The Allogeneic FAP-CAR-IL15 iNKT Therapy MiNK-215 Remodels the Tumor Stroma to Enhance Antitumor Immunity.

Cellular immunotherapies show remarkable efficacy against hematologic malignancies. However, applying these therapies against solid tumors is challenging. Among the obstacles are the lack of tumor-specific antigens and the immunosuppressive tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) expressing fibroblast activation protein (FAP) are key contributors to shaping this immunosuppressive landscape, yet developing effective strategies for targeting these cells remains an ongoing challenge. In this study, we describe the design, generation, and characterization of MiNK-215, an allogeneic human invariant NK T (iNKT) cell therapy in which iNKT cells were engineered to express an FAP-targeting chimeric antigen receptor (CAR) and to secrete IL15 to remodel the TME and enhance antitumor activity. MiNK-215 modulated multifunctional immune responses by enhancing T-cell responsiveness, dendritic cell activation, M1 macrophage polarization, and tumor killing. In a lung tumor mouse model, MiNK-215 depleted FAP+ CAFs, enhanced antigen-specific T-cell infiltration, and promoted durable antitumor immunity without off-target toxicity. These findings were extended to human organoid models of treatment-refractory microsatellite-stable colorectal cancer liver metastases, establishing FAP-CAR-IL15 iNKT cells as a promising strategy to overcome immunotherapy resistance in solid tumors. See related Spotlight by Albelda, p. 184.