IL-15 装甲增强靶向 claudin 18.2 的 CAR-T 细胞在同系小鼠肿瘤模型中的抗肿瘤疗效

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.