T-bet overexpression modulates CAR T cell effector functions

Abstract Adoptive transfer of T cells modified with a chimeric antigen receptor (CAR) are highly effective in patients hematologic malignancies. However, many relapse and CAR have shown minimal efficacy against solid tumors. Our lab others that standard designs fail to promote differentiation into canonical cell subsets. generate both type-1 type-2 cytokines simultaneously, challenging the traditional paradigm Th1 Th2 programs mutually exclusive. We sought control this by overexpressing transcription factor T-bet drive more effector response. CD28-costimulated showed reduction cytokine production. In an immune-competent syngeneic mouse model B acute lymphoblastic leukemia, increased expansion, generation KLRG1 +CD127 −effector cells, decreased expression exhaustion-associated markers PD1, TIM3, LAG3 through initial expansion contraction phases Despite this, Tbet overexpression drove late hypo-functionality leukemic relapse. 4-1BB-costimulated which tend weaker response than led potency, prolonging survival over mice treated CAR. Furthermore, polyfunctionality low-antigen density leukemia when compared cells. These results demonstrate potential T-bet-overexpression as strategy modulate strength Supported funding from University Colorado School Medicine Human Immunology Immunotherapy Initiative