Abstract 1331: MiNK-215, an IL-15 armored FAP-targeting CAR iNKT cell therapy, effectively treats human organoid models of treatment-refractory MSS colorectal cancer (CRC) liver metastases

Abstract The presence of liver metastases in patients with microsatellite-stable (MSS) or mismatch repair proficient (pMMR) colorectal cancer (CRC) is associated with poor response to current pharmacological treatments, including immune checkpoint blockade (ICB). The tumor microenvironment (TME) of CRC liver metastases is characterized by a highly immunosuppressive phenotype that includes poor immunogenicity, a paucity of dendritic cells, elimination of tumor-specific effector T cells, and an abundance of immunosuppressive intrahepatic Kupffer cells and myeloid-derived suppressor cells. This underscores the urgent need for innovative therapeutic approaches targeted specifically to patients with CRC liver metastases. Here we describe MiNK-215, an IL-15 armored FAP-targeting CAR iNKT cell therapy, derived from the AgenT-797 allogeneic iNKT platform, as a potential novel therapeutic approach for patients with CRC liver metastases. To better model ICB refractory human MSS CRC liver metastases, we developed an ex vivo human organoid model that recapitulates the histological and immunological features of human disease. Organoids were comprised of MSS CRC cells engineered to express nuclear GFP and HLA-A2-NY-ESO-1, hepatocytes, Kupffer cell-enriched non-parenchymal cells, and HLA-matched peripheral blood mononuclear cells (PBMCs) supplemented with NY-ESO-1-reactive T cells. Organoid models of CRC lung metastases, which are traditionally more responsive to ICB therapy were also developed to compare the models to clinical experience and further validate their usefulness. Models were treated with Fc-enhanced anti-CTLA-4 (botensilimab) and anti-PD-1 (balstilimab) antibodies, or MiNK-215 to assess tumor killing and immune activation. Botensilimab and balstilimab enhanced T cell activation and cytotoxicity of CRC tumor cells in the absence of “normal” liver cells and in lung organoids. However, they were less effective in organoid models of CRC with liver metastases consistent with clinical observations. In contrast, MiNK-215 potently enhanced tumor killing by T cells in models of CRC with liver metastases. Tumor killing in CRC liver organoid models by MiNK-215 was associated with depletion of immune suppressive FAP-expressing stellate cells and increased CD8+ T cell infiltration. Our findings demonstrate that in treatment-refractory CRC-liver metastatic organoid models, MiNK-215 overcomes the limitations of ICB therapy to home to sites of disease, reprogram the TME, recruit tumor-reactive T cells and enhance tumor killing. Ex-vivo human CRC liver and lung metastatic organoid models are a novel platform that can be leveraged to rapidly identify new therapeutic approaches for potential clinical evaluation. Citation Format: Shanmugarajan Krishnan, Bishnu Joshi, Justin Keith, Ryan Frazier, Barbara Kalinowska, Jin San Choi, Stephanie Sanders, Shannon Boi, Olivier Le Tonqueze, Nick Kushner, Kah Teong Soh, Robert Stein, Tyler J. Curiel, Marc A. van Dijk, Enoch Kim, Eleni Chantzoura, Nils-Petter Rudqvist, Dhan Chand. MiNK-215, an IL-15 armored FAP-targeting CAR iNKT cell therapy, effectively treats human organoid models of treatment-refractory MSS colorectal cancer (CRC) liver metastases abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1331.