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<!DOCTYPE html> <html lang="en" class="no-js"> <head> <meta charset="UTF-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width, initial-scale=1"> <title>Efficacy and safety of novel multiple-chain DAP-CAR-T cells targeting mesothelin in ovarian cancer and mesothelioma: a single-arm, open-label and first-in-human study | Genome Medicine | Full Text</title> <meta name="citation_abstract" content="Despite remarkable achievements in applying chimeric antigen receptor (CAR)-T cells to treat hematological malignancies, they remain much less effective against solid tumors, facing several challenges affecting their clinical use. We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma. In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity. We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME. Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma. ChiCTR.org.cn, ChiCTR2100046544 . May 21, 2021."/> <meta name="journal_id" content="13073"/> <meta name="dc.title" content="Efficacy and safety of novel multiple-chain DAP-CAR-T cells targeting mesothelin in ovarian cancer and mesothelioma: a single-arm, open-label and first-in-human study"/> <meta name="dc.source" content="Genome Medicine 2024 16:1"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="BioMed Central"/> <meta name="dc.date" content="2024-11-15"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2024 The Author(s)"/> <meta name="dc.rights" content="2024 The Author(s)"/> <meta name="dc.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="dc.description" content="Despite remarkable achievements in applying chimeric antigen receptor (CAR)-T cells to treat hematological malignancies, they remain much less effective against solid tumors, facing several challenges affecting their clinical use. We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma. In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity. We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME. Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma. ChiCTR.org.cn, ChiCTR2100046544 . May 21, 2021."/> <meta name="prism.issn" content="1756-994X"/> <meta name="prism.publicationName" content="Genome Medicine"/> <meta name="prism.publicationDate" content="2024-11-15"/> <meta name="prism.volume" content="16"/> <meta name="prism.number" content="1"/> <meta name="prism.section" content="OriginalPaper"/> <meta name="prism.startingPage" content="1"/> <meta name="prism.endingPage" content="17"/> <meta name="prism.copyright" content="2024 The Author(s)"/> <meta name="prism.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="prism.url" content="https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-024-01405-5"/> <meta name="prism.doi" content="doi:10.1186/s13073-024-01405-5"/> <meta name="citation_pdf_url" content="https://genomemedicine.biomedcentral.com/counter/pdf/10.1186/s13073-024-01405-5"/> <meta name="citation_fulltext_html_url" content="https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-024-01405-5"/> <meta name="citation_journal_title" content="Genome Medicine"/> <meta name="citation_journal_abbrev" content="Genome Med"/> <meta name="citation_publisher" content="BioMed Central"/> <meta name="citation_issn" content="1756-994X"/> <meta name="citation_title" content="Efficacy and safety of novel multiple-chain DAP-CAR-T cells targeting mesothelin in ovarian cancer and mesothelioma: a single-arm, open-label and first-in-human study"/> <meta name="citation_volume" content="16"/> <meta name="citation_issue" content="1"/> <meta name="citation_publication_date" content="2024/12"/> <meta name="citation_online_date" content="2024/11/15"/> <meta name="citation_firstpage" content="1"/> <meta name="citation_lastpage" content="17"/> <meta name="citation_article_type" content="Research"/> <meta name="citation_fulltext_world_readable" content=""/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.1186/s13073-024-01405-5"/> <meta name="DOI" content="10.1186/s13073-024-01405-5"/> <meta name="size" content="208758"/> <meta name="citation_doi" content="10.1186/s13073-024-01405-5"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1186/s13073-024-01405-5&api_key="/> <meta name="description" content="Despite remarkable achievements in applying chimeric antigen receptor (CAR)-T cells to treat hematological malignancies, they remain much less effective against solid tumors, facing several challenges affecting their clinical use. We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma. In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity. We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME. Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma. ChiCTR.org.cn, ChiCTR2100046544 . May 21, 2021."/> <meta name="dc.creator" content="Xu, Tongpeng"/> <meta name="dc.creator" content="Tian, Tian"/> <meta name="dc.creator" content="Wang, Chen"/> <meta name="dc.creator" content="Chen, Xiaofeng"/> <meta name="dc.creator" content="Zuo, Xiangrong"/> <meta name="dc.creator" content="Zhou, Hanyu"/> <meta name="dc.creator" content="Bai, Jianan"/> <meta name="dc.creator" content="Zhao, Chenhui"/> <meta name="dc.creator" content="Fu, Sujie"/> <meta name="dc.creator" content="Sun, Chongqi"/> <meta name="dc.creator" content="Wang, Ting"/> <meta name="dc.creator" content="Zhu, Ling"/> <meta name="dc.creator" content="Zhang, Jingzhi"/> <meta name="dc.creator" content="Wang, Enxiu"/> <meta name="dc.creator" content="Sun, Ming"/> <meta name="dc.creator" content="Shu, Yongqian"/> <meta name="dc.subject" content="Human Genetics"/> <meta name="dc.subject" content="Metabolomics"/> <meta name="dc.subject" content="Bioinformatics"/> <meta name="dc.subject" content="Medicine/Public Health, general"/> <meta name="dc.subject" content="Cancer Research"/> <meta name="dc.subject" content="Systems Biology"/> <meta name="citation_reference" content="citation_journal_title=Blood Cancer J; citation_title=CAR-T cell therapy: current limitations and potential strategies; citation_author=RC Sterner, RM Sterner; citation_volume=11; citation_publication_date=2021; citation_pages=69; citation_doi=10.1038/s41408-021-00459-7; citation_id=CR1"/> <meta name="citation_reference" content="citation_journal_title=Clin Pharmacol Ther; citation_title=CAR T-cell therapy in hematologic malignancies: a voyage in progress; citation_author=SA Holstein, MA Lunning; citation_volume=107; citation_publication_date=2020; citation_pages=112-122; citation_doi=10.1002/cpt.1674; citation_id=CR2"/> <meta name="citation_reference" content="citation_journal_title=N Engl J Med; citation_title=Cilta-cel or standard care in lenalidomide-refractory multiple myeloma; citation_author=J San-Miguel, B Dhakal, K Yong, A Spencer, S Anguille, MV Mateos, C Fernandez de Larrea, J Martinez-Lopez, P Moreau, C Touzeau; citation_volume=389; citation_publication_date=2023; citation_pages=335-347; citation_doi=10.1056/NEJMoa2303379; citation_id=CR3"/> <meta name="citation_reference" content="citation_journal_title=Journal For Immunotherapy of Cancer; citation_title=Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma; citation_author=X Qu, G An, W Sui, T Wang, X Zhang, J Yang, Y Zhang, L Zhang, D Zhu, J Huang; citation_volume=10; citation_publication_date=2022; citation_pages=e005145; citation_doi=10.1136/jitc-2022-005145; citation_id=CR4"/> <meta name="citation_reference" content="citation_journal_title=Front Immunol; citation_title=CAR T cells for solid tumors: new strategies for finding, infiltrating, and surviving in the tumor microenvironment; citation_author=M Martinez, EK Moon; citation_volume=10; citation_publication_date=2019; citation_pages=128; citation_doi=10.3389/fimmu.2019.00128; citation_id=CR5"/> <meta name="citation_reference" content="citation_journal_title=Mol Cancer; citation_title=Tumor buster - where will the CAR-T cell therapy 'missile' go?; citation_author=C Qu, H Zhang, H Cao, L Tang, H Mo, F Liu, L Zhang, Z Yi, L Long, L Yan; citation_volume=21; citation_publication_date=2022; citation_pages=201; citation_doi=10.1186/s12943-022-01669-8; citation_id=CR6"/> <meta name="citation_reference" content="citation_journal_title=Front Immunol; citation_title=CAR-T therapy for pediatric high-grade gliomas: peculiarities, current investigations and future strategies; citation_author=L Antonucci, G Canciani, A Mastronuzzi, A Carai, G Baldo, F Bufalo; citation_volume=13; citation_publication_date=2022; citation_pages=867154; citation_doi=10.3389/fimmu.2022.867154; citation_id=CR7"/> <meta name="citation_reference" content="citation_journal_title=Front Immunol; citation_title=Revolution of CAR engineering for next-generation immunotherapy in solid tumors; citation_author=T Yu, SK Yu, Y Xiang, KH Lu, M Sun; citation_volume=13; citation_publication_date=2022; citation_pages=936496; citation_doi=10.3389/fimmu.2022.936496; citation_id=CR8"/> <meta name="citation_reference" content="citation_journal_title=Cancer Cell; citation_title=Engineering CAR-T cells for next-generation cancer therapy; citation_author=M Hong, JD