Abstract A018: Sitagliptin potentiates glioblastoma tumor cell killing by EGFRvIII-targeting CAR T cells

Abstract Glioblastoma (GBM) is a grade IV glioma with a high incidence rate and limited survival outcome. Historically, chimeric antigen receptor (CAR) T cell therapy has been shown to be an effective treatment for hematological malignancies. However, in solid tumors, such as glioblastoma, CAR T cell therapy has been less successful due to the heterogeneous composition of GBM and the immunosuppressive tumor microenvironment. One approach to address T cell exhaustion and lack of persistence is to use adjuvant enhancers that may be able to increase CAR T cell efficiency. Sitagliptin is a drug that has primarily been used as a treatment for type II diabetes; however, it may also be effective in targeting glioma cells through enhancing T cell activity via dipeptidyl peptidase 4 (DPP4) inhibition. DPP4 can limit dendritic cell (DC) activity by breaking down chemokines and cytokines, while sitagliptin offers the potential to prevent these molecules from being degraded. This could increase DC activity and allow for greater activation of T cells. As combination therapies have been shown to be effective at addressing the heterogeneity of GBM, this study utilized CAR T cells with the addition of the sitagliptin drug. U87MG cells were engineered to express the EGFR variant III (EGFRvIII) protein, green fluorescent protein, and click beetle green luciferase protein. An EGFRvIII-targeting CAR, 2173 41BBz CAR, was lentivirally transduced in T cells obtained from a healthy donor. Impedance cytotoxicity assays were carried out on the Axion Biosystems ZHT analyzer using U87vIII target cells, 2173 41BBz CAR T cells, and three varying doses of sitagliptin: 50uM, 100uM, and 200uM. Combination treatment across all doses produced a synergistic effect against U87vIII tumor cell killing, with the greatest cytotoxicity observed for the 200uM dose of sitagliptin. At 24 hours post CAR T cell addition, target cells treated with sitagliptin at a dose of 200uM showed a ∼92% cytolysis with a p-value of 0.0010. Future research will focus on the mechanism of sitagliptin’s actions, starting by evaluating cytokine levels as an indication of enhanced T cell activity. Collectively, these findings suggest that sitagliptin may improve cytotoxicity against a larger portion of the heterogeneous glioblastoma tumor, potentially through increased activation of T cells. Citation Format: Laura O'Sullivan, Payal Grover, Sydney Dumont, Oriana Teran Pumar, Defne Bayik, Donald M. O'Rourke, Zev A. Binder. Sitagliptin potentiates glioblastoma tumor cell killing by EGFRvIII-targeting CAR T cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A018.