E45\u003C\u002Fa\u003E). Furthermore, NK-92 cancer cell line has received FDA approval for clinical phase patient trials (\u003Ca href=\"#B46\"\u003E46\u003C\u002Fa\u003E, \u003Ca href=\"#B47\"\u003E47\u003C\u002Fa\u003E). The NK-92 cancer cell line is well characterized and robust clinical protocols are available for cGMP manufacturing (\u003Ca href=\"#B48\"\u003E48\u003C\u002Fa\u003E). These cells can be genetically engineered, but with a variable efficiency of 4% - 95% (\u003Ca href=\"#B49\"\u003E49\u003C\u002Fa\u003E) and expanded to substantial numbers. However, NK-92 cancer cell line requires irradiation prior to infusion, as it is cytogenetically abnormal. Select advantages and disadvantages with NK cells derived from different tissue sources are shown in \u003Ca href=\"#T2\"\u003ETable 2\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003ETABLE 2\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t002.jpg\" name=\"table 2\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t002.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t002.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t002.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t002.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t002.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t002.jpg\" alt=\"www.frontiersin.org\" id=\"T2\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003ETable 2\u003C\u002Fstrong\u003E Advantages and drawbacks of NK Cells from different sources.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ca id=\"h5\" name=\"h5\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003ENK Cell Expansion for the Creation of Allogeneic Doses\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003ERegardless of how the NK cells are sourced, every method of NK cell expansion can be classified as either a feeder-cell-based system or a feeder-free system. A multitude of cells and cell lines are used as feeders to stimulate allogeneic NK cell expansion. K562 leukemia cells have been successfully used in this regard for several decades (\u003Ca href=\"#B50\"\u003E50\u003C\u002Fa\u003E) and are the most used and well-characterized example. Other examples including EBV transformed lymphoblastoid (EBV-LCL) (\u003Ca href=\"#B51\"\u003E51\u003C\u002Fa\u003E), HEK293 (\u003Ca href=\"#B52\"\u003E52\u003C\u002Fa\u003E), autologous irradiated PBMCs (\u003Ca href=\"#B53\"\u003E53\u003C\u002Fa\u003E), Jurkat cells (\u003Ca href=\"#B54\"\u003E54\u003C\u002Fa\u003E), the Wilms tumor cell line, HFWT (la5), RPMI1866 (\u003Ca href=\"#B55\"\u003E55\u003C\u002Fa\u003E), MM170 (\u003Ca href=\"#B56\"\u003E56\u003C\u002Fa\u003E), and Daudi (\u003Ca href=\"#B57\"\u003E57\u003C\u002Fa\u003E) have also been applied with varying degrees of success. Strategies to prime and propagate NK cells using EBV-transformed lymphoblastoid cells and irradiated PBMCs continue to show promise, but protocols employing K562 cells remain superior in terms of both the magnitude and speed of expansion. Still, many groups attempt to improve the outcome even more by supplementing the culture with antibodies, such as OKT-3 (\u003Ca href=\"#B58\"\u003E58\u003C\u002Fa\u003E, \u003Ca href=\"#B59\"\u003E59\u003C\u002Fa\u003E) and other cyto-stimulants, such as PHA, ionomycin (\u003Ca href=\"#B53\"\u003E53\u003C\u002Fa\u003E), and concanavalin A (\u003Ca href=\"#B60\"\u003E60\u003C\u002Fa\u003E). One group has even claimed an extremely robust average of 50,000-fold expansion in 21 days (about 3 weeks) using a modified K562 line that expresses membrane-bound IL-21 (\u003Ca href=\"#B61\"\u003E61\u003C\u002Fa\u003E). A potential pitfall of employing feeder cells is that they are associated with a multitude of regulatory concerns. These cells must be stringently qualified using cumbersome assays and viral testing to ensure that they are free of microbial contaminants, such as mycoplasma (\u003Ca href=\"#B62\"\u003E62\u003C\u002Fa\u003E). Moreover, additional actions need to be taken to ensure that the final product is free from the feeder cells. This has encouraged researchers to develop and employ several feeder-free systems in the cultivation of NK cells.\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003ETo date, there has been a clear trade-off in that feeder-free systems alleviate many regulatory concerns but result in much lower yields. Several cell-free methods can be explored to activate and stimulate NK cells, including cytokines, and antibodies. Cytokines represent the most widely studied and earliest feeder-free method for activating NK cells. IL-2 is the most potent NK cell stimulant and elicits immunostimulatory signaling, increases cytokine release (\u003Ca href=\"#B63\"\u003E63\u003C\u002Fa\u003E), promotes cell motility (\u003Ca href=\"#B63\"\u003E63\u003C\u002Fa\u003E), and enhances cytotoxicity (\u003Ca href=\"#B64\"\u003E64\u003C\u002Fa\u003E). More recently, many alternative immunogenic cytokines have garnered attention for NK stimulation, including interleukins-15, -21, -12, -18, and -27. Much like IL-2, IL-15 stimulates NK cell proliferation, immunostimulatory receptor expression, and cytotoxicity (\u003Ca href=\"#B65\"\u003E65\u003C\u002Fa\u003E, \u003Ca href=\"#B66\"\u003E66\u003C\u002Fa\u003E), which makes it a great candidate to be used as an NK stimulant in a stand-alone fashion. In addition, it boasts several benefits over IL-2. Marks-Konczalik and colleagues reported that IL-15 inhibited activation-induced cell death that results from continuous IL-2 stimulation (\u003Ca href=\"#B67\"\u003E67\u003C\u002Fa\u003E)and unlike IL-2, IL-15 does not induce activation and proliferation of Tregs (\u003Ca href=\"#B68\"\u003E68\u003C\u002Fa\u003E), which results in peripheral tolerance and potentially leads to a more robust anti-tumor response. However, there is a tradeoff, research conducted by Felices et al. recently demonstrated that sustained IL-15 signaling results in exhausted NK cells and a loss of \u003Ci\u003Ein vitro\u003C\u002Fi\u003E and \u003Ci\u003Ein vivo\u003C\u002Fi\u003E efficacy (\u003Ca href=\"#B69\"\u003E69\u003C\u002Fa\u003E). Several groups have tried to stimulate NK cells with lower doses of IL-2 or IL-15 in combination with some of the other cytokines