A New Approach to Modulating CAR T Cell Activity

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Abstract Chimeric antigen receptor (CAR) T cells targeting CD19 are highly effective in children with refractory/relapsed acute lymphoblastic leukemia (ALL), including those with primary refractory or CNS disease. Current CAR T cell therapies infuse patients with T cells constitutively expressing CARs, which are not susceptible to any controllable regulation. Cytokine release syndrome (CRS) and CAR-associated neurotoxicity (CAN), both of which can be fatal, arise from uncontrolled CAR T cell activation and expansion. While a few pharmacological management approaches have been attempted to overcome this issue, they are often suboptimal. In addition, chronic B-cell aplasia from persistent CD19 CAR T cells requires monthly infusions of immunoglobulin, which is burdensome and expensive, especially for pediatric patients facing potentially a lifetime need. Here, we propose to develop a system for controllable CAR T cells that can be turned on and off as needed. We have previously demonstrated that exogenous expression of the tyrosine phosphatase SHP-1 acts as a negative regulator to dampen T cell activation. Recently, we have developed an inducible and reversible protein degradation system for SHP-1 by adapting the plant Auxin-induced degron (AID) system for T cells. Combining these two tools in Aim 1, we propose to develop CD19 CAR T cells that will be kept basally dormant through overexpression of SHP-1. However, upon administration of Auxin, the CAR T cells can be temporarily and reversibly activated through the degradation of SHP-1. As the doses of Auxin sufficient to activate the AID system had no significant toxicities in humans, we do not foresee a problem translating this system into the clinic. In Aim 2, we will examine the efficacy of this novel CAR T cell system in a murine model of ALL. In Aim 3, we will expand the studies to test whether this regulatable CAR T cells system can control and/or limit CAR T cell-associated toxicities using a muring model of ALL, CRS and neurotoxicity. Such an exogenously regulatable CAR T cell system may provide clinicians a tool to avoid/limit severe CRS and CAN, and allow repopulation of the B-cell compartment after a sufficient treatment course. This approach will greatly enhance the safety of CD19 CAR T cells and is likely applicable to CARs for other malignancies, including solid tumors, where on-target, off-tissue cytotoxicity is more problematic.