Abstract ROR1 (Receptor tyrosine kinase-like Orphan Receptor 1) is a tumor-associated antigen widely expressed in solid tumors and is a promising target for CAR T cell therapy in pancreatic cancer. Cell-based immunotherapy has met with limited success due in part to the immunosuppressive tumor microenvironment (TME). Here we demonstrate that armoring our previously described1 ROR1 CAR T cell product with interleukin-18 (IL18) enhanced expansion, persistence, and antitumor efficacy against pancreatic cell lines both in vitro and in vivo. ROR-1-specific CAR-T cells were generated in human T cells using lentiviral vectors (LV) expressing a second generation CAR alone, CAR+ constitutive IL-18, or CAR+NFAT-IL18. IL18-ROR1 CAR T cells expanded 1.5 fold more, preserved naïve phenotype, and had reduced LAG3 expression (37% vs 81%) vs CAR. In vitro armored CAR cytotoxicity, determined by xCelligence tumor co-culture assays, was equal to or greater than CAR alone against ROR1(+) tumor cell lines. In an AsPC-1 mouse xenograft model, each CAR construct exhibited anti-tumor efficacy, with IL-18 expressing CARs displaying significantly greater tumor control. The constitutive IL18-CAR completely cleared tumor at day 28 post-T cell infusion and showed increased persistence throughout the study when compared to ROR1 CAR-T lacking IL-18 (Fig.1). CAR+NFAT-IL18 similarly controlled tumor growth compared to UTD. In summary, IL18 armored CAR T cells significantly improved the expansion, persistence, and antitumor efficacy of ROR1 CARs in pancreatic cancer xenograft models. Importantly, NFAT-promoter-based regulation of ROR1 CAR T may offer a viable approach to regulating potential toxicity while retaining boosted IL-18 induced activity. This armoring strategy may offer a promising approach solid tumor indications and warrants further preclinical and translational investigation. Reference: 1. Tran TM et al. J Immunother Cancer 2024;12(4) Citation Format: Bal Krishna Chand Thakuri, Saule Nurmukhambetova, Tri Tran, Ngoc Tran, Peirong Hu, Pradyot Dash, Rimas J Orentas, Alun Carter, . Armoring ROR1 CAR T cells with IL18 improves CAR T cell function and cytotoxicity against pancreatic cancer cell-lines in vitro and in vivo abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4281.
Thakuri et al. (Fri,) studied this question.