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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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Clinical Research and Public Health Immunology Article has an altmetric score of 3

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

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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 3

MIF analysis of tumor TGF-β pathway activation.

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MIF analysis of tumor TGF-β pathway activation.
(A) Heatmap shows patter...
(A) Heatmap shows patterns of log2 FC in nuclear H-scores of TGF-β pathway signaling proteins after treatment compared with before treatment for each patient (n = 14). (B) Dot plot shows the log2 FC in nuclear H-scores of TGF-β pathway signaling proteins in the stroma or tumor parenchyma after treatment compared with before treatment (n = 14). Most stromal cells were immune (mean, 79%; range, 59%–93%), based on size and morphology. Significance was determined with a 1-sample t test; the P value in red is significant. (C) Representative photomicrographs of pre- and post-treatment tumor Ki67 expression for patient 13, measured by immunofluorescence. Scale bars: 50 μm. (D) Box-and-whisker plots show the log2 FC in the tumor or stromal nuclear Ki67 H-score after treatment compared with before treatment in patients who did (n = 5) or did not (n = 9) have a PR. Significance was determined with a 2-tailed Mann-Whitney U test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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