IMMU-45. CAR-T TREATMENT OF NOVEL MOUSE MODEL OF EGFRVIII+ GBM MIRRORS CLINICAL TRIAL OUTCOMES AND PROVIDES A SYNGENEIC PLATFORM FOR THE INVESTIGATION OF CAR-T MECHANISMS OF ACTION

Abstract

Abstract Despite the recent successes in cancer immunotherapy, brain tumors continue to present a significant challenge due to the unique relationship between the CNS and the immune system. Adoptive cell transfer of chimeric antigen receptor T-cells (CAR-T cells) targets tumor-associated and tumor-specific antigens. Multiple clinical trials testing CAR-T cells in the brain tumor setting have demonstrated the feasibility and safety, but also highlighted the limitations and continued need for treatment improvement. These challenges include recurrence of tumor cells that do not express the target antigens and induction of immuno-regulatory mechanisms, such as PD-L1 expression within the tumor. In this study, we used a murine GBM cell line (SB28), engineered to express the tumor-specific neoantigen human epidermal growth factor receptor variant III, to study the in vivo effects of EGFRvIII-CAR T-cells in a novel fully immunocompetent mouse model. SB28 cells have been shown to recapitulate key characteristics of human GBM, such as aggressive growth, low mutation burden, and resistance to immune checkpoint blockade therapy, and therefore, allow us to investigate many clinically relevant questions and variations in treatment protocol. Intravenous administration of CAR-transduced murine T-cells in EGFRvIII-expressing SB28 tumors showed survival benefit only when preceded by a lymphodepleting regimen. Despite prolonging survival, EGFRvIII-CAR-T cells were not curative, and the recurrent tumors displayed profound antigen loss, similar to post-treatment human tumor samples. Preliminary mechanistic studies revealed upregulation of IFNγ-inducible molecules, such as PD-L1 on tumor cells and tumor-infiltrating myeloid cells, as well as the emergence of a small, but discreet population of activated antigen presenting cells. Currently ongoing studies are aimed at delineating the exact molecular and cellular changes in the tumor microenvironment in response to the EGFRvIII-CAR T-cell treatment, in combination with clinically relevant therapies targeting the largely immunosuppressive tumor myeloid compartment