Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors

CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (T-reg) cells suppress the immune response via inhibitory factors such as transforming growth factor-beta (TGF-beta). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-beta receptor 2 (DNR) can simultaneously shield them from TGF-beta. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8(+) T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-beta shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.