Work

270 AgenT-797, an allogeneic iNKT cell therapy, enables tumor-cell killing in a human organoid model of immune checkpoint inhibitor–refractory colorectal cancer liver metastases

Year: 2026

Type: conference-abstract

Abstract: Background In microsatellite-stable/mismatch repair–proficient (MSS/pMMR) colorectal cancer (CRC), liver metastases create a uniquely tolerogenic immune microenvironment that limits T-cell priming, effector function, and responsiveness to immune checkpoint inhibitor (ICI) therapy. This immune resistance likely reflects a convergence of factors, including impaired antigen presentation, loss or dysfunction of tumor-reactive T cells, and enrichment of immunosuppressive myeloid populations such as Kupffer cells and myeloid-derived suppressor cells. Invariant natural killer T (iNKT) cells are uniquely positioned to address these barriers by combining direct cytotoxicity with broad innate and adaptive immune modulation. AgenT-797 is an allogeneic, off-the-shelf iNKT cell therapy with tissue-homing and immune-reconditioning properties, including enhancement of T-cell responsiveness, recruitment of cytotoxic lymphocytes, activation of dendritic cells, and depletion or repolarization of suppressive M2-like macrophages. 1–4 Given the complementary mechanisms of iNKT-cell and ICI therapy, we evaluated AgenT-797 alone and in combination with botensilimab, an Fc-enhanced anti-CTLA-4 antibody, and balstilimab, an anti-PD-1 antibody, in a human-relevant CRC liver metastasis organoid model designed to recapitulate ICI-refractory disease.Methods ICI-refractory CRC liver metastases were modeled using a multicellular ex vivo organoid system.5 Each organoid integrated CRC cells co-expressing nuclear GFP and HLA-A2-restricted NY-ESO-1, primary hepatocytes, Kupffer cell-enriched non-parenchymal cells, and HLA-matched PBMCs. NY-ESO-1-specific TCR-engineered T (TCR-T) cells were titrated to a suboptimal dose to model the effector insufficiency characteristic of MSS/pMMR liver metastases. Organoids were treated with AgenT-797 alone and in combination with TCR-T cells, with or without botensilimab and balstilimab. Readouts included quantification of immune-cell infiltration, T-cell activation, cytokine production, granzyme B induction, and tumor-cell killing.Results Organoids recapitulated key features of CRC liver metastases, including elevated CXCL12, FAP, and TGF-β expression, and enrichment of M2-like macrophages. Consistent with clinical experience, ICI alone showed limited activity. Despite antigen specificity, TCR-T cells demonstrated limited tumor-cell killing. In contrast, AgenT-797 enhanced TCR-T-cell activation and T-cell infiltration into tumor-cell-containing organoid regions, increased IFN-γ and granzyme B production, and augmented tumor-cell killing. Addition of botensilimab and balstilimab further amplified these effects, consistent with cooperative remodeling of the tumor microenvironment toward a pro-inflammatory, cytotoxic state ( figure 1).Conclusions AgenT-797 reconditioned suppressive CRC liver metastasis organoids from an immune-resistant state toward a cytotoxic, T-cell-permissive microenvironment. Addition of botensilimab and balstilimab further enhanced this activity, supporting a mechanistically complementary strategy to address liver-associated immune resistance in MSS/pMMR CRC. These findings support the ongoing Phase 2 evaluation of AgenT-797 with botensilimab and balstilimab in patients with CRC liver metastases ( NCT07550088).References Popis M, et al. AgenT-797 cell therapy can be combined with next-generation immune checkpoint inhibitors (ICI) and/or bi-specific engagers to improve anti-cancer response. Poster presented at the Annual Society for Immunotherapy of Cancer Congress, Houston, TX, USA. 2024. Poster #753.Hadfield MJ, et al. Overcoming resistance to programmed cell death protein (PD-1) blockade with allogeneic invariant natural killer-T cells. Oncogene 2024;43:758–762.Niedzielska M, et al. CAR-iNKT cells: redefining the frontiers of cellular immunotherapy. Front Immunol. 2025;16:1625426.Garmezy B, et al. AgenT-797, an allogeneic iNKT cell therapy, demonstrates durable clinical activity in solid tumors: Updated Phase I findings (NCT05108623). Poster presented at the Annual Society for Immunotherapy of Cancer Congress, National Harbor, MD, USA. 2025. Poster #1344.Chantzoura E, et al. The allogeneic FAP-CAR-IL-15 therapy MiNK-215 remodels the tumor stroma to enhance antitumor immunity. Cancer Immunol Res. 2026;14:243–260.Abstract 270 Figure 1AgenT-797 enhances T-cell infiltration and effector function in CRC liver metastasis organoids, alone and in combination with botensilimab and balstilimab. CRC liver met organoids were treated with agenT-797, NY-ESO-1 TCR-T cells, and/or BOT/BAL. (A) Representative images; (B-C) Secreted IFN-γ and GZMB by Luminex. Points = individual organoids. One-way ANOVA with Tukey test

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0270