{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T21:59:58Z","timestamp":1793915998386,"version":"4.8.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T00:00:00Z","timestamp":1690329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82073337"],"award-info":[{"award-number":["82073337"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Claudin 18.2 (CLDN18.2)-targeting chimeric antigen receptor (CAR)-modified T cells are one of the few cell therapies currently producing an impressive therapeutic effect in treating solid tumors; however, their long-term therapeutic efficacy is not satisfactory with a short duration of response. Transgenic expression of interleukin (IL)-15 has been reported to promote T-cell expansion, survival, and function and enhance the antitumor activity of engineered T cells <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Therefore, this study aimed to explore whether IL-15 modification would increase the antitumor activity of CLDN18.2-targeting CAR-modified T (CAR-T) cells in immunocompetent murine tumor models. CLDN18.2-specific CAR-T cells with (H9 CAR-IL15) or without transgenic IL-15 expression (H9 CAR) were generated by retroviral transduction of mouse splenic T cells. <jats:italic>In vitro<\/jats:italic>, compared with H9 CAR T cells, H9 CAR-IL15 T cells exhibited better expansion and viability in the absence of antigen stimulation, with a less differentiated and T-cell exhausted phenotype; although IL-15 modification did not affect the production of effector cytokines and cytotoxic activity in the short-term killing assay, it moderately improved the <jats:italic>in vitro<\/jats:italic> recursive killing activity of CAR-T cells against CLDN18.2-expressing tumor cells. <jats:italic>In vivo<\/jats:italic>, H9 CAR T cells showed no antitumor activity against CLDN18.2-expressing pancreatic tumors in immunocompetent mice without lymphodepleting pretreatment; however, H9 CAR-IL15 T cells produced significant tumor-suppressive effects. Furthermore, H9 CAR-IL15 T cells exhibited greater <jats:italic>in vivo<\/jats:italic> expansion and tumor infiltration when combined with lymphodepleting preconditioning, resulting in superior antitumor activity in two murine tumor models and a survival advantage in one tumor model. We further demonstrated that recurrent tumors following H9 CAR-IL15 T-cell therapy downregulated CLDN18.2 expression, suggesting immune escape through the selection of antigen-negative cells under persistent CAR-T-cell immune pressure. In conclusion, our findings provide preclinical evidence supporting the clinical evaluation of IL-15-expressing CLDN18.2 CAR-T cells in patients with CLDN18.2-positive tumors.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1165404","type":"journal-article","created":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T08:33:06Z","timestamp":1690360386000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":35,"title":["IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models"],"prefix":"10.3389","volume":"14","author":[{"given":"Hongtai","family":"Shi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiao","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyuan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaisong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huafeng","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songbing","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2116","DOI":"10.3390\/cancers12082116","article-title":"Molecular bases of mechanisms accounting for drug resistance in gastric adenocarcinoma","volume":"12","author":"Marin","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095-3941.2019.0252","article-title":"The challenge of drug resistance in pancreatic ductal adenocarcinoma: a current overview","volume":"16","author":"Quinonero","year":"2019","journal-title":"Cancer Biol Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S149619","article-title":"Gastric cancer: epidemiology, prevention, classification, and treatment","volume":"10","author":"Sitarz","year":"2018","journal-title":"Cancer Manag Res"},{"key":"B5","doi-asserted-by":"publisher","first-page":"10","DOI":"10.14740\/wjon1166","article-title":"Epidemiology of pancreatic cancer: global trends, etiology and risk factors","volume":"10","author":"Rawla","year":"2019","journal-title":"World J Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-021-00329-9","article-title":"Genetic engineering of T cells for immunotherapy","volume":"22","author":"Ellis","year":"2021","journal-title":"Nat Rev Genet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s40364-022-00385-1","article-title":"Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy","volume":"10","author":"Cao","year":"2022","journal-title":"biomark Res"},{"key":"B8","unstructured":"Astellas Announces Zolbetuximab Meets Primary Endpoint in Phase 3 SPOTLIGHT Trial as First-Line Treatment in Claudin 18.2 Positive, HER2-Negative Locally Advanced or Metastatic Gastric and Gastroesophageal Junction (GEJ) Cancers"},{"key":"B9","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/s41571-022-00704-3","article-title":"Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours","volume":"20","author":"Flugel","year":"2023","journal-title":"Nat Rev Clin Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djy134","article-title":"Claudin18.2-specific chimeric antigen receptor engineered T cells for the treatment of gastric cancer","volume":"111","author":"Jiang","year":"2019","journal-title":"J Natl Cancer Inst"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01800-8","article-title":"Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results","volume":"28","author":"Qi","year":"2022","journal-title":"Nat Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.684642","article-title":"Engineered cytokine signaling to improve CAR T cell effector function","volume":"12","author":"Bell","year":"2021","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-0777","article-title":"Coexpression of IL7 and CCL21 increases efficacy of CAR-T cells in solid tumors without requiring preconditioned lymphodepletion","volume":"26","author":"Luo","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-1811","article-title":"Eradication of neuroblastoma by T cells redirected with an optimized GD2-specific chimeric antigen receptor and interleukin-15","volume":"25","author":"Chen","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-16-0376","article-title":"Transgenic