Abstract B022: Synergistic epigenetic modulation with a TCRβ-targeted IL-2 fusion molecule enhances CD8+ T cell-mediated MHC-I independent tumor control via an antibody-linked mechanism

Abstract Background: Epigenetic silencing of MHC-I and poor T cell infiltration and function in the tumor microenvironment (TME) are prevalent in solid malignancies and associate with lack of clinical response to immune checkpoint blockade (ICB), prompting the need for novel combination approaches able to provide clinical benefit. STAR0602 is a first-in-class bifunctional fusion protein that simultaneously engages a nonclonal mode of T cell receptor (TCR) activation with IL-2R costimulation to promote selective activation/expansion of target Vβ6/Vβ10 T cells, prevalent across human cancers. Here, we examined the tumor-suppressive ability and mode of action of a murine surrogate of STAR0602 (mSTAR1302), which targets murine TCRVβ13.2/13.3, in combination with the class I HDAC inhibitor (HDACi) Entinostat, an epigenetic modulator that enhances tumor immune cell recognition, in multiple ICB-refractory tumor models devoid of MHC-I. Methods: mSTAR1302 and/or Entinostat were administered to mice bearing β2-microglobulin (B2m)-deleted (MHC-Inull) breast (EMT6) and colorectal (MC38) tumors. Anti-tumor efficacy, survival, and protective memory were monitored. Comprehensive transcriptomic, proteomic and immune cell profiling of tumor, tumor-draining lymph node (tdLN), and spleen were conducted along with immune depletion studies. Antigen-specific IFN T cell responses were evaluated by ELISpot. Results: Combination therapy elicited significant enhancement in tumor suppression and prolonged survival benefit with tumor-specific protective memory in both EMT6 and MC38 β2m-KO tumors relative to single agent therapy. Tumor suppression was independent of NK cells and CD4+ T cells and associated with sustained activation, expansion, and increased functionality of Vβ13+ CD8+ T cells. Tumor single-cell transcriptomic and spatial proteomic analyses in combination-treated mice highlight complementary mechanisms of tumor suppression beyond CD8+ T cells, associated with plasma B cells and FcgR3/4+ M1-like macrophage dominant TME driven by mSTAR1302, further enhanced with the addition of HDACi. The dependency on CD8+ T cells for activity of tumor M1 macrophages and B cells with heightened presence of IgG2a antibodies in combination-treated tumors suggest a potential role for tumor lysis via antibody-dependent phagocytosis when MHC-I/TCR CD8 engagement is absent. Ongoing mechanistic investigation of this myeloid/lymphoid crosstalk in MHC-I+ and MHC-Inull tumors will provide deeper insight into the mode of action of this combination therapy. Conclusion: Collectively, these data highlight an alternative mechanism of tumor suppression when direct MHC-I/TCR engagement is absent. This supports the use of STAR0602 in combination with HDAC inhibitors for the treatment of solid malignancies including those resistant to current ICB therapies. Citation Format: Katherine L. Lothstein, Lisa K. Poppe, Christine M. Minnar, Asma S. Khelifa, Ainara Meler, Nicholas Roller, Masaya Miyamoto, David Peeney, Andrew Bayliffe, Zhen Su, James L. Gulley, Jeffrey Schlom, Sofia R. Gameiro. Synergistic epigenetic modulation with a TCRβ-targeted IL-2 fusion molecule enhances CD8+ T cell-mediated MHC-I independent tumor control via an antibody-linked mechanism abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B022.