or they have developed cytokine schedules to alleviate some of the drawbacks associated with persistent stimulation with the one cytokine over the entire expansion protocol (\u003Ca href=\"#B70\"\u003E70\u003C\u002Fa\u003E). IL-21 alone is not sufficient to stimulate significant NK-cell expansion (\u003Ca href=\"#B71\"\u003E71\u003C\u002Fa\u003E, \u003Ca href=\"#B72\"\u003E72\u003C\u002Fa\u003E), however, there is a synergistic proliferative effect when IL-21 is combined with other immunostimulatory cytokines like IL-2 and IL-15 (\u003Ca href=\"#B71\"\u003E71\u003C\u002Fa\u003E, \u003Ca href=\"#B72\"\u003E72\u003C\u002Fa\u003E). Furthermore, the addition of IL-21 to NK cell culture has been associated with increased immunostimulatory cytokine production (\u003Ca href=\"#B73\"\u003E73\u003C\u002Fa\u003E) and upregulation of perforin and granzyme A and B (\u003Ca href=\"#B74\"\u003E74\u003C\u002Fa\u003E), leading to enhanced NK cell cytotoxicity (\u003Ca href=\"#B75\"\u003E75\u003C\u002Fa\u003E, \u003Ca href=\"#B76\"\u003E76\u003C\u002Fa\u003E). IL-12, IL-18, and IL-27 are slightly less characterized but have also displayed the ability to positively contribute to NK cell expansion, especially when used in conjunction with the IL-2 or IL-15. Research demonstrates that IL-12 can have a synergistic effect with IL-2, which results in enhanced NK cell cytokine secretion, proliferation, and cytotoxic capacity (\u003Ca href=\"#B77\"\u003E77\u003C\u002Fa\u003E, \u003Ca href=\"#B78\"\u003E78\u003C\u002Fa\u003E). IL-18 and IL-27 have recently been combined with IL-15 to boost NK cell fold expansion (\u003Ca href=\"#B79\"\u003E79\u003C\u002Fa\u003E). Another advantage of combining the cytokines can result in a lower dose of the individual cytokines, which can lead to a higher percentage of memory NK cells (\u003Ca href=\"#B19\"\u003E19\u003C\u002Fa\u003E). The combination of IL-12, IL-15, and IL-18 drives preferential expansion of memory-like NK cells, which exhibit heightened responses when they encounter tumor cells (\u003Ca href=\"#B79\"\u003E79\u003C\u002Fa\u003E–\u003Ca href=\"#B81\"\u003E81\u003C\u002Fa\u003E) and longer lifespans following engraftment (\u003Ca href=\"#B79\"\u003E79\u003C\u002Fa\u003E–\u003Ca href=\"#B81\"\u003E81\u003C\u002Fa\u003E). An additional benefit of these cells is an increased capacity to produce immunostimulatory cytokines upon secondary challenge. This memory response is an intrinsic quality that is passed on to all cellular progeny (\u003Ca href=\"#B79\"\u003E79\u003C\u002Fa\u003E–\u003Ca href=\"#B81\"\u003E81\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EApart from these most common feeder-cell and feeder-free cytokine systems, several groups have moved towards strategies that are a hybrid of the two. Several groups have engineered feeder cells that express immunostimulatory signaling molecules, such as 41BB, IL-15 (\u003Ca href=\"#B82\"\u003E82\u003C\u002Fa\u003E, \u003Ca href=\"#B83\"\u003E83\u003C\u002Fa\u003E), and IL-21 (\u003Ca href=\"#B63\"\u003E63\u003C\u002Fa\u003E, \u003Ca href=\"#B84\"\u003E84\u003C\u002Fa\u003E–\u003Ca href=\"#B86\"\u003E86\u003C\u002Fa\u003E) on their cell surfaces. These strategies have resulted in highly cytotoxic NK cells that display both extremely high proliferative capacities (up 50,000-fold expansion) (\u003Ca href=\"#B61\"\u003E61\u003C\u002Fa\u003E), extended survival, and the ability to secrete immunogenic cytokines, leading many groups to adopt these methods into their clinical protocols. This approach has recently been taken one step further to avoid safety concerns by stimulating NK cells with K562-mb21-41BBL cell lysates (\u003Ca href=\"#B87\"\u003E87\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003EMost of the experiments and trials discussed in this review have utilized small-scale, open methods for NK cell activation and expansion, such as flasks and G-Rex vessels. However, these methods are hampered by logistical hurdles, inconsistencies, and safety concerns. To reach the desired cell numbers for allogeneic manufacturing and clear all regulatory and safety hurdles associated with drug approval, it will be necessary to develop closed, and automated systems with large-scale capabilities. Hence, clinical scale NK cell manufacturing development suitable for effective allogeneic therapy production is a priority. Several options have been explored, including a G-Rex-based method that was developed under good manufacturing practice (GMP) conditions and required little to no manual intervention for the 8- to 10-day expansion and yielded 19 billion functional NK cells (\u003Ca href=\"#B88\"\u003E88\u003C\u002Fa\u003E). Another example of static culture is the use of large, gas-permeable culture bags, which were successfully applied in combination with feeder cells, antibodies, and cytokines to yield an NK cell fold expansion of 15,000 (\u003Ca href=\"#B89\"\u003E89\u003C\u002Fa\u003E). A more recent trend for achieving clinical scale NK cell expansion has been the use of bioreactors. In addition to large cell capacity, these devices are highly adaptable for closed and automated manufacturing processes (\u003Ca href=\"#f4\"\u003EFigure 4\u003C\u002Fa\u003E). Robust NK cell expansion with the Xuri Cell Expansion System W25 (Cytiva) has been demonstrated by several groups (\u003Ca href=\"#B90\"\u003E90\u003C\u002Fa\u003E–\u003Ca href=\"#B92\"\u003E92\u003C\u002Fa\u003E). The most common approach is to expand the isolated NK cells in static culture before transferring them to rocking bioreactors, which effectively nourish high cell densities (\u003Ca href=\"#B90\"\u003E90\u003C\u002Fa\u003E–\u003Ca href=\"#B92\"\u003E92\u003C\u002Fa\u003E). These workflows were able to generate 50 billion highly cytotoxic NK cells (\u003Ca href=\"#B91\"\u003E91\u003C\u002Fa\u003E). Stirred tanks are another type of dynamic culture bioreactor that has gained favor in the NK cell therapy community. Pierson and colleagues first demonstrated that the cultivation of NK cells in a 750ml-stirred tank significantly outperforms that in a comparable static vessel (\u003Ca href=\"#B93\"\u003E93\u003C\u002Fa\u003E). Moreover, it was recently shown that NK cell propagation in 2L stirred tanks scaled up exceptionally well to 50L stir tanks (\u003Ca href=\"#B94\"\u003E94\u003C\u002Fa\u003E) making this platform an excellent fit for allogeneic manufacturing workflows. Aside from the well-known wave motion reactors and stirred tank reactors, there has also been success using lesser-characterized reactors, such as the ZRP Bioreactor 50M, which was able to grow massive amounts of highly pure and functional NK cells (\u003Ca href=\"#B95\"\u003E95\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 4\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g004.