Authors: Chibawanye Ene, MD, PhD; Shannon Kreuser; Miyeon Jung; Ian Parney; Courtney Crane; Eric Holland (Seattle, WA)

Introduction Immunotherapy for glioblastoma have been largely unsuccessful, in part, because molecular heterogeneity drives selective elimination of only a subset of tumor cells. Therefore, therapeutic success in patients will require achieving an ‘abscopal effect’ where following focused radiation therapy, non-targeted tumor cells are attacked by the immune system. It remains unclear how glioblastoma respond to focused radiation in terms of failure location and whether immunotherapy could amplify the immune response to tumor outside the radiation field. Methods We evaluated patterns of treatment failure and outcomes in glioblastoma patients receiving stereotactic radiosurgery (SRS; N=47). To optimize the abscopal effect, we developed a genetically-engineered mouse model of bilateral glioblastoma. Here, one side of the mouse brain has a tumor treated by focal radiation and the contralateral untreated tumor is used as a readout of abscopal therapeutic efficacy following anti-PD-L1 immunotherapy. Results In glioblastoma patients receiving SRS, increasing age (>60 years) as associated with more ‘out of field’ treatment failure (P=0.036) and poor survival (P=0.001). In mice, we find that focal radiation of one tumor combined with anti-PD-L1 immunotherapy induced an immunological response against tumor cells outside the radiation field and enhanced survival (P<0.05). Significant macrophage and T-cell infiltration occurred in mesenchymal subtype-like tumors (N=6-8 mice per group, P <0.01). In proneural subtype-like tumors, macrophage infiltration alone was associated with ‘out of field’ tumor regression (N=8 mice per group, P<0.05). In-vitro , treatment of mouse macrophages with anti-PD-L1 antibodies induced significant gene expression changes and enhanced phagocytosis in an ERK-dependent fashion. All 3 commercially available human anti-PD-L1 antibodies also induced ERK signaling with varying efficacies. Conclusions Focal radiation combined with anti-PD-L1 therapy induces an immunological response to un-irradiated glioblastoma. We are currently optimizing other treatment combinations that could also be readily assessed in phase I human clinical trials.

Ronald L. Bittner Award on Brain Tumor Research