CAR T cell therapy has attained unprecedented success in the treatment of hematological malignancies. However, clinical benefit in solid tumor indications has been limited, potentially in part due to suppressive solid tumor microenvironments (TME) that inhibit T cell effector function and persistence. While the provision of cytokine support can help CAR T cells overcome suppressive TME, combining CAR T therapy with systemically-administered cytokines/cytokine mimetics can result in toxicities and locally secreted cytokines may enhance rejection of allogeneic cell products by host cells. For this reason we had previously designed and tested a novel cytokine-stimulated CAR T cell designated TurboCARs. TurboCAR T cells coexpress a CAR and a Turbo domain (i.e. a homodimeric cytokine receptor chimera) that transmits CAR T cell-intrinsic cytokine signals, resulting in enhanced potency, expansion and persistence in preclinical studies. However, TurboCAR T cells may remain sensitive to inhibition by immune barriers, such as negative signaling through the PD1 receptor. We reasoned that a two-pronged approach aimed at inhibiting immune-suppressive PD1 signaling while simultaneously transmitting immune-potentiating cytokine signaling may augment CAR T cell activity in solid tumors. To this end, we engineered PD1 TurboCAR T cells, in which the Turbo domain is fused to a PD1 ectodomain that serves as a dominant-negative receptor. The PD1 ectodomain was further modified for high-affinity binding to PD1 ligands, allowing for preferential ligand sequestration and more effective inhibition of endogenous PD1 signaling. Despite having a larger lentiviral vector cargo, PD1 TurboCAR T cell products remained manufacturable and retained a favorable memory phenotype. PD1 TurboCAR T cells directed towards PDL1-expressing solid tumor target cells showed increased functionality compared to CAR T cells combined with PD1 blockade or to the parental TurboCAR T cells alone. In conclusion, PD1 TurboCARs augmented with a PD1 dominant negative ectodomain conferred CAR T cells with resistance to PD1-mediated inhibition, while simultaneously transmitting cytokine signals in a CAR T cell-intrinsic fashion. As an all-in-one product, PD1 TurboCAR T cells may obviate the need for combination therapy with anti-PD1 antibodies, while circumventing safety risks associated with systemic cytokine administration.
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