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g004.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g004.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g004.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g004.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g004.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g004.jpg\" alt=\"www.frontiersin.org\" id=\"f4\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 4\u003C\u002Fstrong\u003E Bioreactors offer several advantages to the clinical manufacturing of cell therapies. The shift from static vessels on the left toward dynamic bioreactors on the right allows for several process improvements, such as scalability, automated and closed operation, digital integration, and intimate control of liquids. These capabilities result in increased safety and consistency, reduced labor requirement and cost, and improved quality of cellular output.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ca id=\"h6\" name=\"h6\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003ENK Cell Therapy Packaging and Release Testing\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EOnce the desired expansion is achieved, a major challenge is the downstream processing of these cells and preparing the allogeneic doses. Manufacturing and storing these “off-the-shelf” doses remotely, requires cryopreservation, which is often problematic in the case of NK cells. In addition to a loss in cell viability, it is common to see a significant drop in cytotoxicity after thawing. This functional loss routinely corresponds to a reduction in the expression of CD16 on NK cell surfaces (\u003Ca href=\"#B63\"\u003E63\u003C\u002Fa\u003E). However, many groups are attempting to mitigate these issues with different strategies. A few more promising examples are to expose thawed cells to IL-2 immediately, thereby restoring their cytotoxic capacity (\u003Ca href=\"#B60\"\u003E60\u003C\u002Fa\u003E), using twice as many cells in the dose to compensate for the reduced function per cell (\u003Ca href=\"#B96\"\u003E96\u003C\u002Fa\u003E), and inoculating the NK cells immediately after thawing them (\u003Ca href=\"#B37\"\u003E37\u003C\u002Fa\u003E, \u003Ca href=\"#B96\"\u003E96\u003C\u002Fa\u003E). A separate, but related concern, is a 6-fold decrease in motile NK cells following cryopreservation (\u003Ca href=\"#B37\"\u003E37\u003C\u002Fa\u003E). Efforts to develop effective cryopreservation solutions that preserve NK cell numbers and functionality are currently a priority to carry this field forward.\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003EBeyond viability and cytotoxicity issues following the cryopreservation and recovery cycle, there is a multitude of other criteria that should be considered before confidently releasing the NK cells for administration as a therapeutic dose. Safety is the overarching theme for most of these considerations. Several of these requirements are focused on confirming that there are no undesirable trespassers in the dose, such as endotoxins, mycoplasma, bacteria, or feeder cells if they were used for expansion. Confirmation that the dose consists of the desired cellular population is also highly important in preventing the onset of adverse effects that these cellular contaminants can cause. This can be done by setting a minimum requirement for the percent of CD56\u003Csup\u003Epos\u003C\u002Fsup\u003E\u002FCD3\u003Csup\u003Eneg\u003C\u002Fsup\u003E cells and a maximum allowed amount of CD3\u003Csup\u003Epos\u003C\u002Fsup\u003E T cells, CD19\u003Csup\u003Epos\u003C\u002Fsup\u003E B cells, and CD14\u003Csup\u003Epos\u003C\u002Fsup\u003E monocytes that can safely be released in a dose. These are the key regulatory principles that agencies across different geographical locations will require for cell therapies. Several additional ideas could be incorporated to further ensure therapeutic efficacy. An example of this could be flow cytometric characterization of activating receptors, such as NCRs, NKG2D, NKG2C, NKG2E, 2B4 and the inhibitory receptors NKG2A and KIRs. In addition, indicators of cytotoxic capabilities, CD16 and CD25, markers of differentiation status, CD62L, CD45, HLA-DR, CD69, and CD57, and functional analysis of IFNγ or TGF-β can be included (\u003Ca href=\"#B20\"\u003E20\u003C\u002Fa\u003E) (\u003Ca href=\"#f5\"\u003EFigure 5\u003C\u002Fa\u003E). It may also be beneficial to modify the cellular requirement based on the characteristics of the disease state. The tumors and surrounding microenvironments pose significant obstacles that are directly opposed to the proper function of adoptive cell therapies, such as NK cell therapies (\u003Ca href=\"#B97\"\u003E97\u003C\u002Fa\u003E). While many of the escape mechanisms are identified, there is often no way to identify which ones a particular tumor is employing. Thus, understanding the individual challenges associated with each tumor through a standardized molecular imprint could go a long way in cultivating the most effective cell therapy or combination therapy.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 5\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g005.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g005.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g005.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g005.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g005.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g005.