Ferritin aggregation: A neotype and universal engager for CAR T cell avidity engineering against diverse refractory leukemias

Although promising, chimeric antigen receptor T (CAR T) cell therapy for treating leukemias still faces critical challenge of antigen modulation, which causes resistance. Building from our clinical insight that both diverse types of leukemia cells and corresponding CAR T cells strongly express CD71 (a ferritin receptor), we design a ferritin aggregation cell engager (FACE), which can anchor to CAR T cell surface, guide CAR T cells to face leukemia cells, and facilitate CAR recognition of cognate antigen. In vitro and in vivo experiments with diverse leukemia patient-derived cells and leukemia patient-derived xenograft models show that our FACE-CAR T cells succeed in enhancing therapeutic efficacy with good biosafety, lowering the antigen threshold for overcoming antigen modulation, and even loading chemodrugs in ferritin for combination therapy. Such an avidity engineering provides a neotype, facile, universal and flexible approach for improving the efficacy of CAR T cell therapy for diverse refractory leukemias.