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IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models

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. Tra...

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Autores principales: Shi, Hongtai, Li, Andi, Dai, Zhenyu, Xue, Jiao, Zhao, Qi, Tian, Jiyuan, Song, Dandan, Wang, Hao, Chen, Jianan, Zhang, Xiaokang, Zhou, Kaisong, Wei, Huafeng, Qin, Songbing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10410263/
https://www.ncbi.nlm.nih.gov/pubmed/37564658
http://dx.doi.org/10.3389/fimmu.2023.1165404
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author Shi, Hongtai
Li, Andi
Dai, Zhenyu
Xue, Jiao
Zhao, Qi
Tian, Jiyuan
Song, Dandan
Wang, Hao
Chen, Jianan
Zhang, Xiaokang
Zhou, Kaisong
Wei, Huafeng
Qin, Songbing
author_facet Shi, Hongtai
Li, Andi
Dai, Zhenyu
Xue, Jiao
Zhao, Qi
Tian, Jiyuan
Song, Dandan
Wang, Hao
Chen, Jianan
Zhang, Xiaokang
Zhou, Kaisong
Wei, Huafeng
Qin, Songbing
author_sort Shi, Hongtai
collection PubMed
description 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 in vitro and in vivo. 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. In vitro, 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 in vitro recursive killing activity of CAR-T cells against CLDN18.2-expressing tumor cells. In vivo, 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 in vivo 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.
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spelling pubmed-104102632023-08-10 IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models Shi, Hongtai Li, Andi Dai, Zhenyu Xue, Jiao Zhao, Qi Tian, Jiyuan Song, Dandan Wang, Hao Chen, Jianan Zhang, Xiaokang Zhou, Kaisong Wei, Huafeng Qin, Songbing Front Immunol Immunology 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 in vitro and in vivo. 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. In vitro, 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 in vitro recursive killing activity of CAR-T cells against CLDN18.2-expressing tumor cells. In vivo, 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 in vivo 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. Frontiers Media S.A. 2023-07-26 /pmc/articles/PMC10410263/ /pubmed/37564658 http://dx.doi.org/10.3389/fimmu.2023.1165404 Text en Copyright © 2023 Shi, Li, Dai, Xue, Zhao, Tian, Song, Wang, Chen, Zhang, Zhou, Wei and Qin https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). 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.
spellingShingle Immunology
Shi, Hongtai
Li, Andi
Dai, Zhenyu
Xue, Jiao
Zhao, Qi
Tian, Jiyuan
Song, Dandan
Wang, Hao
Chen, Jianan
Zhang, Xiaokang
Zhou, Kaisong
Wei, Huafeng
Qin, Songbing
IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models
title IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models
title_full IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models
title_fullStr IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models
title_full_unstemmed IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models
title_short IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models
title_sort il-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting car-t cells in syngeneic mouse tumor models
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10410263/
https://www.ncbi.nlm.nih.gov/pubmed/37564658
http://dx.doi.org/10.3389/fimmu.2023.1165404
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