A hematopoietic stem cell shield for AML-directed immunotherapy

This challenge in optimal antigen selection leads to deleterious on-target toxicity, particularly in the context of CAR T cell persistence.

CAR T cells targeting CD371, a type II transmembrane glycoprotein, have shown potent anti-leukemic activity in phase I trials to date; however, CD371 is wildly expressed throughout the normal myeloid compartment. Here we identify that CD371 is dispensable for normal human HSC and myeloid cell function, map the epitope of a CD371 CAR T cell currently in phase I trials, develop a base-editing strategy to shield normal hematopoiesis from CD371-directed immunotherapy, and describe an off-the-shelf approach to target AML while sparing normal hematopoiesis through the use of CD371 CAR T cells.