The allogeneic FAP-CAR-IL15 iNKT therapy MiNK-215 remodels the tumor stroma to enhance antitumor immunity

Abstract Cellular immunotherapies show remarkable efficacy against hematological 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 in shaping this immunosuppressive landscape, yet developing effective strategies for targeting these cells remains an ongoing challenge. Here, we describe the design, generation, and characterization of MiNK-215, an allogeneic human invariant natural killer T (iNKT) cell therapy in which iNKT cells were engineered to express a FAP-targeting chimeric antigen receptor (CAR) and to secrete interleukin-15 (IL-15) 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 (MSS-CRC) liver metastases, establishing FAP-CAR-IL-15 iNKT cells as a promising strategy to overcome immunotherapy resistance in solid tumors.