Modulating costimulation in CAR T cells to enhance antitumor efficacy

Roswell Park Cancer Institute Corp, Buffalo NY

Investigators

Abstract

Project Summary Innovative adoptive cellular therapies have emerged as revolutionary treatment options for patients with hematologic malignancies. One such promising strategy, Chimeric Antigen Receptor (CAR) T cell therapy, involves genetic modification of autologous T cells to express a CAR, redirecting the cytotoxic response of T cells towards hematologic tumors expressing human B cell maturation antigen (hBCMA) on multiple myeloma or CD19 on B cell lymphomas and leukemias. While response rates to CAR T cell therapy are strikingly high in patients with hematologic malignancies, most patients experience disease relapse, highlighting the urgent need to improve CAR T cell efficacy for a durable response. Preliminary data from our lab and published literature indicate that targeting endogenous CD28 on CAR T cells is a viable approach to enhance CAR T cell efficacy. The CAR contains a costimulatory domain (such as CD28), which undergoes activation upon ligation of the target antigen to the CAR, delivering costimulatory signals to contribute to CAR T cell activation, leading to subsequent CAR T cell effector functions. Importantly, as the CAR is integrated into T cells, T cells also express natural endogenous CD28, which can engage CD28 ligands in the tumor microenvironment or on other T cells themselves, providing yet another source of costimulatory signals that contribute to CAR T cell activation. Interestingly preliminary data from our lab show that deletion of endogenous CD28 enhances the functional persistence of CAR T cells in vivo. As such, we hypothesize that endogenous CD28 contributes to the overstimulation of CAR T cells which increases exhaustion, decreases persistence, and hampers efficacy. To test our hypothesis, will rigorously evaluate how knockout of endogenous CD28 using CRISPR/Cas9 technology affects CAR T cell function and efficacy using established preclinical in vitro and in vivo models. These studies have the potential to identify a novel role of endogenous CD28 in hindering CAR T cell efficacy, while highlighting a clinically relevant strategy to improve CAR T cell efficacy.