Abstract C014: A novel TCRβ-directed IL-2 fusion molecule promotes stem-like CD8+ T cells with self-renewing properties in the peripheral lymphoid tissue, further expanded by HDAC inhibition to elicit a sustained anti-tumor therapeutic response

Abstract Background: Deficient T cell infiltration and function within the tumor microenvironment (TME) commonly underlie resistance to immune checkpoint blockade (ICB) in solid malignancies. Novel combination therapies may overcome these barriers, providing clinical benefit across solid tumors. STAR0602 is a first-in-class bifunctional antibody fusion protein, that simultaneously engages a nonclonal mode of T cell receptor (TCR) activation with IL-2R costimulation to promote activation and expansion of target Vβ6/10 T cells, highly prevalent across human cancers. Here, we examined the tumor-suppressive ability and mode of action of a murine surrogate of STAR0602 (mSTAR1302), which targets the prevalent murine TCRVβ13.2/13.3, in combination with the class I HDAC inhibitor (HDACi) Entinostat, an epigenetic modulator that enhances tumor immune recognition, in multiple tumor models irrespective of ICB responsiveness. Methods: mSTAR1302 and/or Entinostat were administered to mice bearing ICB-responsive breast (EMT6) and ICB-refractory colorectal (CT26; KRasG12Dmut) tumors. Anti-tumor efficacy, survival, and protective memory were monitored. Comprehensive transcriptomic, proteomic and immune profiling of tumor, tumor-draining lymph node (tdLN), and spleen cell populations was conducted along with immune cell depletion studies. Antigen-specific IFN T cell responses were evaluated by ELISpot. Results: Combination therapy induced significant enhancement in tumor suppression, eradication, and prolonged survival in EMT6 and CT26 tumors relative to single agent therapies, and eliciting protective memory. Tumor suppression was independent of CD4+ T cells and associated with sustained activation and expansion of functional Vβ13+ CD8+ T cells. Single cell proteomic and transcriptomic analysis demonstrated mSTAR1302 to increase TCF1+ stem-like memory CD8+ T cell populations in the tdLN, furthered enhanced with the addition of Entinostat. Trajectory analysis of TCF1+ stem-like memory Vβ13+ CD8+ T cells expanded by combination therapy in the tdLN denoted TME differentiation into cytolytic effector CD8+ T cells exhibiting a reduced exhaustion signature. Ongoing studies examining immune crosstalk within these stemness ecosystems will enhance our understanding of its mechanistic contribution to tumor suppression. Conclusions: Collectively, these data demonstrate the antitumor effects of non-canonical TCRVβ13/IL-2R targeting to be significantly augmented by combination with Entinostat. These effects are associated with TCRVβ13/IL-2R targeting augmenting CD8+ T cell self-renewal properties, further enhanced with HDACi combination. Collectively, this data supports the clinical use of STAR0602 in combination with HDAC inhibitors for patients harboring solid malignancies irrespective of ICB sensitivity. Citation Format: Katherine L. Lothstein, Christine M. Minnar, Asma S. Khelifa, Masaya Miyamoto, Ainara Meler, Lisa K. Poppe, Nicholas Roller, David Peeney, Andrew Bayliffe, Zhen Su, James L. Gulley, Jeffrey Schlom, Sofia R. Gameiro. A novel TCRβ-directed IL-2 fusion molecule promotes stem-like CD8+ T cells with self-renewing properties in the peripheral lymphoid tissue, further expanded by HDAC inhibition to elicit a sustained anti-tumor therapeutic response 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 C014.