Clubb, YY Chen; citation_volume=38; citation_publication_date=2020; citation_pages=473-488; citation_doi=10.1016/j.ccell.2020.07.005; citation_id=CR9"/> <meta name="citation_reference" content="citation_journal_title=Cancer Discov; citation_title=The basic principles of chimeric antigen receptor design; citation_author=M Sadelain, R Brentjens, I Rivière; citation_volume=3; citation_publication_date=2013; citation_pages=388-398; citation_doi=10.1158/2159-8290.CD-12-0548; citation_id=CR10"/> <meta name="citation_reference" content="citation_journal_title=Nat Biotechnol; citation_title=Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo; citation_author=S Rafiq, OO Yeku, HJ Jackson, TJ Purdon, DG Leeuwen, DJ Drakes, M Song, MM Miele, Z Li, P Wang; citation_volume=36; citation_publication_date=2018; citation_pages=847-856; citation_doi=10.1038/nbt.4195; citation_id=CR11"/> <meta name="citation_reference" content="citation_journal_title=Nat Med; citation_title=4–1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors; citation_author=AH Long, WM Haso, JF Shern, KM Wanhainen, M Murgai, M Ingaramo, JP Smith, AJ Walker, ME Kohler, VR Venkateshwara; citation_volume=21; citation_publication_date=2015; citation_pages=581-590; citation_doi=10.1038/nm.3838; citation_id=CR12"/> <meta name="citation_reference" content="citation_journal_title=Annu Rev Biochem; citation_title=Nanobodies: natural single-domain antibodies; citation_author=S Muyldermans; citation_volume=82; citation_publication_date=2013; citation_pages=775-797; citation_doi=10.1146/annurev-biochem-063011-092449; citation_id=CR13"/> <meta name="citation_reference" content="citation_journal_title=Biomarker Research; citation_title=Nanobody-based CAR-T cells for cancer immunotherapy; citation_author=P Safarzadeh Kozani, A Naseri, SMJ Mirarefin, F Salem, M Nikbakht, S Evazi Bakhshi, P Safarzadeh Kozani; citation_volume=10; citation_publication_date=2022; citation_pages=24; citation_doi=10.1186/s40364-022-00371-7; citation_id=CR14"/> <meta name="citation_reference" content="citation_journal_title=Nat Biotechnol; citation_title=IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor; citation_author=K Adachi, Y Kano, T Nagai, N Okuyama, Y Sakoda, K Tamada; citation_volume=36; citation_publication_date=2018; citation_pages=346-351; citation_doi=10.1038/nbt.4086; citation_id=CR15"/> <meta name="citation_reference" content="citation_journal_title=Am J Hematol.; citation_title=A novel adoptive synthetic TCR and antigen receptor (STAR) T-Cell therapy for B-Cell acute lymphoblastic leukemia; citation_author=J Wang, X Zhang, Z Zhou, Y Liu, L Yu, L Jia, J Yang, J Li, H Yu, W Li; citation_volume=97; citation_issue=8; citation_publication_date=2022; citation_pages=992-1004; citation_doi=10.1002/ajh.26586; citation_id=CR16"/> <meta name="citation_reference" content="citation_journal_title=Cancer Immunol Res; citation_title=Generation of potent T-cell immunotherapy for cancer using DAP12-based, multichain, chimeric immunoreceptors; citation_author=E Wang, L-C Wang, C-Y Tsai, V Bhoj, Z Gershenson, E Moon, K Newick, J Sun, A Lo, T Baradet; citation_volume=3; citation_publication_date=2015; citation_pages=815-826; citation_doi=10.1158/2326-6066.CIR-15-0054; citation_id=CR17"/> <meta name="citation_reference" content="citation_journal_title=Immunotherapy; citation_title=Coexpression of c-Jun in multiple-chain DAP-CAR-engineered T-cells for solid tumor therapy; citation_author=T Xu, C Wang, X Chen, J Bai, E Wang, M Sun; citation_volume=14; citation_publication_date=2022; citation_pages=1457-1466; citation_doi=10.2217/imt-2022-0171; citation_id=CR18"/> <meta name="citation_reference" content="citation_journal_title=Can Res; citation_title=Discovery of mesothelin and exploiting it as a target for immunotherapy; citation_author=I Pastan, R Hassan; citation_volume=74; citation_publication_date=2014; citation_pages=2907-2912; citation_doi=10.1158/0008-5472.CAN-14-0337; citation_id=CR19"/> <meta name="citation_reference" content="citation_journal_title=J Hematol Oncol; citation_title=A novel mycobacterial Hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesothelioma; citation_author=J Yuan, S Kashiwagi, P Reeves, J Nezivar, Y Yang, NH Arrifin, M Nguyen, G Jean-Mary, X Tong, P Uppal; citation_volume=7; citation_publication_date=2014; citation_pages=15; citation_doi=10.1186/1756-8722-7-15; citation_id=CR20"/> <meta name="citation_reference" content="citation_journal_title=Expert Opin Biol Ther; citation_title=Mesothelin-targeted CAR-T cell