Chimeric antigen receptor (CAR) T cells have been successfully used to treat B cell malignancies, but faces many obstacles in solid tumors. A major challenge is the immune-suppressive effects induced by PD-L1 expression in tumors and CD80/86 that ligate with CTLA-4 and are expressed in myeloid-derived immune suppressive cells. Dual blockade of PD-1 and CTLA-4 with monoclonal antibodies has achieved promising anti-tumor effects in clinics. Here, we designed two switch receptor constructs. One contains the truncated extracellular domain of human PD1, costimulatory domains of 4-1BB and TLR2, and the CD3z signaling domain (cPD-1). cPD-1 T cells specifically lysed PD-L1+ tumor cell lines and augmented cytokine secretion in vitro. In addition, cPD-1 T cells were able to suppress the growth of lung cancer, gastric cancer, and osteosarcoma in xenografts. The other construct, similarly, is composed of the truncated extracellular domain of murine Ctla4, human CD28, TLR2, and CD3z signaling domains (cmCtla-4). Because CD80/CD86 are expressed in murine myeloid cells rather than human tumor cells in PDX models, cmCtla4 T cells targeted mouse myeloid cells that were abundant in tumors but not human tumor cells. We found that cmCtla4 T cells hindered tumor growth in gastric cancer PDX. In combination, cPD-1 and cmCtla4 T cells synergistically induced superior anti-tumor effects in lung cancer PDX. Taken together, our findings demonstrated the anti-tumor function of switched immune checkpoint receptors and revealed a strategy of combining T cells targeting both tumor cells and tumor microenvironment, promoting clinical investigation of these chimeric switch-receptor T cells for cancer treatment.

Citation Format: Peng Li, Le Qin, Xinru Wei, Ruocong Zhao, Yunxin Lai. A combination of chimeric switch-receptor T cells targeting both PD1 and CTLA4 suppresses tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3564.