expression of IL15 improves antiglioma activity of IL13Ralpha2-CAR T cells but results in antigen loss variants","volume":"5","author":"Krenciute","year":"2017","journal-title":"Cancer Immunol Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2010.75","article-title":"Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma\/leukemia effects and safety","volume":"24","author":"Hoyos","year":"2010","journal-title":"Leukemia"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-19-0293","article-title":"Glypican-3-specific CAR T cells coexpressing IL15 and IL21 have superior expansion and antitumor activity against hepatocellular carcinoma","volume":"8","author":"Batra","year":"2020","journal-title":"Cancer Immunol Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001229","article-title":"Modulating TNFalpha activity allows transgenic IL15-Expressing CLL-1 CAR T cells to safely eliminate acute myeloid leukemia","volume":"8","author":"Ataca Atilla","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20192203","article-title":"Optimized gene engineering of murine CAR-T cells reveals the beneficial effects of IL-15 coexpression","volume":"218","author":"Lanitis","year":"2021","journal-title":"J Exp Med"},{"key":"B20","volume-title":"Anti-claudin18.2 antibody and use thereof.","author":"Zhou","year":"2021"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzz027","article-title":"P329G-CAR-J: a novel Jurkat-NFAT-based CAR-T reporter system recognizing the P329G Fc mutation","volume":"32","author":"Darowski","year":"2019","journal-title":"Protein Eng Des Sel"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2021.02.024","article-title":"Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity","volume":"29","author":"Murad","year":"2021","journal-title":"Mol Ther"},{"key":"B23","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.ccell.2020.11.005","article-title":"Immunogenic chemotherapy enhances recruitment of CAR-T cells to lung tumors and improves antitumor efficacy when combined with checkpoint blockade","volume":"39","author":"Srivastava","year":"2021","journal-title":"Cancer Cell"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2017.08.010","article-title":"The potential and promise of IL-15 in immuno-oncogenic therapies","volume":"190","author":"Robinson","year":"2017","journal-title":"Immunol Lett"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.11.7226","article-title":"Primary human T lymphocytes engineered with a codon-optimized IL-15 gene resist cytokine withdrawal-induced apoptosis and persist long-term in the absence of exogenous cytokine","volume":"175","author":"Hsu","year":"2005","journal-title":"J Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1186\/s12967-022-03626-x","article-title":"Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy","volume":"20","author":"Zhang","year":"2022","journal-title":"J Transl Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.880108","article-title":"Transgenic expression of IL15 retains CD123-redirected T cells in a less differentiated state resulting in improved anti-AML activity in autologous AML PDX models","volume":"13","author":"Mu-Mosley","year":"2022","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-09-241398","article-title":"IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell-mediated rejection of systemic lymphoma in immunodeficient mice","volume":"115","author":"Markley","year":"2010","journal-title":"Blood"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-02-072843","article-title":"Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes","volume":"110","author":"Quintarelli","year":"2007","journal-title":"Blood"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018028332","article-title":"First-in-human trial of rhIL-15 and haploidentical natural killer cell therapy for advanced acute myeloid leukemia","volume":"3","author":"Cooley","year":"2019","journal-title":"Blood Adv"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-3468","article-title":"IL15 by continuous intravenous infusion to adult patients with solid tumors in a phase I trial induced dramatic NK-cell subset expansion","volume":"25","author":"Conlon","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00607-3","article-title":"Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion","volume":"19","author":"Amini","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2022-005187","article-title":"GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma","volume":"10","author":"Gargett","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.6435","article-title":"Interleukin-15 promotes angiogenesis in vivo","volume":"233","author":"Angiolillo","year":"1997","journal-title":"Biochem Biophys Res Commun"},{"key":"B35","article-title":"Production of interleukin 15 by human colon cancer cells is associated with induction of mucosal hyperplasia, angiogenesis, and metastasis","volume":"9","author":"Kuniyasu","year":"2003","journal-title":"Clin Cancer Res"},{"key":"B36","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.omtm.2022.08.008","article-title":"Applying a clinical lens to animal models of CAR-T cell therapies","volume":"27","author":"Duncan","year":"2022","journal-title":"Mol Ther Methods Clin Dev"},{"key":"B37","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.omto.2017.12.003","article-title":"CD19 CAR T cells expressing IL-12 eradicate lymphoma in fully lymphoreplete mice through induction of host immunity","volume":"8","author":"Kueberuwa","year":"2018","journal-title":"Mol Ther Oncolytics"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4086","article-title":"IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor","volume":"36","author":"Adachi","year":"2018","journal-title":"Nat Biotechnol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910607","article-title":"Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors","volume":"382","author":"Liu","year":"2020","journal-title":"N Engl J Med"},{"key":"B40","year":""}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1165404\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T08:33:14Z","timestamp":1690360394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1165404\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,26]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2023.1165404"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1165404","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,26]]},"article-number":"1165404"}}