Sensitive CAR T cells redefine targetable CD70 expression in solid tumors [RNA-seq OV]

Overcoming tumor antigen heterogeneity in solid tumors 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 potential candidate, confined to immune cell subsets and aberrantly expressed in many solid tumors, albeit heterogeneously. We find that CD70 expression in heterogeneous tumors is not binary but ranges from high to very low, appearing negative. We show that CD70-heterogeneous tumors are efficiently eliminated by highly sensitive CD70 receptors where prototypic CAR T cells fail. We further identify an epigenetic signature that predicts targetable expression. These findings provide a potential strategy to treat a broad range of solid tumors. Overall design: For the orthotopic ovarian model, 5×10E5 FFLuc-Tdtomato OV4 were injected into the ovary of female NSG mice aged 6-8 weeks. 32 days later, tumor cells from the ovary were digested into single cell suspensions using the Tumor Dissociation Kit, human (Miltenyi Biotec) and CD70LO and CD70HI tumor cells were isolated by FACs for bulk RNA and ATAC sequencing.