Sensitive CAR T cells redefine targetable CD70 expression in solid tumors

Solid tumor antigen heterogeneity is a major challenge for cancer immunotherapies, including chimeric antigen receptor (CAR) T cells. Unlike CD19 for B cell malignancies, no target with pan-cellular expression in solid tumors and absence in normal vital cells has been identified. CD70 is a promising candidate, physiologically confined to immune cell subsets and aberrantly expressed in many cancers. We show that heterogeneous CD70 expression in tumors is epigenetically regulated, ranging from high to very low in individual cells, appearing negative by conventional detection methods. Using a highly sensitive CD70 receptor, HLA-independent T cell (HIT) receptor coexpressing CD80 and 4-1BBL for costimulation, we efficiently eliminated CD70-heterogeneous tumors that evade prototypic CAR T cells. These findings provide a potential strategy to treat a broad range of solid tumors.