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g005.jpg\" alt=\"www.frontiersin.org\" id=\"f5\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 5\u003C\u002Fstrong\u003E Natural killer cell-specific strategies for NK cell therapy release criteria. In addition to verifying that cell therapies are free from endotoxins, mycoplasma, bacteria, and feeder cells, there is a multitude of cell markers that can be selected to ensure that the therapeutic population possesses desired phenotypic and functional qualities. T cells, monocytes, and B cells must be removed for safety. Receptors and cytokines can then be evaluated to confirm that the outgoing cell population is responsive, cytotoxic, and safe.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ca id=\"h7\" name=\"h7\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003ECAR-NK Engineering\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EWhen NK cells are engineered with a tumor-specific chimeric antigen receptor (CAR), superior NK cell elicited cytotoxicity and improved cell infiltration into the tumor microenvironment are noticed. Genetic modification of NK cells by transducing with CAR receptors directed against tumor specific antigens may enhance both NK cell tumor specificity and NK cell persistence. CARs are engineered receptor proteins that recognize a target antigen on tumor cells and are successfully used in T cell therapy for lymphoid leukemias. Most of the CAR-T trials are restricted to autologous therapies, which are cumbersome, although strikingly efficient in targeted tumor cell killing (\u003Ca href=\"#B98\"\u003E98\u003C\u002Fa\u003E). The development of allogeneic CAR-T cells is challenging, as these treatments must be specifically tailored to avoid graft \u003Ci\u003Eversus\u003C\u002Fi\u003E host diseases (GVHD) and elimination by the host immune system (\u003Ca href=\"#B99\"\u003E99\u003C\u002Fa\u003E). In contrast, several advantages are recognized with CAR-NK cell therapy over CAR-T cell therapy clinical approaches. First, there are less side effects such as low\u002Fno GVHD (\u003Ca href=\"#B100\"\u003E100\u003C\u002Fa\u003E), cytokine release syndrome (\u003Ca href=\"#B101\"\u003E101\u003C\u002Fa\u003E) and neurotoxicity (\u003Ca href=\"#B102\"\u003E102\u003C\u002Fa\u003E). Second, CAR-NK cells can also eliminate tumor cells efficiently in a CAR-independent manner through their stimulatory and inhibitory receptors and CD16-mediated ADCC (\u003Ca href=\"#B103\"\u003E103\u003C\u002Fa\u003E). Therefore, several researchers are exploring different approaches to genetically engineer NK cells with CARs to augment the efficiency of NK cells to kill tumors (\u003Ca href=\"#B104\"\u003E104\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003ENK cells are successfully engineered to express CARs against several tumor-specific antigen targets and are shown to be efficient for \u003Ci\u003Ein vitro\u003C\u002Fi\u003E and \u003Ci\u003Ein vivo\u003C\u002Fi\u003E killing of tumor cells in experimental investigational studies. Human iPSC-derived NK cells engineered with specific CAR constructs demonstrated significantly enhanced targeted anti-tumor activity in an ovarian cancer xenograft model (\u003Ca href=\"#B105\"\u003E105\u003C\u002Fa\u003E). Although autologous NK cells can be generated \u003Ci\u003Ein vitro\u003C\u002Fi\u003E, they have limited efficiency against own patient’s tumor cells. There are currently 72 clinical trials using CAR-NK cell lines and 35 primary CAR-NK preclinical studies based on PubMed and Global data (\u003Ca href=\"http:\u002F\u002Fwww.carnkreview.com\"\u003Ewww.carnkreview.com\u003C\u002Fa\u003E) targeting different tumors (\u003Ca href=\"#B106\"\u003E106\u003C\u002Fa\u003E). However, only 5 studies are ongoing in phase I & II clinical trials at \u003Ca href=\"http:\u002F\u002Fwww.clincaltrials.gov\"\u003Ewww.clincaltrials.gov\u003C\u002Fa\u003E (\u003Ca href=\"#T3\"\u003ETable 3\u003C\u002Fa\u003E). CAR constructs for NK cells consist of three domains: an extracellular antigen recognition domain, a transmembrane domain, and an intracellular cytoplasmic signaling domain (\u003Ca href=\"#f6\"\u003EFigure 6\u003C\u002Fa\u003E). The ectodomain contains a single-chain variable fragment (scFv) derived from an antibody recognizing the tumor antigen. The transmembrane domain anchors the CAR structure to the effector cell membrane. CAR recognition of specific antigen triggers intracellular activation domain that results in the killing of the target cells. From the limited number of CAR-NK trials so far, no significant adverse events are noted, and the CAR-NKs showed robust cytolytic activity. In the CAR-NK trials that fit the allogeneic and off-the-shelf approach, CAR-NK cells from a single healthy donor were expanded in cell culture for appropriate dosing. The infused CAR-NKs persisted and expanded at a low level, based on PCR results, for a year within the tumor microenvironment in an ablative conditioning regimen. Most engineered CAR-NK cells are directed against blood-related malignancies, such as CD19 for B cell lymphomas, CD22 for refractory B-cell lymphomas and solid tumors, NKG2D-ligand for pancreatic cancers, and CD33 and ROBO1 specific BiCAR-NK\u002FT for malignant and metastatic solid tumors (\u003Ca href=\"#B107\"\u003E107\u003C\u002Fa\u003E). Barriers to a successful implementation of CAR-NK in solid tumors are recently reviewed, including off-tumor effects, impaired antigen recognition, poor cell trafficking, harsh tumor environment, and immune evasion (\u003Ca href=\"#B108\"\u003E108\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003ETABLE 3\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t003.jpg\" name=\"table 3\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t003.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t003.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t003.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t003.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t003.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t003.jpg\" alt=\"www.frontiersin.org\" id=\"T3\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003ETable 3\u003C\u002Fstrong\u003E On-going CAR-NK Clinical Trials.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 6\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g006.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g006.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g006.