[A first-in-human clinical trial of piggyBac transposon-mediated GMR CAR-T cells against CD116-positive acute myeloid leukemia and juvenile myelomonocytic leukemia].

Although several types of chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) targeting myeloid antigens have been developed for acute myeloid leukemia (AML) globally, significant clinical benefits have not yet been reported. Furthermore, CAR-T cells targeting juvenile myelomonocytic leukemia (JMML) have not yet been developed. All JMML cells and 63-83% of AML cells express granulocyte macrophage-colony stimulating factor (GM-CSF) receptor (GMR, CD116/CD131 complex). Therefore, we created ligand-based CAR-T cells targeting GMR using the piggyBac transposon system. We further redesigned the CAR construct by optimizing the affinity of the antigen-binding region and length of the spacer region. The GMR CAR-T cells with a mutated GM-CSF at residue 21 (E21K) and a G4S spacer showed superior antitumor effects in the human AML-xenograft model. Safety tests revealed that the toxicity of GMR CAR-T cells was restricted to normal monocytes. Based on the promising results of the nonclinical study, we started a first-in-human clinical trial of GMR CAR-T cells in patients with CD116-positive AML and JMML in 2021.