Combination of a novel TCR Vβ chain-directed selective T cell activator with standard of care therapy for head and neck cancer improves antitumor responses and promotes regression of checkpoint-refractory tumor models

Background

Immune checkpoint blockade (ICB) treatment, alone or in combination with standard anticancer 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 (human papillomavirus (HPV) ⁻ ) 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 comprising an antibody targeting Vβ6 and Vβ10 T cell receptors fused to human interleukin-2, has demonstrated clinical activity in anti-programmed death-ligand 1 resistant tumors. A murine surrogate molecule, mSTAR1302, has been shown to induce tumor regression in multiple syngeneic tumor models and enhance antitumor activity in ICB-refractory settings. This study investigates the therapeutic benefit of mSTAR1302 combined with SOC in the mouse oral carcinoma (MOC)1 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) antibody 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 an understanding of the mechanism of action of the combination therapy.

Results

Combination therapy with mSTAR1302, cisplatin, and α-PD-1 promoted robust antitumor activity, higher numbers of mice with complete resolution of tumors, and significantly prolonged survival compared with mSTAR1302 monotherapy or SOC treatment in MOC1 and MOC2 tumors. Tumor-free animals from cohorts treated with the combination therapy demonstrated protection against tumor rechallenge and an overall increase in antigen-specific T cells. Tumor growth inhibition was associated with the expansion of Vβ13 CD8 ⁺ and CD4 ⁺ T cells, characterized by heightened cytotoxic and effector potentials, in both the tumor and the periphery. The therapeutic effect elicited by the combination therapy was strongly dependent on interferon-γ expression. Thus, 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 HPV ⁻ HNSCC.