Abstract 889: The efficacy and safety of PD-L1-specific CAR-T in advanced gastric cancer

Abstract [Purpose] Heterogeneity and the tumor microenvironment are major obstacles to overcoming incurable advanced gastric cancer (AGC). Although Epstein-Barr virus-positive and microsatellite instability subtypes can be detected early and properly treated, they are rare in AGC. In this regard, recent combinational therapy of immune checkpoint inhibitors (ICIs) such as PD-1/PD-L1 inhibitors and other various therapeutics has been tried, but there are clinically limited doses and drug resistance. We hypothesized that CAR-T targeting PD-L1, the common tumor-associated antigen (TAA), which expresses in most advanced cancer cells, would make a significant breakthrough in curing a solid tumor. This study aimed to evaluate the killing effects of anti-PD-L1 CAR-T against gastric cancer cell lines. Removal of PD-L1-expressing cells in the AGC TME will improve the clinical outcomes of current therapies. [Results] We constructed a second-generation PD-L1 CAR lentiviral vector targeting PD-L1, which has an intermediate affinity with PD-L1 in solid tumor TME. As the secondary signaling motif, CD28 was chosen and tested along with the CD3 zeta chain. The effector CAR-T, named Vax-CAR-T, specifically recognized the PD-L1-expressing AGC cell line, SNU638, and exhibited rapid and robust cytotoxic activity in vitro. When compared to untransduced T cells, the level of the CD25 activation marker was higher in Vax-CAR-T cells. Besides, the inhibitory markers of Tim3 and LAG3 were expressed even higher than the untransduced. Despite high Tim3 and LAG3 expression in the final manufacturing process, Vax-CAR-T cells significantly suppressed tumor growth in both bigger (>95mm3) and smaller (≤50mm3) AGC xenograft NSG mouse models. More importantly, Vax-CAR-T-treated mice have well tolerated the CAR-T therapy with no significant adverse events during the CRS monitoring period, 2 weeks after Vax-CAR-T injection and have gradually recovered weight gains 5 days after CAR-T cell injection. [Conclusion] We believe that a new autologous CAR-T targeting PD-L1 could be a promising new tool for removing heterogeneous solid tumors in TME, which would be a significant step forward in improving current conventional and immunotherapeutic strategies. Citation Format: Hye-Seong Park, Eun-Ji Choi, Jae-In Yu, Kyung-Sik Lee, Yeo-Jin Lim, Se-Ryeong Choi, Yoonjoo Choi, Bum Chan Park, Jae Eun Park, Mihwa Kim, Je-Jung Lee, Joon Haeng Rhee. The efficacy and safety of PD-L1-specific CAR-T in advanced gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 889.