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.

The HIP mouse and all of its organs are completely invisible to allogeneic immune cells.

Hypoimmune (HIP) allogeneic cell therapeutics hold the promise to allow off-the-shelf treatments for a broad patient population. Our HIP approach includes the depletion of major histocompatibility complex (MHC) class I and II molecules and the overexpression of Cd47. Here, we report the engineering of HIP mice that stably exhibit the HIP phenotype in all cell types.

Hypoimmune islets achieve insulin independence after allogeneic transplantation in a fully immunocompetent non-human primate.

Allogeneic transplantation of pancreatic islets for patients with difficult-to-control diabetes mellitus is severely hampered by the requirement for continuous immunosuppression and its associated morbidity. We report that allogeneic transplantation of genetically engineered (B2M, CIITA, CD47), primary, hypoimmune, pseudo-islets (p-islets) results in their engraftment into a fully immunocompetent, diabetic non-human primate wherein they provide stable endocrine function and enable insulin independence without inducing any detectable immune response in the absence of immunosuppression. Hypoimmune primary p-islets may provide a curative cell therapy for type 1 diabetes mellitus.

Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques.

Genetic engineering of allogeneic cell therapeutics that fully prevents rejection by a recipient's immune system would abolish the requirement for immunosuppressive drugs or encapsulation and support large-scale manufacturing of off-the-shelf cell products. Previously, we generated mouse and human hypoimmune pluripotent (HIP) stem cells by depleting HLA class I and II molecules and overexpressing CD47 (B2MCIITACD47). To determine whether this strategy is successful in non-human primates, we engineered rhesus macaque HIP cells and transplanted them intramuscularly into four allogeneic rhesus macaques.