Phase 2 balstilimab PD-1 mAb + botensilimab Fc‑enhanced CTLA‑4 mAb + agenT‑797 allo‑iNKT therapy

This Phase 2, open-label, single-arm study tests whether adding cellular therapy to dual checkpoint blockade can generate responses in proficient MMR (MSS/pMMR) metastatic colorectal cancer with active liver metastases—an immunotherapy-resistant setting where the liver microenvironment is thought to promote immune tolerance. Patients receive balstilimab (Agenus; PD-1/CD279–blocking monoclonal antibody) plus botensilimab (Agenus; Fc‑enhanced CTLA‑4–blocking monoclonal antibody designed to amplify immune priming) together with agenT‑797 (MiNK Therapeutics; off‑the‑shelf allogeneic invariant NKT [iNKT] cell therapy intended to drive rapid cytokine signaling and cross-talk with T cells and innate immunity). Treatment runs in repeating 42‑day cycles (up to 9 cycles) with imaging-based objective response rate by RECIST v1.1 as the primary endpoint, plus standard safety monitoring for immune-related AEs and cytokine-type infusion reactions. Eligible patients must have measurable disease with at least one liver target lesion and have received at least one prior systemic line including fluoropyrimidine, oxaliplatin, and irinotecan (and anti‑VEGF and/or anti‑EGFR therapy when appropriate). Today’s care for 2nd line+ MSS mCRC with liver mets is sequential systemic therapy (FOLFOX/FOLFIRI backbones, biologics like bevacizumab or EGFR antibodies when RAS/RAF wild-type, and later-line options such as trifluridine/tipiracil ± bevacizumab, regorafenib, and targeted agents for specific biomarkers), and this study probes whether a “triple-immune” strategy can meaningfully move the needle in a population where PD‑1 therapy alone rarely works.