Abstract A028: Combination therapy with a TCR Vβ-directed bifunctional molecule, cisplatin and anti-PD-1 promotes antitumor activity in immune checkpoint blockade-refractory head and neck murine tumor models

Abstract Background Immune checkpoint blockade (ICB) treatment, alone or in combination with cisplatin and fluorouracil (FU) chemotherapy, is used as first-line treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Yet, a significant proportion of patients with carcinogen-associated HNSCC develop disease relapse or progression within 2 years. Effective treatments for patients who have failed standard of care (SOC) treatment are lacking. STAR0602, a selective, bifunctional T cell agonist consisting of an antibody targeting Vβ6 and Vβ10 T cell receptors fused to human interleukin-2, has demonstrated clinical activity in anti-PD(L)-1 resistant tumors. The murine surrogate, mSTAR1302, has been shown to induce tumor regression in multiple syngeneic tumor models and provided preclinical evidence for enhanced antitumor activity in ICB-refractory settings. This study investigates the therapeutic benefit of mSTAR1302 combined with SOC in the mouse oral carcinoma MOC1 and MOC2 HNSCC tumor models. Methods C57BL/6 mice bearing MOC1 or MOC2 tumors were treated once a week with mSTAR1302, cisplatin and α-programmed cell death protein 1 (PD-1) to determine antitumor efficacy and survival benefit. Immune populations and their effector functions were characterized by flow cytometry and cytokine assays. The tumor microenvironment’s immune architecture was analyzed by multiplex immunofluorescence. Gene expression analysis derived a comprehensive understanding of the multimodal therapy’s mechanism of action. Results Combination therapy with mSTAR1302, cisplatin and α-PD-1 induced a robust antitumor activity, significantly prolonged survival and yielded the highest percentage of tumor resolution in comparison with mSTAR1302 monotherapy or SOC treatment in MOC1 and MOC2 tumors. Tumor-free animals from cohorts treated with the combination therapy demonstrated immune protection against tumor rechallenge and an overall increase in antigen-specific T cells. Tumor growth inhibition was associated with Vβ13 CD4+ and CD8+ T cells expansion and heightened cytotoxic activity. The improved therapeutic effect was strongly dependent on interferon-γ expression. The combination of mSTAR1302 and α-PD-1 enabled control of tumors that progressed following platinum-containing treatment. Conclusion These findings provide a rationale for the combination of STAR0602 and SOC therapy in the clinical setting for patients with recurrent or metastatic carcinogen-associated HNSCC. Citation Format: Francesca Rosato, Ginette S. Santiago-Sanchez, Kellsye P. Fabian, Michelle R. Padget, Jonelle K. Lee, Clint T. Allen, Zhen Su, Jacques Moisan, Madan Katragadda, Andrew Bayliffe, Jeffrey Schlom, James W. Hodge. Combination therapy with a TCR Vβ-directed bifunctional molecule, cisplatin and anti-PD-1 promotes antitumor activity in immune checkpoint blockade-refractory head and neck murine tumor models [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 A028.