Enhanced neoepitope-specific immunity following neoadjuvant PD-L1 and TGF-β blockade in HPV-unrelated head and neck cancer
Jason M. Redman, … , James L. Gulley, Clint T. Allen
Jason M. Redman, … , James L. Gulley, Clint T. Allen
Published June 21, 2022
Citation Information: J Clin Invest. 2022;132(18):e161400. https://doi.org/10.1172/JCI161400.
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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 6

Neoepitope-specific TIL responses.

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Neoepitope-specific TIL responses. (A) Dot plot on the left shows the nu...
(A) Dot plot on the left shows the number of distinct neoepitopes eliciting positive IFN-γ responses in an ELISpot analysis of pre-treatment and post-treatment TILs for each patient (n = 12), ranked from left to right by decreasing percentage of tumor regression within the tumor bed. Dot plot on the right shows the same in patients who did (n = 5) or did not (n = 7) have a PR. Significance was determined with a 2-tailed Mann-Whitney U test. (B) Dot plot on the left shows the number of neoepitope-specific cumulative IFN-γ spots in an ELISpot analysis of pre- and post-treatment TILs for each patient (n = 12), ranked from left to right by decreasing percentage of tumor regression within the tumor bed. Dot plot on the right shows the same in patients who did (n = 5) or did not (n = 7) have a PR. Significance was determined with a 2-tailed Mann-Whitney U test. (C) Dot plots show the in silico–predicted IC50 and TPM counts for putative neoepitopes that elicited (n = 24) or did not elicit (n = 84) IFN-γ responses in TILs. Horizontal bar indicates the median. Significance was determined with a 2-tailed Mann-Whitney U test. (D) Dot plots show the total number of mutations and total number of predicted neoepitopes (IC50 <500 nM) in tumors that did (n = 8) or did not (n = 4) display detectable neoepitope-specific T cell responses in TILs. Significance was determined with a 2-tailed Mann-Whitney U test. (E) Dot plots show the total number of mutations and total number of predicted neoepitopes (IC50 <500 nM) in patients who did (n = 5) or did not (n = 97) have a PR. Significance was determined with a 2-tailed Mann-Whitney U test. (F) Dot plot shows pretreatment tumor quantification of total stromal or tumor myeloid cells in patients whose TILs did (n = 8) or did not (n = 4) display detectable neoepitope-specific T cell responses. Significance was determined with a 2-tailed Mann-Whitney U test. (G) Dot plot shows pretreatment tumor quantification of stromal cells or tumor Tregs from patients whose TILs did (n = 8) or did not (n = 4) display detectable neoepitope-specific T cell responses. Significance was determined with a 2-tailed Mann-Whitney U test.