Abstract
Abstract Despite the recent success of immune checkpoint blockade in various cancer types, glioblastoma (GBM) remains resistant to immunotherapy due to its immunosuppressive features and the poor penetration of systemic agents across the blood-brain barrier (BBB). Recent clinical trials demonstrated the unprecedented efficacy of Fc enhanced anti-CTLA-4, an anti-CTLA-4 antibody with enhanced affinity to Fcγ receptors (FcE-aCTLA-4), against immunologically inactive (‘cold’) tumors. This agent exhibits a high affinity for FcγRIIIA regardless of its polymorphic variants of FcgRIIIA that are known to influence the binding affinity and efficacy of conventional anti-CTLA-4 antibodies. We observed robust expression of FcγRIIIA in tumor-associated macrophages/myeloid cells (TAM) of human GBM, which was most pronounced in newly diagnosed GBM. FcE-aCTLA-4 demonstrated high-affinity binding to FcγRIV, the mouse ortholog of human FcγRIIIA, which was highly expressed on TAMs in mouse gliomas. We evaluated the efficacy of the murine homologous FcE-aCTLA-4 antibody as monotherapy and in combination with other treatments in several murine glioma models. FcE-aCTLA-4 selectively depleted CTLA-4 expressing intra-tumoral regulatory T cells (Tregs) via antibody-dependent phagocytosis by TAMs while spearing peripheral Tregs and other CD4+ T cell populations. In a cohort of 4 GBM patients, doxorubicin delivered with low-intensity pulsed ultrasound and microbubbles (LIPU/MB), a procedure that temporarily opens the BBB, upregulated FcγRIIIA expression on TAMs. Treatment of immunotherapy-resistant murine gliomas with a combination of FcE-aCTLA-4, anti-PD-1, and doxorubicin with concomitant LIPU/MB resulted in over 90% cure rates, which correlated with increased infiltration of activated CD8+ T cells in the brain, and complete rejection upon subsequent tumor rechallenge. Our findings indicate that FcE-aCTLA-4 exhibits a novel immunomodulatory function in GBM, and its therapeutic potential is significantly improved when combined with anti-PD-1, doxorubicin, and delivered by LIPU/MB. This therapy warrants further evaluation in clinical trials.
Published Version
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