786 Evaluation of the immunomodulatory effects of radiation for chimeric antigen receptor T Cell therapy in glioblastoma multiforme

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Background Standard of care treatment for Glioblastoma (GBM) is comprised of surgery and adjuvant chemoradiation. Chimeric Antigen Receptor (CAR) T cell therapy against GBM has demonstrated disease modifying activity in GBM and holds great promise; however, immune-suppressive tumor microenvironment has been identified as a barrier to translation. Radiation has well-known immuno-modulatory properties and may overcome this barrier but radiation dose optimization and integration with CAR T cell therapy is not well understood. Methods The aim of this study was to leverage a murine immunocompetent model of GBM and CAR T cells in order to (1) identify the optimum neoadjuvant radiation dose that conditions the TME, (2) evaluate potential synergy of combination treatment and (3) evaluate potential mechanisms of combined effect. Results In this study, using an immunocompetent syngeneic GBM model, we reveal a dose dependent immunomodulatory effect of radiation, demonstrating that a conditioning dose of 10 Gy activates innate and adaptive tumor-immune microenvironment more effectively than 5 or 20 Gy. The conditioning dose of radiation synergized with CAR T therapy. Additionally, mice treated with 10 Gy in combination with murine IL13Ra2-targeted CAR T cells (mCAR T) demonstrated superior anti-tumor response to mIL13Ra2 positive tumor rechallenge when compared to mice cured with mCAR T cells alone. We have observed that both 10 Gy and mCAR T cell treated tumor bearing mice activate innate and adaptive immune pathways in the tumor microenvironment. Furthermore, tumor rejection after tumor re-challenge was in part c-GAS-STING pathway dependent as STING-/- mice rechallenge tumor did not mount a strong tumor rejection compared to wildtype. Conclusions Together, these findings support combination conditioning low-dose 10 Gy radiation and CAR T cells as a GBM therapeutic strategy. Further, both radiation and CAR T activate innate and adaptive immune pathways in the TME, and result in improved tumor rejection compared to CAR T alone after tumor re-challenge, which we show is partly STING dependent.

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