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g006.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g006.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g006.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g006.jpg\" alt=\"www.frontiersin.org\" id=\"f6\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 6\u003C\u002Fstrong\u003E CAR-NK Molecule Delivery of genetic cargo into NK cells with CAR encoding retro (RV), lenti (LV), or adeno-associated (AAV) vectors. CAR molecule is shown on the right side with single-chain variable fragment (scFv including V\u003Csub\u003EH\u003C\u002Fsub\u003E and V\u003Csub\u003EL\u003C\u002Fsub\u003E chains), hinge, transmembrane (TM), and signaling domain. Co-stimulatory signaling domains are indicated in different colors.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ca id=\"h8\" name=\"h8\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EDelivery Systems to Engineer NK Cells\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003EA critical aspect of CAR-NK generation is the introduction of genetic elements into NK cells, referred to as CAR-NK engineering. Once the genetic element is introduced into NK cells, the subsequent expansion of the CAR-NK cells with the cytotoxic killing of the target tumor cell will be another important consideration. The introduction of genetic material into NK cells is carried out using either viral vectors (retrovirus, lentivirus, and Adeno associated virus) or non-viral methods (mRNA and DNA). Examples of the viral and non-viral vector delivery systems with select pros and cons are shown in \u003Ca href=\"#T4\"\u003ETable 4\u003C\u002Fa\u003E and \u003Ca href=\"#f7\"\u003EFigure 7\u003C\u002Fa\u003E.\u003C\u002Fp\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003ETABLE 4\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t004.jpg\" name=\"table 4\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t004.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t004.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t004.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t004.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t004.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-t004.jpg\" alt=\"www.frontiersin.org\" id=\"T4\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003ETable 4\u003C\u002Fstrong\u003E Advantages and disadvantages with different gene delivery vectors.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"Imageheaders\"\u003EFIGURE 7\u003C\u002Fdiv\u003E\u003Cdiv class=\"FigureDesc\"\u003E\u003Ca href=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g007.jpg\" name=\"\" target=\"_blank\"\u003E\n \u003Cpicture\u003E\n \u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=480&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g007.jpg\" media=\"(max-width: 563px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=370&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g007.jpg\" media=\"(max-width: 1024px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=290&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g007.jpg\" media=\"(max-width: 1441px)\"\u003E\u003Csource type=\"image\u002Fwebp\" srcset=\"https:\u002F\u002Fimages-provider.frontiersin.org\u002Fapi\u002Fipx\u002Fw=410&f=webp\u002Fhttps:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g007.jpg\" media=\"\"\u003E\u003Csource type=\"image\u002Fjpg\" srcset=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g007.jpg\" media=\"\"\u003E \u003Cimg src=\"https:\u002F\u002Fwww.frontiersin.org\u002Ffiles\u002FArticles\u002F732135\u002Ffimmu-12-732135-HTML\u002Fimage_m\u002Ffimmu-12-732135-g007.jpg\" alt=\"www.frontiersin.org\" id=\"f7\" loading=\"lazy\"\u003E\n \u003C\u002Fpicture\u003E\n\u003C\u002Fa\u003E\u003Cp\u003E\u003Cstrong\u003EFigure 7\u003C\u002Fstrong\u003E Delivery technologies to engineer Natural killer cells. Modes of genetic cargo delivery into NK Cells by viral transduction and non-viral electroporation for gene engineering of NK Cells. Specific advantages and limitations are noted below the arrows.\u003C\u002Fp\u003E\u003C\u002Fdiv\u003E\u003Cdiv class=\"DottedLine\"\u003E\u003C\u002Fdiv\u003E\u003Ch3\u003ERetroviral Vector Systems\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003ERecent studies from the Rezvani laboratory at MDACC used retroviral vectors to deliver anti-CD19 CAR into NK cells along with IL-15 and inducible caspase 9. The CAR NK cells were used to treat CD19 positive tumors; 7 of 11 patients (64%) had a complete response (4 of 5 patients with CLL and 4 of 6 with non-Hodgkin’s lymphoma). All 8 patients had an objective response (73%) at 13.8 month follow-up (\u003Ca href=\"#B109\"\u003E109\u003C\u002Fa\u003E). Gene transfer did not change the function or phenotype of NK cells, nor did it change the proliferative or cytotoxic ability post engineering. Another recent study used retroviral vector systems that ectopically expressed iC9\u002FCAR.19\u002FIL15 to generate CAR-CD19-NK cells from cord blood that persisted for a long time in the tumor microenvironment (\u003Ca href=\"#B110\"\u003E110\u003C\u002Fa\u003E, \u003Ca href=\"#B111\"\u003E111\u003C\u002Fa\u003E). In both studies, the retroviral vector ectopically produced IL15 that is crucial for NK cell survival and conditionally expressed a caspase 9 (iC9)- an inducible suicide gene that could be activated to shut off the system by eliminating transduced cells when needed. Though retroviral vector systems have high transfection efficiency, the cDNA can integrate into the NK cell genome causing insertional mutagenesis and sometimes an induction of immune response (\u003Ca href=\"#B112\"\u003E112\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Ch3\u003ELentiviral Vector Systems\u003C\u002Fh3\u003E\u003Cp class=\"mb15\"\u003ELentiviral transduction is the preferred choice to modify NK cells. The lentiviral method allows transduction of primary and non-activated NK cells, and unlike the retroviral vector system, does not require dividing cells (\u003Ca href=\"#B113\"\u003E113\u003C\u002Fa\u003E). Single lentiviral transduction usually results in lower transduction efficiencies, PB NK (<10%) or CB NK (<30%) (\u003Ca