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Background Immune checkpoint blockade (ICB) treatment, alone or in combination with standard anti-cancer therapies, has led to important progress in the treatment of head and neck squamous cell carcinoma (HNSCC). Yet, a significant proportion of patients with carcinogen-associated HNSCC develop disease relapse or progression. 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 MOC1 and MOC2 HNSCC tumor models.Methods C57BL/6 mice bearing MOC1 or MOC2 tumors were treated weekly 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 was conducted to gain a comprehensive understanding of the combination 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.Conclusions These findings provide a rationale for the combination of STAR0602 and SOC therapy in the clinical setting for patients with recurrent or metastatic HPV - HNSCC.Ethics Approval All animal experimental studies were performed under the approval of the NIH Intramural Animal Care and Use Committee. All mice were housed and maintained in accordance with the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) guidelines: NIH AALAC approval: CIO-2.