MODULATION OF CD5 SIGNALING TO ENHANCE ADOPTIVE T-CELL THERAPIES FOR CANCER

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PROJECT SUMMARY Adoptive T-cell immunotherapies and, in particular, chimeric antigen receptor T cells (CART) generated unprecedented responses in patients with highly refractory CD19+ B cell malignancies. However, only a limited number of patients treated with anti-CD19 CART will experience prolonged remission while most patients either do not respond or eventually relapse. Moreover, in the setting of solid cancers, CART cells have generally been disappointing. Increasing CART effector function against cancer would represent a vertical improvement in the field of adoptive T-cell immunotherapy. In this proposal, we aim at increasing the anti-tumor efficacy of CAR T cells by reducing the inhibition of CAR activation. Current approaches to enhance CART efficacy focus on reducing long-term T cell exhaustion by targeting the PD-1/PD-L1 axis. However, there is a lack of investigation on strategies to enhance early CAR and T cell receptor (TCR) signaling, which is critical for effective tumor killing, especially in the setting of the immunosuppressive tumor microenvironment. To this goal, we studied the scavenger receptor CD5. CD5 associates with the TCR complex and inhibits its activation through several mediators, including SHP-1, CBL, CBL-B, and GRB2. The central hypothesis of this grant is that CD5 deletion increases the anti-tumor efficacy of engineered T cells through enhancement of TCR signaling. In our preliminary work, we have found that CRISPR-Cas9 CD5 knock out in CART cells enhances their anti-tumor activity in xenograft models of B-cell leukemia (CART19) and T-cell lymphoma (CART5). Moreover, we demonstrated that, upon stimulation, CD5 knocked-out CART cells show higher phosphorylation of key CAR signaling mediators as compared to wild-type. In Aim#1, we will test the hypothesis that the deletion of CD5 in T cells broadly enhances the anti-tumor efficacy of adoptive T-cell immunotherapies, by studying CD5 knockout in the setting of CAR T cells for solid tumors. In Aim#2, we will test the hypothesis that CD5 deletion augments T-cell anti-tumor activity by disinhibiting CAR signaling by performing in vitro and in vivo mechanistic studies. We will also test the safety of this approach. This hypothesis-driven proposal is highly innovative as it proposes the study of a novel immunomodulatory target - CD5 - and uses cutting edge technologies like digital spatial profiling and single-cell RNA sequencing to investigate CD5 deleted CAR T-cell in vivo in both human and murine models. A successful outcome of the proposed investigations is expected to impact the field of cancer immunotherapy significantly, providing a rational and generalizable approach to improving T-cell immunotherapies and ultimately drive the development of a first-in-human clinical trial of CD5 knocked-out CART for refractory cancers.