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

Frontiers in Immunology

Immunology

Zhenyu Dai¹  Qi Zhao²  Xiaokang Zhang²  Jiao Xue²  Songbing Qin²  Hongtai Shi³  Hao Wang⁴  Dandan Song⁴  Andi Li⁵  Jiyuan Tian⁵  Jianan Chen⁵  Huafeng Wei⁶  Kaisong Zhou⁶ 

[1] Department of Radiology, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People’s Hospital, Yancheng, China;Department of Radiotherapy, The First Affiliated Hospital of Soochow University, Suzhou, China;Department of Radiotherapy, The First Affiliated Hospital of Soochow University, Suzhou, China;Department of Radiation Oncology, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People’s Hospital, Yancheng, China;Innovent Biologics, Inc., Suzhou, China;Innovent Cells Pharmaceuticals, Inc., Suzhou, China;Innovent Cells Pharmaceuticals, Inc., Suzhou, China;Innovent Biologics, Inc., Suzhou, China;

关键词: claudin 18.2;    CAR T cells;    IL-15;    solid tumor;    cellular therapy;   

DOI  :  10.3389/fimmu.2023.1165404

 received in 2023-02-14, accepted in 2023-07-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

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Copyright © 2023 Shi, Li, Dai, Xue, Zhao, Tian, Song, Wang, Chen, Zhang, Zhou, Wei and Qin