TMIC-63. DUAL IMMUNE CHECKPOINT BLOCKADE IN A NOVEL EGFR-DRIVEN MURINE GLIOMA MODEL INCREASES PERIPHERAL T CELL PROLIFERATION BUT FAILS TO PROLONG SURVIVAL

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Abstract Patients with glioblastoma (GBM) survive only 15-18 months following standard-of-care surgical resection and radio-chemotherapy. Immune checkpoint blockade (ICB), effective in extracranial cancers, failed to improve survival in patients with recurrent GBM in a multi-center phase III clinical trial. As such, we are interested in the molecular mechanisms that drive ICB resistance. Oncogenic EGFR activation is observed in ~50% of GBMs and is associated with immunosuppression; however, whether EGFR signaling impairs T cell function in GBM resulting in limited ICB efficacy remains unclear. Therefore, we leveraged the novel MADR-mEGFRvIII glioma model, which expresses murine EGFRvIII under a tetracycline-off system, to investigate the relationship between EGFR activation and responsiveness to dual anti-PD-1 and anti-CTLA-4 (10mg/kg) in vivo. Mice were bled prior to enrollment and weekly thereafter, which confirmed anti-PD-1-PD-1 binding via competitive flow cytometric assay. Following two weeks on treatment, animals were euthanized for immunophenotypic analyses of tumors and tumor-draining lymph nodes. These analyses revealed a significantly increased prevalence of peripheral CD11b+ myeloid cells and enhanced peripheral T cell proliferation, indicated by Ki67 positivity, after treatment with dual ICB compared to isotype control. However, these shifts did not translate to effective ICB-mediated recruitment of peripheral T cells to the tumor microenvironment and no significant survival benefit was observed (p=0.68, n=15/treatment arm). Given our previous findings that EGFR ablation via doxycycline enhanced intratumoral T cell infiltration, we hypothesize the rational combination of EGFR-targeted therapy and ICB will have a synergistic effect; thus, future directions include a study combining the two treatment regimens consisting of a lead-in with doxycycline to increase intratumoral T cell trafficking, followed by treatment with dual ICB. This work will provide insight into the interplay between oncogenic signaling and immunosuppression, contributing to the development of novel combination therapies in treating this lethal disease.