therapy for solid tumors; citation_author=A Klampatsa, V Dimou, SM Albelda; citation_volume=21; citation_publication_date=2021; citation_pages=473-486; citation_doi=10.1080/14712598.2021.1843628; citation_id=CR21"/> <meta name="citation_reference" content="citation_journal_title=Can Res; citation_title=Mesothelin-specific CAR T cells target ovarian cancer; citation_author=E Schoutrop, I El-Serafi, T Poiret, Y Zhao, O Gultekin, R He, L Moyano-Galceran, JW Carlson, K Lehti, M Hassan; citation_volume=81; citation_publication_date=2021; citation_pages=3022-3035; citation_doi=10.1158/0008-5472.CAN-20-2701; citation_id=CR22"/> <meta name="citation_reference" content="citation_journal_title=Biomarker Research; citation_title=Anti-mesothelin CAR T cell therapy for malignant mesothelioma; citation_author=L Castelletti, D Yeo, N Zandwijk, JEJ Rasko; citation_volume=9; citation_publication_date=2021; citation_pages=11; citation_doi=10.1186/s40364-021-00264-1; citation_id=CR23"/> <meta name="citation_reference" content="citation_journal_title=Trends Biotechnol; citation_title=Leveraging single-cell sequencing for chimeric antigen receptor T cell therapies; citation_author=R Castellanos-Rueda, RB Roberto, FS Schlatter, ST Reddy; citation_volume=39; citation_publication_date=2021; citation_pages=1308-1320; citation_doi=10.1016/j.tibtech.2021.03.005; citation_id=CR24"/> <meta name="citation_reference" content="citation_journal_title=Clin Cancer Res; citation_title=A humanized Lym-1 CAR with novel DAP10/DAP12 signaling domains demonstrates reduced tonic signaling and increased antitumor activity in B-cell lymphoma models; citation_author=L Zheng, L Ren, A Kouhi, LA Khawli, P Hu, HR Kaslow, AL Epstein; citation_volume=26; citation_publication_date=2020; citation_pages=3694-3706; citation_doi=10.1158/1078-0432.CCR-19-3417; citation_id=CR25"/> <meta name="citation_reference" content="citation_journal_title=Nat Rev Clin Oncol; citation_title=Chimeric antigen receptor T-cell therapy - assessment and management of toxicities; citation_author=SS Neelapu, S Tummala, P Kebriaei, W Wierda, C Gutierrez, FL Locke, KV Komanduri, Y Lin, N Jain, N Daver; citation_volume=15; citation_publication_date=2018; citation_pages=47-62; citation_doi=10.1038/nrclinonc.2017.148; citation_id=CR26"/> <meta name="citation_reference" content="citation_journal_title=Front Immunol; citation_title=CAR-T cell therapy: mechanism, management, and mitigation of inflammatory toxicities; citation_author=JW Fischer, N Bhattarai; citation_volume=12; citation_publication_date=2021; citation_pages=693016; citation_doi=10.3389/fimmu.2021.693016; citation_id=CR27"/> <meta name="citation_reference" content="citation_journal_title=Curr Hematol Malig Rep.; citation_title=CAR-T cell therapy: the efficacy and toxicity balance; citation_author=KL Chohan, EL Siegler, SS Kenderian; citation_volume=18; citation_publication_date=2023; citation_pages=9-18; citation_doi=10.1007/s11899-023-00687-7; citation_id=CR28"/> <meta name="citation_reference" content="citation_journal_title=Blood; citation_title=Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity; citation_author=L Fultang, S Booth, O Yogev, B Martins da Costa, V Tubb, S Panetti, V Stavrou, U Scarpa, A Jankevics, G Lloyd; citation_volume=136; citation_publication_date=2020; citation_pages=1155-1160; citation_doi=10.1182/blood.2019004500; citation_id=CR29"/> <meta name="citation_reference" content="citation_journal_title=Mol Ther; citation_title=Phase I study of lentiviral-transduced chimeric antigen receptor-modified T cells recognizing mesothelin in advanced solid cancers; citation_author=AR Haas, JL Tanyi, MH O'Hara, WL Gladney, SF Lacey, DA Torigian, MC Soulen, L Tian, M McGarvey, AM Nelson; citation_volume=27; citation_publication_date=2019; citation_pages=1919-1929; citation_doi=10.1016/j.ymthe.2019.07.015; citation_id=CR30"/> <meta name="citation_reference" content="citation_journal_title=Cancer Immunol Immunother; citation_title=Anti-mesothelin CAR-T immunotherapy in patients with ovarian cancer; citation_author=J Chen, J Hu, L Gu, F Ji, F Zhang, M Zhang, J Li, Z Chen, L Jiang, Y Zhang; citation_volume=72; citation_publication_date=2023; citation_pages=409-425; citation_doi=10.1007/s00262-022-03238-w; citation_id=CR31"/> <meta name="citation_reference" content="Xu T, Shu Y, et al. Characterization of mesothelin targeting novel multiple chain DAP-CAR-T cells efficacy in patients with ovarian cancer and mesothelioma through single-cell transcriptomic analysis. HRA006416. 