SECTM1-based CAR T cells enriched with CD7-low/negative subsets exhibit efficacy in CD7-positive malignancies.

CD7 has been found to be a promising chimeric antigen receptor (CAR) T cell target in several clinical trials. However, its expression on normal T cells poses additional challenges in CD7-directed CAR therapy, such as complete fratricide, contamination with malignant cells, and immune suppression due to T-cell aplasia. By taking advantage of evolved affinity between ligand and receptor, we constructed a CD7-directed CAR with the extracellular domain of SECTM1, a natural ligand of CD7, as the recognition domain. SECTM1 CAR T cells killed the majority of T cells with high CD7 expression in vitro. However, SECTM1 CAR T cells with low or negative CD7 expression survived, expanded, and showed strong cytotoxicity to CD7+ malignant cell lines and primary leukemic blasts from patients with T-cell acute lymphoblastic leukemia and acute myelogenous leukemia in vitro. It also exhibited efficacy in inhibiting xenograft tumor growth in vivo. More exploration is needed for clinical efficacy potential to patients with CD7+ malignancies.