MiNK-215: Allogeneic FAP-CAR-IL15 iNKT therapy remodels tumor stroma to enhance anti-tumor immunity
Cellular immunotherapies show remarkable efficacy against hematological malignancies; but face challenges against solid tumors largely attributed to the lack of tumor-specific antigens and immunosuppressive tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), expressing fibroblast activation protein (FAP) are key contributors in shaping this immunosuppressive landscape, yet effective targeting strategies remain an ongoing challenge. Here, we describe MiNK-215, a novel allogeneic human invariant natural killer T (iNKT) cell therapy, engineered to express a FAP-targeting chimeric antigen receptor (CAR) and secrete interleukin-15 (IL-15) to remodel the TME and enhance anti-tumor 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 anti-tumor immunity without off-target toxicity. These findings extended to human organoid models of treatment-refractory Microsatellite Stable Colorectal Cancer (MSS-CRC) liver metastases, establishing FAP-CAR iNKT cells as a promising strategy to overcome immunotherapy resistance in solid tumors. Overall design: RNA-seq profiling of MiNK-215 versus FAP-CAR iNKTs without the IL-15 transgene following 4-hour co-culture with FAP+ A375 cells