Reversing Tumor Immunotherapy Resistance via TME Modulation

T cell infiltration and persistence in solid tumors are crucial for the success of T cell-based immunotherapies, yet the tumor microenvironment (TME) often suppresses T cell access and function. Our ERC-funded research has identified a G protein-coupled receptor (GPCR), activated by a metabolite commonly enriched in solid tumors, that substantially impairs T cells. We showed that inhibition of this GPCR enhances T cell infiltration, persistence, and cytotoxicity, thereby substantially improving the efficacy of CAR-T, TCR-T, and immune checkpoint blockade (ICB) therapies across tumor models of various cancer types.To advance these findings towards clinical applications, we developed monoclonal antibodies (mAb) against this GPCR, which exhibit potent blocking functions and high specificity. Our lead mAb effectively reactivates patient-derived tumor-infiltrating lymphocytes (TILs) against autologous primary tumor cells, underscoring its therapeutic potential.Project REVIVE aims to 1) humanize and optimize our mAbs target this GPCR, 2) conduct preclinical validation to assess efficacy and safety in advanced models, 3) develop predictive biomarkers for patient selection, and 4) establish a comprehensive intellectual property (IP) and commercialization strategy, integrating freedom to operate (FTO) analyses, market assessment, licensing opportunities, and industry partnerships to facilitate clinical translation. By executing these steps, REVIVE will generate an investor-ready, clinically viable, IP-protected antibody targeting this GPCR, supported by comprehensive preclinical validation and a biomarker-driven patient selection strategy. These outcomes will enhance the commercial attractiveness of our therapeutic candidate for licensing or spin-out opportunities, paving the way for future clinical translation and patient benefit.