基于 4-1BB 的 CAR-T 细胞通过自分泌 PD-L1 scFv 抗体有效逆转耗竭并增强抗肿瘤免疫反应

Exhaustion of chimeric antigen receptor (CAR) T cells is one of the limitations for CAR T efficacy in solid tumors and for tumor recurrence after initial CAR T treatment. Tumor treatment with a combination of programmed cell death receptor-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockage and CD28-based CAR T cells has been intensively studied.

However, it remains largely unclear whether autocrine single-chain variable fragments (scFv) PD-L1 antibody can improve 4-1BB-based CAR T cell anti-tumor activity and revert CAR T cell exhaustion.

Here, we studied T cells engineered with autocrine PD-L1 scFv and 4-1BB-containing CAR. The antitumor activity and exhaustion of CAR T cells were investigated in vitro and in a xenograft cancer model using NCG mice. CAR T cells with autocrine PD-L1 scFv antibody demonstrate enhanced anti-tumor activity in solid tumors and hematologic malignancies by blocking the PD-1/PD-L1 signaling.

Importantly, we found that CAR T exhaustion was largely diminished by autocrine PD-L1 scFv antibody in vivo. As such, 4-1BB CAR T with autocrine PD-L1 scFv antibody combined the power of CAR T cells and the immune checkpoint inhibitor, thereby increasing the anti-tumor immune function and CAR T persistence, providing a cell therapy solution for a better clinical outcome.