Funded Grants

The Kristen Grossman SEED GRANT

Grantee: Duke University
Project Lead: Peter Fecci, MD, PHD
Grant Title: The CARE-BEAR Proposal
Program Area: Glioblastoma
Grant Type: UKF Seed Grant
Year Awarded: 2023 and 2024
Amount: $100,000
Duration: 2 years

Summary: Immunotherapies have been notoriously unsuccessful against glioblastoma (GBM) to date. A critical problem facing these approaches is the substantial antigenic heterogeneity that GBMs exhibit. Such heterogeneity has been particularly limiting for CAR T cells, which classically target protein antigens on the surface of tumor cells. Needed are novel means for targeting GBM in a manner that bypasses the typical limitations imposed by tumor heterogeneity.

Our group has recently discovered that the decades-old model for how T cells target and kill tumor cells is incomplete. The traditional model requires that T cells recognize their target antigens solely in the context of MHC molecules and, thus, that GBM and other tumors can escape immune detection by downregulating MHC on their surface. We have found that T cells remain quite capable of killing tumor cells lacking MHC and do so in a manner that bypasses the classical need for T cells to encounter their target antigens on tumors entirely. Instead, T cells prove capable of recognizing a ligand that is both highly and homogenously expressed by tumor cells (particularly those tumor cells lacking MHC), called NKG2DL (Lerner E. et al, Nature Cancer 2023).

This newly discovered mechanism provides an opportunity for bypassing the traditional immunotherapeutic dependence on heterogeneous protein antigens and instead proffers a homogenous tumor target in NKG2DL. We have therefore begun constructing a novel therapeutic that targets both protein antigen and NKG2DL. This proposal is aimed at initial optimization and testing of this platform, en route to ultimate clinical translation.