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Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma.

ABSTRACT: Neoadjuvant PD-1 blockade may be efficacious in some individuals with high-risk, resectable oral cavity head and neck cancer. To explore correlates of response patterns to neoadjuvant nivolumab treatment and post-surgical recurrences, we analyzed longitudinal tumor and blood samples in a cohort of 12 individuals displaying 33% responsiveness. Pretreatment tumor-based detection of FLT4 mutations and PTEN signature enrichment favors response, and high tumor mutational burden improves recurrence-free survival. In contrast, preexisting and/or acquired mutations (in CDKN2A, YAP1, or JAK2) correlate with innate resistance and/or tumor recurrence. Immunologically, tumor response after therapy entails T cell receptor repertoire diversification in peripheral blood and intratumoral expansion of preexisting T cell clones. A high ratio of regulatory T to T helper 17 cells in pretreatment blood predicts low T cell receptor repertoire diversity in pretreatment blood, a low cytolytic T cell signature in pretreatment tumors, and innate resistance. Our study provides a molecular framework to advance neoadjuvant anti-PD-1 therapy for individuals with resectable head and neck cancer.

SUBMITTER: Liu S

PROVIDER: S-EPMC8561238 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma.

Liu Sixue S Knochelmann Hannah M HM Lomeli Shirley H SH Hong Aayoung A Richardson Mary M Yang Zhentao Z Lim Raymond J RJ Wang Yan Y Dumitras Camelia C Krysan Kostyantyn K Timmers Cynthia C Romeo Martin J MJ Krieg Carsten C O'Quinn Elizabeth C EC Horton Joshua D JD Dubinett Steve M SM Paulos Chrystal M CM Neskey David M DM Lo Roger S RS

Cell reports. Medicine 20211019 10

Neoadjuvant PD-1 blockade may be efficacious in some individuals with high-risk, resectable oral cavity head and neck cancer. To explore correlates of response patterns to neoadjuvant nivolumab treatment and post-surgical recurrences, we analyzed longitudinal tumor and blood samples in a cohort of 12 individuals displaying 33% responsiveness. Pretreatment tumor-based detection of <i>FLT4</i> mutations and <i>PTEN</i> signature enrichment favors response, and high tumor mutational burden improves ...[more]

PMID: 34755131

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Project description:BackgroundA single-agent of anti programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) therapy has been explored for resectable lung cancer before surgery. However, the effectiveness and safety of neoadjuvant programmed cell death 1 (PD-1) blockade combined with chemotherapy have not been published.MethodsTwenty-one consecutive patients with potentially resectable squamous cell carcinoma of the lung who received neoadjuvant therapy followed by surgery in Beijing Cancer Hospital were included in this study. Eight patients received two cycles of neoadjuvant platinum-based doublet chemotherapy combined with anti-programmed cell death 1 (anti-PD-1) therapy, while 13 patients received two cycles of neoadjuvant platinum-based doublet chemotherapy only. Chest computed tomography was repeated before neoadjuvant treatment and surgery. Adverse events were monitored. The major pathological response (MPR) rate was determined after surgery. Selected specimens were sent for immunohistochemical and multiplex immunofluorescence analyses, and T-cell receptor DNA sequencing.ResultsCompared with neoadjuvant chemotherapy alone, the combination of PD-1 blockade and chemotherapy increased the pathological complete response rate (37.5% vs. 7.69%) and MPR rate (50% vs. 38.46%). The pathological and radiological evaluations are not consistent. No unknown adverse effects were reported for all the patients. More tumor infiltrating lymphocytes were observed in patients who received PD-1 blockade. No unknown pathological features associated with PD-1 blockade were found. Immune suppression in the peritumoral spaces around the residual tumor cells was observed. The amino acid sequences of the T-cell receptors are not significantly shared among the patients.ConclusionsThe combination of neoadjuvant chemotherapy and PD-1 blockade is safe and feasible, and might indicate an increased MPR and pathological complete response rate. More investigations are needed for the best combination of the neoadjuvant therapy.

Project description:BackgroundAntibodies that block programmed death 1 (PD-1) protein improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade.MethodsIn this pilot study, we administered two preoperative doses of PD-1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD-L1), mutational burden, and mutation-associated, neoantigen-specific T-cell responses.ResultsNeoadjuvant nivolumab had an acceptable side-effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD-L1-positive and PD-L1-negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T-cell clones that were found in both the tumor and peripheral blood increased systemically after PD-1 blockade in eight of nine patients who were evaluated. Mutation-associated, neoantigen-specific T-cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab.ConclusionsNeoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD-1 blockade. Treatment induced expansion of mutation-associated, neoantigen-specific T-cell clones in peripheral blood. (Funded by Cancer Research Institute-Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621 .).

Dataset Information

Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma.

Publications

Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma.

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