Though CAR T cells have been effective against certain blood cancers, they have not been for solid tumors. Now, a new form of highly sensitive CAR T cells aims to overcome one of the biggest barriers in solid tumor immunotherapies – the way solid tumors lack a single, widely shared surface target. By engineering an ultra-sensitive receptor capable of detecting even the smallest amounts of the protein CD70, researchers report they were able to eradicate kidney, ovarian, and pancreatic tumors in preclinical models. The findings provide a potential strategy to treat a broad range of solid tumors. Chimeric antigen receptors (CARs) are engineered molecular “homing devices” that augment the functions of immune cells to recognize and attack specific disease targets. CAR T cells targeting CD19 have transformed the treatment of certain blood cancers and have shown success in producing lasting remissions in patients who have shown resistance to other therapies. However, unlike many blood cancers, solid tumors lack a single, widely shared surface target that is consistently present on cancer cells and largely absent from healthy tissues. Previous studies have suggested that CD70 could be a promising target for future CAR T immunotherapies, as it is abnormally overproduced in several solid tumors. Yet CD70 expression within these tumors is uneven – some cancer cells display it abundantly while others express little or none.

To better understand the limitations of CAR therapy in these tumors, Sophie Hanina and colleagues developed patient-derived xenograft laboratory models that recreate the patchwork expression of CD70 seen in patients with kidney cancer. Hanina et al. found that CD70 expression exists on a spectrum in all tumor cells; even those labeled CD70-negative expressed very low levels of CD70, though not at a level high enough to be detected and destroyed by conventional CAR T cells. Building on this finding, the authors engineered a far more sensitive and highly selective chimeric antigen receptor called HLA-independent T cell (HIT) receptor and show in mouse and cell models that it can detect and eliminate tumor cells with very low CD70 expression. According to the findings, these CD70-HIT cells completely and durably eradicated tumors with mixed levels of CD70 expression across models of renal, ovarian, and pancreatic cancers. “Twenty or more solid tumor types express CD70 heterogeneously,” write the authors. “Our findings position CD70 as a pan-cancer target and provide a model for uncovering additional stealth targets amenable to sensitive immunotherapeutic approaches in the face of apparent tumor antigen heterogeneity.”