UCLA

Adoptive T-cell therapy is a cancer treatment strategy where T cells from a cancer patient are harvested, modified ex vivo to target tumor cells, and subsequently reinfused back into the patient’s body. Although remarkably successful against blood-based B-cell malignancies, efficacy has been limited against solid tumors, in large part due to the immunosuppressive tumor microenvironment (TME). Among the many inhibitory factors in the TME, transforming growth factor-beta (TGF-β) plays a prominent role in suppressing anti-tumor immunity through both direct inhibition of T-cell cytotoxicity, as well as recruitment and polarization of immunosuppressive cell types such as myeloid-derived suppressor cells and regulatory T cells. We therefore hypothesized that T-cell function in the solid TME could be potentiated by pairing tumor-targeting CARs with TGF-β CARs that program T-cell activation, rather than inhibition, in the presence of TGF-β. Wefirst verified that TGF-β CAR expression is neither counterproductive to cytotoxic T-cell function, nor does it pose a significant risk of toxicity. Pairing TGF-β CARs with tumor-specific TCRs or CARs did not significantly enhance therapeutic outcomes of adoptive T-cell transfer in preclinical models of melanoma and prostate cancer, warranting further engineering efforts. In models of glioblastoma, however, single-chain bispecific CAR-T cells targeting TGF-β and tumor antigen were not only more resistant to tumor-mediated dysfunction, but also remodeled the immune-cell composition of the tumor microenvironment to potentiate anti-tumor immunity.