href=\"#B114\"\u003E114\u003C\u002Fa\u003E). In Japan, a study led by Dr. Ueda used a lentiviral system to express CAR-NK-GPC3 for solid tumors of hepatocellular carcinoma (HCC) and ovarian cancers that are treated in \u003Ci\u003Ein vivo\u003C\u002Fi\u003E animal models with good success (\u003Ca href=\"#B115\"\u003E115\u003C\u002Fa\u003E). Recent studies have improved the efficiencies of lentiviral delivery, by using statins to upregulate the low-density lipoprotein (LDL) receptor on NK cells enhancing the transduction efficiency by 30-50% (\u003Ca href=\"#B116\"\u003E116\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003EPseudotyped lentiviral particles are glycoproteins derived from other enveloped viruses that enable the tropism of the lentiviral. The ability to generate CAR-NK cells depends on the envelope protein lentivirals express. Vesicular stomatitis virus G glycoprotein (VSV-G) pseudotype particles showed the highest transduction efficiency of primary NK cells compared to retroviral vectors (\u003Ca href=\"#B117\"\u003E117\u003C\u002Fa\u003E). Feline endogenous retrovirus envelope protein RD114-TR was similar to VSV-G pseudotype particles for primary human NK cells (\u003Ca href=\"#B118\"\u003E118\u003C\u002Fa\u003E). Further, a Baboon envelope pseudotyped lentiviral vector BaEV-LV was significantly better than both the RD-114-TR and VSV-G pseudotyped lentiviral vector (\u003Ca href=\"#B119\"\u003E119\u003C\u002Fa\u003E). Choosing which LV pseudotypes VSV-G \u003Ci\u003Eversus\u003C\u002Fi\u003E RD114-TR \u003Ci\u003Eversus\u003C\u002Fi\u003E BaEV-LV has the best transduction efficiency should be an essential consideration for CAR-NK generation. The advantages and disadvantages of different LV pseudotypes have been recently reviewed (\u003Ca href=\"#B120\"\u003E120\u003C\u002Fa\u003E, \u003Ca href=\"#B121\"\u003E121\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Ch3\u003EAdeno Associated Viral Delivery\u003C\u002Fh3\u003E\u003Cp class=\"mb0\"\u003EAlternative viral vectors with a better safety profile are adenovirus-associated virus (AAV) vectors. One way to improve the efficiency of NK cell cytotoxicity is by blocking their inhibitory receptors. Using CRISPR\u002Fcas9 driven delivery by recombinant adeno-associated virus serotype6 (rAAV6), highly efficient knockout of A Disintegrin and Metalloproteinase-17 (ADAM17) and programmed cell death 1 (PDCD1) genes in NK cells was accomplished (\u003Ca href=\"#B121\"\u003E121\u003C\u002Fa\u003E). KO of ADAM17 and PDCD1 improved NK activity, cytokine production and cancer cell cytotoxicity. These approaches demonstrate an easy-to-use strategy for efficient gene editing and delivery with AAV vector systems for NK cell therapies (\u003Ca href=\"#B121\"\u003E121\u003C\u002Fa\u003E). However, one limitation with AAV is its packaging capacity (~5kb) that limits a large gene transfer. NK cells in general have a low propensity for viral transduction, and higher cell death. Hence, commercially available viral transduction enhancers such as LentiBOOST, PGE2, PS, Vectofusin-1, ViraDuctin, Retronectin, Stauro and 7-hydroxy stauro are sometimes employed to improve vector transduction.\u003C\u002Fp\u003E\u003Ch3\u003ENon-Viral DNA Transfection and mRNA-Electroporation\u003C\u002Fh3\u003E\u003Cp class=\"mb15\"\u003ESuccessful electroporation of DNA into the NK-92 cancer cell line was shown, but not in primary NK cells from PBMCs or cord blood (\u003Ca href=\"#B33\"\u003E33\u003C\u002Fa\u003E). Recently, an improved method with NK cells expanded with IL-2 was reported with 40% efficiency of DNA plasmid transfer (\u003Ca href=\"#B122\"\u003E122\u003C\u002Fa\u003E). Following DNA transfer by electroporation, the viability of NK cells was lower, due to harsh electroporation conditions, and the DNA transfection efficiency was less compared to resting NK cells. The real advantage of this approach is complex constructs can also be transferred efficiently into the cells. Plasmid DNA of small (~3.5Kb) and large sizes (~12.5Kb) are transferred with a substantial increase of transfection up to 5-fold compared to the standard electroporation approach (\u003Ca href=\"#B123\"\u003E123\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003ESome researchers are exploring electroporation to express CAR molecules on NK cells (\u003Ca href=\"#B124\"\u003E124\u003C\u002Fa\u003E, \u003Ca href=\"#B125\"\u003E125\u003C\u002Fa\u003E). Unlike DNA electroporation, mRNA electroporation of NK cells may be an efficient alternative, but it induces only transient expression of the transferred gene. mRNA electroporation efficiencies are usually high (80-90%) for PBMCs or cord blood cells and require cytokine stimulation such as IL-2 for post-transduction expansion or the use of feeder cells that are engineered to secrete IL2 for better viability of cells (\u003Ca href=\"#B126\"\u003E126\u003C\u002Fa\u003E). Transfection efficiency with mRNA by electroporation depends on the dose of mRNA (25-200 ug\u002Fml) (\u003Ca href=\"#B127\"\u003E127\u003C\u002Fa\u003E). High dose of mRNA results in poor viability of cells following transfection. In general, post electroporation expansion is contraindicated with mRNA approaches as it leads to dilution of the mRNA.\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003ERecently another charge-based chemical method has been tried successfully to deliver CAR mRNA into non-dividing NK cells using a nucleofection approach that showed high efficiency (\u003Ca href=\"#B128\"\u003E128\u003C\u002Fa\u003E). A specific advantage of using mRNA delivery system is the transient expression of protein by mRNA, thus avoids the risk of genome integration, least expensive to manufacture and savings of time (\u003Ca href=\"#B129\"\u003E129\u003C\u002Fa\u003E). Another strategy that has been less frequently used for stable non-viral gene delivery is employing DNA transposons to transduce NK cells which is cost effective, has large cargo (ex: CAR in combination with activating receptors or cytokines) deliver capacity with stable integration. Their disadvantages include potential insertional mutagenesis and the transposon must be delivered as DNA (\u003Ca href=\"#B130\"\u003E130\u003C\u002Fa\u003E, \u003Ca href=\"#B131\"\u003E131\u003C\u002Fa\u003E). Despite the limitations described above, the most successful non-viral gene delivery for primary NK cells is still rapid transient expression by electroporation.