Hypoimmune CD19 CAR T cells treat allogeneic mice with features of spontaneous systemic lupus erythematosus.

Hypoimmune (HIP) MHC class I- and II-deficient and CD47-overexpressing CD19 CAR T cells were generated and tested in an allogeneic NZB/W mouse model of spontaneous systemic lupus erythematosus with established disease. HIP CAR T cells showed persistent engraftment, achieved lasting deep tissue B cell depletion, diminished antibody levels and systemic pro-inflammatory cytokine levels, mitigated proteinuria and glucosuria, alleviated structural kidney injury, and improved survival after 21 weeks. HIP CAR T cells did not induce any immune activation in this fully allogeneic model and thus completely escaped allorejection. In contrast, MHC-replete, non-HIP-edited wild-type (WT) CD19 CAR T cells induced a strong adaptive immune response and vanished quickly without inducing meaningful B cell depletion and without improving disease markers or survival. Conditioning of NZB/W mice with irradiation did not enhance the HIP CAR T cell efficacy and might hint at their potency for autoimmune patients without prior lymphodepletion.