Abstract

Insights into Immune Checkpoint Blockade Biology in EGFR-Driven Mouse Models of Glioblastoma

Alain Charest, Associate Professor, Beth Israel Deaconess Medical Center, Cancer Research Institute, Department of Medicine, Harvard Medical School

Glioblastoma Multiforme (GBM) is a lethal disease with a median survival of approximately 15 months and a 5-year relative survival rate of 3%, despite an aggressive standard of care treatment regimen consisting of fractionated radiation and the chemotherapeutic agent Temozolomide (TMZ). This abysmal lack of response makes it clear that alternative therapeutic approaches must be explored. Phenomenal advances have been made in characterizing the molecular features of GBM through the cataloging of genomic data obtained through the efforts of The Cancer Genome Atlas. Despite these tumor-cell centric advancements, much less is known about how the tumor microenvironment plays a role in the maintenance, evolution, and response to therapies for GBMs. The adaptive immune system is endowed with intrinsic anti-tumor activity. However, many malignant tumors, including GBM, are associated with significant systemic and micro-environmental immunosuppression. Often, tumors escape immune surveillance by over-expressing a class of proteins known as immune checkpoints, resulting in uncontrolled growth of the tumors. Antibody-mediated inhibition of two immune checkpoint cell surface proteins (programmed death-1 [PD-1] and cytotoxic T-lymphocyte antigen-4 [CTLA-4]), has exhibited dramatic and durable responses across a spectrum of malignancies. However, the clinical potential of these antibodies in patients with GBM is not known. Here we systematically evaluated the antitumor efficacy of antibodies targeting the immune checkpoint molecules PD-1 and CTLA-4 when administered as single-agent therapies and in combination with (XRT-TMZ) in an EGFR-driven genetically engineered immunocompetent mouse model of GBM. Treatment with anti PD-1 and anti CTLA-4 antibodies resulted in a significant increase in survival when compared to either control untreated animals and XRT-TMZ treated mice. Our results support the clinical evaluation of immune checkpoint blockade as single agents and in the context