\u003C\u002Fp\u003E\u003Ch3\u003EEngineering NK Cell Receptors\u003C\u002Fh3\u003E\u003Cp class=\"mb15\"\u003EFor CAR-engineered cells to act, identifying specific tumor antigens as targets is a challenge, whether for T cells or NK cells. Human NK cells have innate inhibitory receptors such as KIRs and NKG2A molecules that recognize MHC class I and evoke response through immunoreceptors tyrosine-based inhibitory motif (ITIM). T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on T and NK cells and is a promising emerging target for cancer immunotherapy. TIGIT interacts with ligands CD115 and CD112 expressed on tumor cells. There is evidence that TIGIT blockade can help tumor regression (\u003Ca href=\"#B132\"\u003E132\u003C\u002Fa\u003E).\u003C\u002Fp\u003E\u003Cp class=\"mb15\"\u003EIn contrast, activating receptors on NK cells such as NKG2D and DNAX accessory molecule 1 (DNAM-1) play a crucial role in tumor surveillance since this receptor has a wide range of ligands that provide target specificity (\u003Ca href=\"#B133\"\u003E133\u003C\u002Fa\u003E). Preclinical study data using CAR-NKG2D is promising in colorectal cancer patients (\u003Ca href=\"#B124\"\u003E124\u003C\u002Fa\u003E) and multiple myeloma patients (\u003Ca href=\"#B134\"\u003E134\u003C\u002Fa\u003E). Natural cytotoxicity receptors (NCRs) like NKp30, NKp44, and NKp46, can recognize multiple stress ligands in infection and oncogenic transformation. Harnessing these receptors on NK cells and their ligands on tumor cells is another new strategy to create CAR-NK cells that can induce anti-tumor immunity.\u003C\u002Fp\u003E\u003Cp class=\"mb0\"\u003EWith the advances made in viral and non-viral gene delivery approaches to generate better CAR-NK molecules, there will be a heightened focus on how these cells perform in clinical trials over the next few years. These results will help determine whether CAR-NKs can effectively target and kill tumor cells (\u003Ca href=\"#B135\"\u003E135\u003C\u002Fa\u003E). The viability of CAR-NK cells in the tumor microenvironment is central to the success of therapy, in addition to the repeated dosing of the cells. CAR engineering of NK cells primarily resides between two choices of stable high expression by viral vectors or rapid transient expression of non-viral delivery systems using electroporation.\u003C\u002Fp\u003E\u003Ca id=\"h9\" name=\"h9\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConclusions and Perspectives\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003ENK cells are critical in immune surveillance of invading viruses and kill tumor cells without the need of tumor specific antigen presentation. Pre-clinical data from early phase clinical trials has significantly increased our knowledge for the use of allogeneic donor NK cells across a wide range of hematological malignancies and solid tumors. Recent advances include developing NK cell expansion protocols without the use of feeders, serum, activation technologies, validation of NK cells from different tissue sources, ability to selectively use donor NK cells with minimal HLA matching, genetic modification to create CAR-NK constructs, and transfer of genetic material using viral and nonviral delivery technologies. These advances point towards a true “off-the-shelf” NK cell therapy. Despite impressive advances, there are multiple outstanding challenges with NK cell therapies. Methods following good manufacturing practices to generate large clinical doses from a single healthy donor and selective expansion appropriate NK cell subsets with best predictive KIR\u002FHLA are needed. Additionally, tumor immune evasion remains a large barrier. Once the NK or CAR-NK cells are infused into the patient, the long-term persistence of these cells \u003Ci\u003Ein-vivo\u003C\u002Fi\u003E in the tumor microenvironment needs to be ensured and monitored. Another limitation with NK and CAR-NK cells is the memory property \u003Ci\u003Ein vivo\u003C\u002Fi\u003E, which is not fully understood as in the case of memory T cells in adaptive immunity. Identifying novel CAR targets and generation of NK specific CAR constructs will enable CAR-NK cell homing and persistence in solid tumors contributing to breakthrough approaches driving allogeneic NK therapies towards the next frontier of cancer immunotherapy.\u003C\u002Fp\u003E\u003Ca id=\"h10\" name=\"h10\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAuthor Contributions\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003EEH, EZ, TS, AH, NK and MCV wrote the manuscript and, SB prepared figures. All authors contributed to the article and approved the submitted version.\u003C\u002Fp\u003E\u003Ca id=\"h11\" name=\"h11\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EConflict of Interest\u003C\u002Fh2\u003E\u003Cp class=\"mb0\"\u003EEH, EZ, TS-N, AH, SB, NK, and MV had compensated employment at Thermo Fisher Scientific.\u003C\u002Fp\u003E\u003Ca id=\"h12\" name=\"h12\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EPublisher’s Note\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\u003C\u002Fp\u003E\u003Ca id=\"h13\" name=\"h13\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EAcknowledgments\u003C\u002Fh2\u003E\u003Cp class=\"mb15\"\u003EThe authors thank Dr. Jonathan Chesnut for the support, review and Dr. Premkumar Jayaraman for proofreading the manuscript. Further, the authors acknowledge BioRender (\u003Ca href=\"https:\u002F\u002FBioRender.com\"\u003EBioRender.com\u003C\u002Fa\u003E) for the software to create figures.\u003C\u002Fp\u003E\u003Ca id=\"h14\" name=\"h14\"\u003E\u003C\u002Fa\u003E\u003Ch2\u003EReferences\u003C\u002Fh2\u003E\u003Cdiv class=\"References\" style=\"margin-bottom:0.5em; margin-left:2em;\"\u003E\u003Cp class=\"ReferencesCopy1\" style=\"margin-left:0.7em; text-indent:-1.1em;\"\u003E\u003Ca name=\"B1\" id=\"B1\"\u003E\u003C\u002Fa\u003E 1. Bryceson YT, March ME, Barber DF, Ljunggren HG, Long EO. 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Immunol.