Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-b blockade in HPV-unrelated head and neck cancer
The Journal of clinical investigation
Clinical Trials; Immunology; Immunotherapy
BACKGROUND: Head and neck squamous cell carcinoma not associated with human papillomavirus (HPV-unrelated HNSCC) is associated with high rates of recurrence and poor survival. METHODS: We conducted a clinical trial in 14 patients with newly diagnosed, HPV-unrelated HNSCC to evaluate the safety and efficacy of neoadjuvant bintrafusp alfa, a bifunctional fusion protein that blocks programmed death-ligand 1 (PD-L1) and neutralizes transforming growth factor-beta (TGF-). RESULTS: Bintrafusp alfa was well tolerated, and no treatment-associated surgical delays or complications occurred. Objective pathologic responses were observed and 12 of 14 patients (86%) were alive and disease free at one year. Alterations in regulatory T cell infiltration and spatial distribution relative to proliferating CD8 T cells indicated reversal of Treg immunosuppression in the primary tumor. Detection of neoepitope-specific tumor T cell responses, but not viral-specific responses, correlated with development of a pathologic response. Detection of neoepitope-specific responses and pathologic responses in tumors was not correlated with genomic features or tumor antigenicity but was associated with reduced pre-treatment myeloid cell tumor infiltration. These results indicate that dual PD-L1 and TGF- blockade can safely enhance tumor antigen-specific immunity and highlight the feasibility of multi-mechanism neoadjuvant immunotherapy in patients with HPV-unrelated HNSCC. CONCLUSION: Our studies provide new insight into the ability of neoadjuvant immunotherapy to induce polyclonal neoadjuvant-specific T cell responses in tumors and suggest that features of the tumor microenvironment, such as myeloid cell infiltration, may be a major determinant of enhanced anti-tumor immunity following such treatment.
Redman, Jason M.; Friedman, Jay; Robbins, Yvette; Sievers, Cem; Yang, Xinping; Lassoued, Wiem; Sinkoe, Andrew; Papanicolau-Sengos, Antonios; Lee, Chyi-Chia R.; Marte, Jennifer L.; Turkbey, Evrim B.; Mydlarz, Wojciech; Joshi, Arjun S.; London, Nyall R.; Pierce, Matthew; Taylor, Rodney J.; Hong, Steven; Nguyen, Andrew; Soon-Shiong, Patrick; Schlom, Jeffrey; Gulley, James L.; and Allen, Clint T., "Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-b blockade in HPV-unrelated head and neck cancer" (2022). GW Authored Works. Paper 1088.