TMOD-32. Novel immunocytokine CD80/IL2v synergizes with α-PD-1 for treatment of preclinical murine glioblastoma models

Abstract Anti-PD-1 checkpoint blockade immunotherapy has not been successful as a monotherapy for the treatment of glioblastoma (GBM) patients. Reasons for failure of immunotherapy in GBM treatment include the onset of systemic immune suppression in these patients. Our lab was one of the first to successfully model peripheral immunosuppression using preclinical murine GBM models. We observe low circulating T cell counts and atrophy of immune organs in multiple pre-clinical murine glioma models. We hypothesized that restoration of the peripheral immune system could be achieved through combined treatment with anti-PD1 checkpoint blockade plus novel immunocytokine CD80/IL2v. GI-101 and GI-102 are novel CD80/IL-2v immunocytokines designed to selectively activate immune cells by targeting IL-2Rβγ while minimizing IL-2Rα binding. GI-101 retains partial IL-2Rα affinity; GI-102 has none. Both enhance immune cell proliferation and activation in cancer patients, with extended half-life and tumor-directed delivery via CD80. We therefore treated GL261 harboring C57Bl/6 mice with combination therapy consisting of anti-PD-1 checkpoint blockade plus GI-101 or GI-102. Animals treated with anti-PD1 plus GI-101 or GI-102 had significantly increased TCRb+ CD4+ and TCRb+ CD8+ T cell infiltration resulting in tumor clearance plus extended survival when compared to mock treated controls. Importantly, peripheral immune cell populations are preserved in animals treated with this combination therapy. Atrophy of the spleen associated with anti-PD-1 immunotherapy is also overcome with the supplementation of GI-101 or GI-102 to anti-PD-1 checkpoint blockade therapy. Furthermore, through immune depletion strategies, we determined that both CD4+ T cells and CD8+ T cells were the critical immune cell type required for these therapeutic effects. These findings imply that anti-PD-1 checkpoint blockade supplemented with fusion protein that includes CD80, and engineered IL-2 cytokine could be effective in treating human GBM.