\u003C\u002Fi\u003E 12:732135. doi: 10.3389\u002Ffimmu.2021.732135\u003C\u002Fp\u003E\u003Cp id=\"timestamps\"\u003E\u003Cspan\u003EReceived:\u003C\u002Fspan\u003E 28 June 2021; \u003Cspan\u003EAccepted:\u003C\u002Fspan\u003E 01 November 2021;\u003Cbr\u003E\u003Cspan\u003EPublished:\u003C\u002Fspan\u003E 01 December 2021.\u003C\u002Fp\u003E\u003Cdiv\u003E\u003Cp\u003EEdited by:\u003C\u002Fp\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F469526\"\u003EJohn - Maher\u003C\u002Fa\u003E, King’s College London, United Kingdom\u003C\u002Fdiv\u003E\u003Cdiv\u003E\u003Cp\u003EReviewed by:\u003C\u002Fp\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F1389556\"\u003ECaroline Hull\u003C\u002Fa\u003E, Leucid Bio, United Kingdom\u003Cbr\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F31783\"\u003EDean Anthony Lee\u003C\u002Fa\u003E, The Research Institute at Nationwide Children’s Hospital, United States\u003Cbr\u003E\u003Ca href=\"https:\u002F\u002Floop.frontiersin.org\u002Fpeople\u002F332261\"\u003ERobert J. Canter\u003C\u002Fa\u003E, University of California, Davis, United States\u003C\u002Fdiv\u003E\u003Cp\u003E\u003Cspan\u003ECopyright\u003C\u002Fspan\u003E © 2021 Heipertz, Zynda, Stav-Noraas, Hungler, Boucher, Kaur and Vemuri. This is an open-access article distributed under the terms of the \u003Ca rel=\"license\" href=\"http:\u002F\u002Fcreativecommons.org\u002Flicenses\u002Fby\u002F4.0\u002F\" target=\"_blank\"\u003ECreative Commons Attribution License (CC BY)\u003C\u002Fa\u003E. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\u003C\u002Fp\u003E\u003Cp\u003E\u003Cspan\u003E*Correspondence:\u003C\u002Fspan\u003E Mohan C. Vemuri, \u003Ca id=\"encmail\"\u003EbW9oYW4udmVtdXJpQHRoZXJtb2Zpc2hlci5jb20=\u003C\u002Fa\u003E\u003C\u002Fp\u003E\u003Cdiv class=\"clear\"\u003E\u003C\u002Fdiv\u003E\u003C\u002Fdiv\u003E",menuHtml:"\u003Cul class=\"flyoutJournal\"\u003E\u003Cli\u003E\u003Ca href=\"#h1\"\u003EAbstract\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h2\"\u003ENatural Killer Cell Biology\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h3\"\u003ENK Cell-Based Strategies in Clinical Trials Targeting Different Indications\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h4\"\u003ESources of Natural Killer Cells for Immunotherapy\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h5\"\u003ENK Cell Expansion for the Creation of Allogeneic Doses\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h6\"\u003ENK Cell Therapy Packaging and Release Testing\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h7\"\u003ECAR-NK Engineering\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h8\"\u003EDelivery Systems to Engineer NK Cells\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h9\"\u003EConclusions and Perspectives\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h10\"\u003EAuthor Contributions\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h11\"\u003EConflict of Interest\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h12\"\u003EPublisher’s Note\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h13\"\u003EAcknowledgments\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003Cli\u003E\u003Ca href=\"#h14\"\u003EReferences\u003C\u002Fa\u003E\u003C\u002Fli\u003E\u003C\u002Ful\u003E"},files:[{name:"EPUB.epub",fileServerPackageEntryId:f,type:{code:ay,name:ay}},{name:P,fileServerPackageEntryId:P,type:{code:s,name:s}},{name:P,fileServerPackageEntryId:f,type:{code:s,name:s}},{name:az,fileServerPackageEntryId:az,type:{code:"NLM_XML",name:"XML"}},{name:"Provisional PDF.pdf",fileServerPackageEntryId:f,type:{code:s,name:s}}]},currentArticlePageMetaInfo:{title:aA,link:[{rel:"canonical",href:aB}],meta:[{hid:A,property:A,name:A,content:aC},{hid:aD,property:aD,name:"title",content:aA},{hid:aE,property:aE,name:A,content:aC},{hid:aF,name:aF,content:"Natural Killer cells,CAR-NK cells,Immunotherapy,NK cell expansion,lentiviral delivery,AAV delivery,Killer immune receptors,GMP 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Immunol.","1664-3224",void 0,13,18,12,"fimmu-12-732135.pdf",1920,"por-journal.com",7,"escubed.org",1918,"fipp","https:\u002F\u002Fd2csxpduxe849s.cloudfront.net\u002Fmedia\u002FE32629C6-9347-4F84-81FEAEF7BFA342B3\u002FB8A9338D-D05F-42BE-A5B9BE8019A37824\u002Fwebimage-78EBA97D-B178-435E-B00557EE47446315.png","22C10171-81B3-4DA6-99342F272A32E8BB","jpg","2022-06-27T09:59:56Z","fimmu",35,"10.3389\u002Ffimmu.2021.732135","Current Perspectives on “Off-The-Shelf” Allogeneic NK and CAR-NK Cell Therapies","\u003Cp\u003ENatural killer cells (NK cells) are the first line of the innate immune defense system, primarily located in peripheral circulation and lymphoid tissues. They kill virally infected and malignant cells through a balancing play of inhibitory and stimulatory receptors. In pre-clinical investigational studies, NK cells show promising anti-tumor effects and are used in adoptive transfer of activated and expanded cells, \u003Citalic\u003Eex-vivo\u003C\u002Fitalic\u003E. NK cells express co-stimulatory molecules that are attractive targets for the immunotherapy of cancers. Recent clinical trials are investigating the use of CAR-NK for different cancers to determine the efficiency. Herein, we review NK cell therapy approaches (NK cell preparation from tissue sources, ways of expansion \u003Citalic\u003Eex-vivo\u003C\u002Fitalic\u003E for “off-the-shelf” allogeneic cell-doses for therapies, and how different vector delivery systems are used to engineer NK cells with CARs) for cancer immunotherapy.\u003C\u002Fp\u003E",1446932,"Erica L.","Evan R.","BioProduction, Thermo Fisher Scientific","Tor Espen","Andrew D.","Shayne E.",1534933,"Navjot",675032,"Mohan C.",469526,"United Kingdom",332261,31783,1389556,"Caroline",{},527,"Cancer Immunity and Immunotherapy","cancer-immunity-and-immunotherapy","EPUB","fimmu-12-732135.xml","Frontiers | Current Perspectives on “Off-The-Shelf” Allogeneic NK and CAR-NK Cell Therapies","https:\u002F\u002Fwww.frontiersin.org\u002Fjournals\u002Fimmunology\u002Farticles\u002F10.3389\u002Ffimmu.2021.732135\u002Ffull","Natural killer cells (NK cells) are the first line of the innate immune defense system, primarily located in peripheral circulation and lymphoid tissues. 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