CD4 depletion synergizes with Super-2 and IL33 (S233) armored CAR-T therapy to control B16F10 melanoma but not MC38 colon adenocarcinoma growth 3600

Abstract Description Chimeric Antigen Receptor-T (CAR-T) cells have shown great efficacy against many liquid cancers but have failed against solid tumors. This is due to contributing factors such as the immunosuppressive tumor microenvironment, the inability for CAR-T cells to traffic to and infiltrate the correct tissues, and the poor persistence and diminishing effector activity of CAR-T cells in vivo. Our lab developed an armored CAR-T cell that constitutively expresses IL-2 superkine and IL-33 (S233) that significantly delays tumor growth and extends survival in multiple murine solid cancer models. We recently observed that S233 armored CAR-T therapy synergizes with CD4 depletion (αCD4) treatment to further delay tumor growth and extend survival in intra-dermal B16F10 melanoma but not MC38 colon adenocarcinoma. To understand this difference, we conducted phenotypic analysis of S233 CAR-T cells in both models with and without αCD4 and found that armored CAR-T cells expressed multiple checkpoint inhibitory receptors and appeared more activated, and less stem-like compared to non-armored CAR-T cell controls. However, αCD4 treatment significantly increased the frequency of terminally exhausted (Tex) CAR-T cells in the B16F10 but not MC38 model. These findings highlight the dynamic and differential role that CD4+ T cells play in different cancers. They also suggest that CD4+ T cells can limit CAR-T cell effector activity and their propensity to become exhausted in cancer. Funding Sources Supported by NIH/NCI grant CA271553 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)