2024. https://bigd.big.ac.cn ."/> <meta name="citation_reference" content="Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-Seq data. Github. https://github.com/rcastelo/GSVA ."/> <meta name="citation_reference" content="Efremova M, Vento-Tormo M, Teichmann S, Vento-Tormo R. CellphoneDB v2: inferring cell-cell communication from combined expression of multi-subunit receptor-ligand complexes. Github. https://github.com/ventolab/CellphoneDB ."/> <meta name="citation_author" content="Xu, Tongpeng"/> <meta name="citation_author_institution" content="Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China"/> <meta name="citation_author" content="Tian, Tian"/> <meta name="citation_author_institution" content="Department of Geriatric Hematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China"/> <meta name="citation_author" content="Wang, Chen"/> <meta name="citation_author_institution" content="Nanjing CART Medical Technology Co., Ltd, Nanjing, People’s Republic of China"/> <meta name="citation_author" content="Chen, Xiaofeng"/> <meta name="citation_author_institution" content="Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China"/> <meta name="citation_author" content="Zuo, Xiangrong"/> <meta 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We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma. Methods In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity. Results We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME. Conclusions Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma. Trial registration ChiCTR.org.cn, ChiCTR2100046544 . May 21, 2021."/> <meta property="og:image" content="https://static-content.springer.com/image/art%3A10.1186%2Fs13073-024-01405-5/MediaObjects/13073_2024_1405_Fig1_HTML.png"/> <script type="application/ld+json">{"mainEntity":{"headline":"Efficacy and safety of novel multiple-chain DAP-CAR-T cells targeting mesothelin in ovarian cancer and mesothelioma: a single-arm, open-label and first-in-human study","description":"Despite remarkable achievements in applying chimeric antigen receptor (CAR)-T cells to treat hematological malignancies, they remain much less effective against solid tumors, facing several challenges affecting their clinical use. We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma. In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity. We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME. Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma. ChiCTR.org.cn, \n ChiCTR2100046544\n \n . 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class="u-display-none">Fig. 3 | Genome Medicine</div><article><header class="u-mb-16"><h1 class="c-article-satellite-title u-h1" data-test="top-caption" id="Fig3">Fig. 3</h1><p class="c-article-satellite-subtitle">From: <a data-test="subtitle" data-article-title="true" data-track="click" data-track-action="back to article" data-track-label="link" data-track-category="figure" href="/articles/10.1186/s13073-024-01405-5">Efficacy and safety of novel multiple-chain DAP-CAR-T cells targeting mesothelin in ovarian cancer and mesothelioma: a single-arm, open-label and first-in-human study</a></p></header><div class="c-article-figure-content"><figure data-test="figure"><div class="c-article-figure-content-image"><div class="c-article-figure-content-image-inline"><picture><source type="image/webp" srcset="//media.springernature.com/full/springer-static/image/art%3A10.1186%2Fs13073-024-01405-5/MediaObjects/13073_2024_1405_Fig3_HTML.png?as=webp"><img aria-describedby="Fig3" 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The pharmacokinetics of KT032 cells in patients’ peripheral blood were assessed using qPCR and flow cytometry. <b>B</b> ELISA analysis of IFN-γ levels in patients’ peripheral blood. <b>C</b> ELISA analysis of TNFα levels in patients’ peripheral blood. <b>D</b> ELISA analysis of IL-2 levels in patients’ peripheral blood. <b>E</b> ELISA analysis of IL-4 levels in patients’ peripheral blood. <b>F</b> ELISA analysis of IL-6 levels in patients’ peripheral blood. <b>G</b> ELISA analysis of IL-10 levels in patients’ peripheral blood</p></div><div class="c-article-figure-button-container hide-print"><a class="c-article__pill-button" data-test="back-link" data-track="click" data-track-action="back to article" data-track-label="button" data-track-category="figure" href="/articles/10.1186/s13073-024-01405-5#Fig3"><span>Back to article page</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" 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