Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-β blockade in HPV-unrelated head and neck cancer
Jason M. Redman, Jay Friedman, Yvette Robbins, Cem Sievers, Xinping Yang, Wiem Lassoued, Andrew Sinkoe, Antonios Papanicolau-Sengos, Chyi-Chia Lee, Jennifer L. Marte, Evrim Turkbey, Wojtek Mydlarz, Arjun Joshi, Nyall R. London Jr., Matthew Pierce, Rodney Taylor, Steven Hong, Andy Nguyen, Patrick Soon-Shiong, Jeffrey Schlom, James L. Gulley, Clint T. Allen
Jason M. Redman, Jay Friedman, Yvette Robbins, Cem Sievers, Xinping Yang, Wiem Lassoued, Andrew Sinkoe, Antonios Papanicolau-Sengos, Chyi-Chia Lee, Jennifer L. Marte, Evrim Turkbey, Wojtek Mydlarz, Arjun Joshi, Nyall R. London Jr., Matthew Pierce, Rodney Taylor, Steven Hong, Andy Nguyen, Patrick Soon-Shiong, Jeffrey Schlom, James L. Gulley, Clint T. Allen
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Clinical Research and Public Health Immunology

Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-β blockade in HPV-unrelated head and neck cancer

Abstract

BACKGROUND Head and neck squamous cell carcinoma not associated with HPV (HPV-unrelated HNSCC) is associated with a high rate 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 TGF-β.RESULTS Bintrafusp alfa was well tolerated, and no treatment-associated surgical delays or complications occurred. Objective pathologic responses (PRs) were observed, and 12 of the 14 (86%) patients were alive and disease free at 1 year. Alterations in Treg infiltration and spatial distribution relative to proliferating CD8+ T cells indicated a reversal of Treg immunosuppression in the primary tumor. Detection of neoepitope-specific tumor T cell responses, but not virus-specific responses, correlated with the development of a PR. Detection of neoepitope-specific responses and PRs in tumors was not correlated with genomic features or tumor antigenicity but was associated with reduced pretreatment myeloid cell tumor infiltration. These results indicate that dual PD-L1 and TGF-β blockade can safely enhance tumor antigen–specific immunity and highlight the feasibility of multimechanism neoadjuvant immunotherapy for patients with HPV-unrelated HNSCC.CONCLUSION Our studies provide 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 antitumor immunity following such treatment.TRIAL REGISTRATION ClinicalTrials.gov NCT04247282.FUNDING This work was funded by the Center for Cancer Research, the NCI, and the Intramural Research Program of the NIDCD, NIH. Bintrafusp alfa was provided by the health care business of Merck KGaA (Darmstadt, Germany), through a Cooperative Research and Development Agreement with the NCI. Additional funding was provided by ImmunityBio through a Cooperative Research and Development Agreement with the NIDCD.

Authors

Jason M. Redman, Jay Friedman, Yvette Robbins, Cem Sievers, Xinping Yang, Wiem Lassoued, Andrew Sinkoe, Antonios Papanicolau-Sengos, Chyi-Chia Lee, Jennifer L. Marte, Evrim Turkbey, Wojtek Mydlarz, Arjun Joshi, Nyall R. London Jr., Matthew Pierce, Rodney Taylor, Steven Hong, Andy Nguyen, Patrick Soon-Shiong, Jeffrey Schlom, James L. Gulley, Clint T. Allen

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Figure 2

Primary tumor and LN responses.

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Primary tumor and LN responses. (A) Waterfall plot shows primary tumor P...
(A) Waterfall plot shows primary tumor PRs (n = 14), ranked from left to right by decreasing percentage of tumor regression within the tumor bed. A PR was defined as a pTR of 50% or greater; a non-PR was defined as a pTR of less than 50%. (B) Waterfall plot shows primary tumor radiographic responses (n = 14), calculated as the percentage of change in the product of the longest primary tumor lengths and widths, ranked from left to right in the same order as in A. The asterisks indicate that the primary tumor was not visible on the CT scan. (C) Waterfall plot shows LN PRs (n = 14), ranked from left to right by decreasing percentage of primary tumor regression within the tumor bed. A PR was defined as a pTR of 50% or greater. The pound signs indicate patients who had suspicious LNs on pretreatment workup but were found to be pathologically N0 and considered to have a possible LN CR. (D) Waterfall plot shows LN radiographic responses (n = 14), calculated as the percentage of change in the product of the largest bidirectional diameter of a target suspicious LN, ranked from left to right in the same order as in A. In patients with LNs positive for carcinoma, the volume of all positive nodes was considered. For patients with suspicious nodes negative for carcinoma pathologically, only the radiographically suspicious LN volume was considered. The asterisks indicate that no clinically suspicious or pathologically positive LNs were found. The bottom black (yes) and white (no) boxes indicate patients with a disease-free status 1 year after completing the study.