Abstract 4070: Engineering TRAIL-expressing immune cells to target GI malignancies

Abstract

Abstract While adoptive cell therapies, such as chimeric antigen receptor (CAR) T cells, have had promising results in hematologic malignancies, their translation to solid tumors has been mostly unsuccessful. A significant limitation to use of adoptive cell therapy in solid tumors has been life-threatening off-target toxicities, including acute respiratory toxicity and cytokine release syndrome. The native T cell program releases a diverse range of toxic proteins upon activation, including interferons, interleukins, perforins, and granzymes. Rather than activate the native T-cell program, selective expression of tumor-targeting agents may be advantageous. TNF-related apoptosis-inducing ligand (TRAIL) is known to selectively target tumor cells with minimal toxicity to normal tissues. We therefore engineered Jurkat (a human CD4+ T cell leukemia cell line) and THP-1 (a human monocytic leukemia cell line) cells to constitutively express wild-type TRAIL using a third-generation lentivirus system. These cells killed multiple cell lines across colorectal and pancreatic cancer, thus representing a possible therapeutic strategy to target GI malignancies. Furthermore, the addition of the ferroptosis induced erastin enhanced cytotoxicity of TRAIL-engineered cells, suggesting that targeting ferroptosis in addition to apoptosis is a promising strategy for enhancing immune killing. Future work will focus on overcoming TRAIL resistance, tumor trafficking, and alteration of the tumor microenvironment. Citation Format: Praveen R. Srinivasan, Shengliang Zhang, Wafik S. El-Deiry. Engineering TRAIL-expressing immune cells to target GI malignancies. [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 4070.