EXTH-15. A NOVEL IMMUNE-BASED TREATMENT STRATEGY FOR COMBATTING PROTEIN TUMOR HETEROGENEITY

Abstract

Abstract Cell-based immunotherapy has revolutionized the treatment of many hematological malignancies but has mostly fail against solid tumors, including glioblastoma (GBM). The reason for this failure is multi-fold, but one of the most significant barriers is the extensive intratumoral heterogeneity that characterizes these tumors. Unfortunately, this problem has not been eliminated by personalized medicine strategies aimed at sequencing individual tumors and targeting the uncovered neoantigens. Thinking “outside the box” led us to examine other types of tumor-specific alterations that might more ubiquitously characterize tumor cells, while still being targetable by an immune-based platform. Our investigations led us to the phospholipid phosphatidylserine (PS). PS is typically present on the cytoplasm-facing side of the plasma membrane, where it remains out of view to the immune system. Cellular stresses can lead to dysregulation of processes that keep PS facing internally and instead promote PS exposure on the cell surface. We show here that tumor cells frequently lose the capacity to regulate their plasma membrane and exhibit detectable levels of PS on their surface. Moreover, inducing cell stress through radiation and chemotherapy of tumor cells further enhanced PS exposure. In this study, we aimed to target PS with an immune-based therapy. To this end, we engineered a bi-specific T cell engager (BiTE) consisting of the natural high-affinity PS receptor TIM4 linked to an anti-CD3scFv. This TIM4 BiTE is hypothesized to redirect all T cells to PS, resulting in T cell-mediated killing of tumor cells with exposed PS. Indeed, TIM4 BiTE facilitated potent killing of multiple human tumor cell lines in vitro, including in models of protein heterogeneous tumors. When TIM4 BiTE was delivered intratumorally to a heterogeneous glioma-bearing mouse, survival was significantly extended. These data provide evidence that targeting PS with an immune-based platform represents a potential novel treatment strategy for combatting tumor heterogeneity.