Abstract 5569: CAR-T cells with αPDL1/CD28 switch-receptor synergize radiotherapy and anti-PD1 therapy in solid tumors

Abstract

Abstract The therapeutic efficacy of CAR-T cells in solid tumors, unlike in hematologic tumor, is greatly limited by the insufficient infiltration and persistence of CAR-T cells as well as the immunosuppressive tumor microenvironment. The aim of this study was to overcome these obstacles by introducing an αPDL1/CD28 switch-receptor construct and by seeking combinatorial strategies for CAR-T cells in solid tumors. We found that in non-transduction T cells, the cytokine release and T cell proliferation were repressed in response to PD-L1 protein, while T cells that express αPDL1/CD28 switch-receptor showed enhanced functions, indicating that αPDL1/CD28 could revert PD-L1 inhibition into CD28 costimulation. CAR-T cells with αPDL1/CD28 switch-receptor showed better effector function than that of unitary CAR-T in vitro studies and significant responses in tumor-bearing mice, with more effector memory T cells infiltrated in the tumor. On this basis, PD-1 inhibitor can further enhance the efficacy and persistence of αPDL1/CD28 CAR-T cells, especially in PDL1+ tumor models. We found in vitro studies that radiotherapy increased the expression of T-cell recruiting chemokines and promoted CAR-T cell transmigration. In tumor-bearing mice, synergistic anti-tumor efficacy of mice treated with radiotherapy and αPDL1/CD28 CAR-T cells was further observed. Finally, triple therapy with radiotherapy and anti-PD1 plus αPDL1/CD28 CAR-T cells maximized antitumor responses and induced complete cures in the tumor-bearing mice. Our study suggests that αPDL1/CD28 augments the function of CAR-T cells, and the combinatorial regime of αPDL1/CD28 CAR-T cells, radiotherapy and anti-PD1 in solid tumors could be further investigated. Citation Format: Limei Yin, Wenbo Wang, Zhuoran Yao, Jianxin Xue, Ruizhan Tong, Hui Wang, Shuangsi Liao, Laduona Wang, Yue Zheng, Feifei Na, Min Yu, Xuanwei Zhang, Youling Gong, Meijuan Huang, Xianming Mo, Chong Chen, You Lu. CAR-T cells with αPDL1/CD28 switch-receptor synergize radiotherapy and anti-PD1 therapy in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5569.