4-1BB-Based CAR T Cells Effectively Reverse Exhaustion and Enhance the Anti-Tumor Immune Response through Autocrine PD-L1 scFv Antibody

Abstract

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.

The synergistic immunotherapeutic impact of engineered CAR-T cells with PD-1 blockade in lymphomas and solid tumors: a systematic review

“…However, the application of CAR-T cell therapy for solid tumors poses significant challenges, including tumor infiltration and trafficking difficulties, cytokine release syndrome, on-target offtumor toxicity, and T-cell exhaustion within the complex tumor microenvironment (38,(169)(170)(171)(172).Till date, various types of combination immunotherapies have been studied, such as CAR-T cell with anti PD-L1 (173), double immune checkpoint inhibitor therapy such as anti PD-1/PD-L1 plus anti-CTLA-4 (174), and CAR-T cells with anti PD-1 (175). In a study by Cheng et al (2023) combination of 4-1BB CAR-T and autocrine anti PD-L1 scFv improved the anti-tumor response of CAR-T cells along with improved persistence. However, the study was conducted in a mouse xenograft model and needs to be conducted in clinical patients for a better assessment of actual outcomes (176).…”

“…In a study by Cheng et al (2023) combination of 4-1BB CAR-T and autocrine anti PD-L1 scFv improved the anti-tumor response of CAR-T cells along with improved persistence. However, the study was conducted in a mouse xenograft model and needs to be conducted in clinical patients for a better assessment of actual outcomes (176). The double checkpoint blockade strategy, particularly the combination of nivolumab (anti-PD-1 mAb) and ipilimumab (anti-CTLA-4), received FDA approval in October 2020 as a first-line treatment option (145), a meta-analysis by Zhao et al (2022) revealed that five out of the ten patients receiving nivolumab in addition to ipilimumab experienced at least one grade ≥ 3 adverse event, and approximately nine of the ten patients experienced at least one adverse event.…”

Chimeric Antigen Receptor T-Cell Therapy for Glioblastoma

“…Additionally, CAR T cells can secrete PD-L1 single-chain antibodies that block PD-1/PD-L1 signaling in vitro and in NCG mouse xenograft cancer models, thereby enhancing the antitumor activity in solid tumors. Furthermore, in vivo autocrine PD-L1 single-chain antibodies greatly reduce CAR T-cell depletion [62].…”