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.

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Publication Details

Journal
Cancer Immunology Research
Published
2025-11-14
DOI
https://doi.org/10.1158/2326-6066.cir-25-0349
Primary Topic
CAR-T cell therapy research
Type
article
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article

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

Xavier Michelet, John Pravin, Jennifer S. Buell, Efrat Altman-Sharoni et al.
Cancer Immunology Research
CAR-T cell therapy research
article

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

Xavier Michelet, John Pravin, Jennifer S. Buell, Efrat Altman-Sharoni, Reed Masakayan, Justin G. Keith, Alan F. Chalmers, Priyadarshini Iyer, Olivier Le Tonquèze, Gerard Rubí-Sans, Mark A. Exley, Stephanie Sanders, Martyna Popis, Kah Teong Soh, Georgios Antonopoulos, Vignesh Venkatraman, Paul Ibbett, Emmanuel Briend, Chinar Pathak, Tyler Jay Curiel, Dhan Chand, Shannon K. Boi, Marco A. Purbhoo, Eleni Chantzoura, Nick Kushner, Jin San Choi, Marc Van Dijk, Bishnu Joshi, Alvaro Sebastian-Yague, Rachel Smith, Shanmugarajan Krishnan, Robert B. Stein, Deborah Wright, E. Edmund Kim, Stephen Addis, Sara Farahi, Olga Ignatovich, Magdalena Niedzielska, Moira Pinzan-Rossi
article en

Abstract

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.

Cancer Immunology ResearchVol. 14(2)
Dartmouth College (US), Dartmouth Institute for Health Policy and Clinical Practice (US), Agenus (United States) (US), United Therapeutics (United Kingdom) (GB), Antagen Pharmaceuticals (United States) (US), Dartmouth Psychiatric Research Center (US), Winston-Salem/Forsyth County Schools (US), Accent Therapeutics (United States) (US), Lonza (United States) (US), Io Therapeutics (United States) (US), Bioenergy Life Science (United States) (US), Lonza (Switzerland) (CH)
Openalex Percentile: Top 53%
CAR-T cell therapy research
DOISourceOpenAlex
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