Abstract
CD117 is a cell-surface receptor expressed on hematopoietic stem and progenitor cells and acute myeloid leukemia (AML), and thus CD117-targeting chimeric antigen receptor T cells (CART117) can function as both conditioning for hematopoietic stem cell transplantation and a therapy for AML. We developed human and mouse CART117 to evaluate the safety and feasibility of targeting CD117 in preclinical mouse models. Human CART117 had potent anti-tumor activity while also mediating significant hematopoietic toxicity in a humanized mouse model. Murine CART117 (mCART117) led to systemic and hematopoietic toxicity without anti-leukemic benefit in immunocompetent C57BL/6 mice. Intriguingly, mCART117 was able to eliminate CD117+ cells in the spleen but not in the bone marrow (BM). Of note, proliferation of BM CD117+ cells in response to lymphodepleting chemotherapy amplified mCART117-mediated systemic toxicity. Alternative lymphodepletion with radiation ameliorated the systemic toxicity of mCART117 but did not improve anti-leukemic efficacy. Immunodeficient mice given mCART117 in the absence of lymphodepletion died from severe pancytopenia, and this effect was recapitulated by regulatory T cell depletion in immunocompetent mice. Increasing CD117 expression on AML improved the anti-leukemic efficacy and toxicity profile of mCART117. In conclusion, mCART117 anti-leukemic activity is impaired in immunocompetent mice when CD117 is expressed at physiological levels on AML.