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ImportanceProliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape revealed a cytotoxic T-cell-rich microenvironment, providing strong rationale to investigate immune checkpoint therapy.ObjectiveTo determine the safety and clinical activity of anti-programmed cell death 1 protein (PD-1) therapy to treat high-risk PVL.Design, setting, and participantsThis nonrandomized, open-label, phase 2 clinical trial was conducted from January 2019 to December 2021 at a single academic medical center; median (range) follow-up was 21.1 (5.4-43.6) months. Participants were a population-based sample of patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia).InterventionPatients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab (480 mg intravenously) every 28 days, followed by rebiopsy and intraoral photographs at each visit.Main outcomes and measuresThe primary end point was the change in composite score (size and degree of dysplasia) from before to after treatment (major response [MR]: >80% decrease in score; partial response: 40%-80% decrease). Secondary analyses included immune-related adverse events, cancer-free survival (CFS), PD-1 ligand 1 (PD-L1) expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response.ResultsA total of 33 patients were enrolled (median [range] age, 63 [32-80] years; 18 [55%] were female), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%) (95% CI, 20.4%-54.8%) had a response by composite score (3 MRs [9%]), 4 had progressive disease (>10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the trial, with a 2-year CFS of 73% (95% CI, 53%-86%). Two patients (6%) discontinued because of toxic effects; 7 (21%) experienced grade 3 to 4 immune-related adverse events. PD-L1 combined positive scores were not associated with response or CFS. Of 20 whole-exome sequenced patients, all 6 patients who had progression to OSCC after nivolumab treatment exhibited 9p21.3 somatic copy-number loss on pretreatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss.Conclusions and relevanceThis immune checkpoint therapy precancer nonrandomized clinical trial met its prespecified response end point, suggesting potential clinical activity for nivolumab in high-risk PVL. Findings identified immunogenomic associations to inform future trials in this precancerous disease with unmet medical need that has been difficult to study.Trial registrationClinicalTrials.gov Identifier: NCT03692325.

Background: In the era of immune checkpoint blockade, the role of cancer vaccines in immune priming has provided additional potential for therapeutic improvements. Prior studies have demonstrated delayed type hypersensitivity and anti-tumor immunity with vaccines engineered to secrete granulocytemacrophage colony-stimulating factor (GM-CSF). The safety, efficacy and antitumor immunity of GM-CSF secreting vaccine in patients with previously treated stage III or IV melanoma needs further investigation. Methods: In this phase II trial, excised lymph node metastases were processed to single cells, transduced with an adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1x106, 4x106, or 1x107 tumor cells, and were injected intradermally and subcutaneously at weekly and biweekly intervals. The primary endpoints were feasibility of producing vaccine in stage III patients and determining the proportion of patients alive at two years in stage IV patients. Results: GM-CSF vaccine was successfully developed and administered in all 61 patients. Toxicities were restricted to grade 1-2 local skin reactions. The median OS for stage III patients (n = 20) was 71.1 (95% CI, 43.7 to NR) months and 14.9 (95%CI, 12.1 to 39.7) months for stage IV patients. The median PFS in stage III patients was 50.7 (95%CI, 36.3 to NR) months and 4.1 (95% CI, 3.0-6.3) months in stage IV patients. In the overall population, the disease control rate was 39.3% (95%CI, 27.1 to 52.7%). In stage III patients, higher pre-treatment plasma cytokine levels of MMP-1, TRAIL, CXCL-11, CXCL-13 were associated with improved PFS (p<0.05 for all). An increase in post-vaccination levels of IL-15 and TRAIL for stage III patients was associated with improved PFS (p=0.03 for both). Similarly, an increase in post-vaccination IL-16 level for stage IV patients was associated with improved PFS (p=0.02) and clinical benefit. Conclusions: Vaccination with autologous melanoma cells secreting GM-CSF augments antitumor immunity in stage III and IV patients with melanoma, is safe, and demonstrates disease control. Luminex data suggests that changes in inflammatory cytokines and immune cell infiltration promote tumor antigen presentation and subsequent tumor cell destruction. Additional investigation to administer this vaccine in combination with immune checkpoint inhibitors is needed. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the role of patients' personal social networks (SNs) in accessing head and neck cancer (HNC) care through patients' and health care workers' (HCWs) perspectives. Study Design: Qualitative study. Setting: Tertiary HNC centers at 2 academic medical centers, including 1 safety net hospital. Methods: Patients with newly diagnosed HNC, and HCWs caring for HNC patients, aged ≥18 years were recruited between June 2022 and July 2023. Semistructured interviews were conducted with both patients and HCWs. Inductive and deductive thematic analysis was performed with 2 coders (κ = 0.82) to analyze the data. Results: The study included 72 participants: 42 patients (mean age 57 years, 64% female, 81% white), and 30 HCWs (mean age 42 years, 77% female, 83% white). Four themes emerged: (1) Patients' SNs facilitate care through various forms of support, (2) patients may hesitate to seek help from their networks, (3) obligations toward SNs may act as barriers to seeking care, and (4) the SN composition and dedication influence care‐seeking. Conclusion: Personal SNs play a vital role in prompting early care‐seeking among HNC patients. SN‐based interventions could enhance care and improve outcomes for HNC patients. [ABSTRACT FROM AUTHOR]

About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti–programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8+ T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8+ tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX+) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX+ZNF683+CD8+ TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103+PD-1+CD8+ T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683+CTX+ TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683+CTX+ TILs is a major mechanism of response in the immediate postneoadjuvant setting. Editor's summary: Immune checkpoint blockade (ICB) such as anti-PD-1 reinvigorates tumor-specific T cell responses, but the mechanisms underlying specific clinical responses remain unclear. Using single-cell transcriptomics and TCR sequencing, Oliveira et al. analyzed tumor specimens from patients with head and neck cancer enrolled in a phase II clinical trial testing two doses of neoadjuvant anti–PD-1 before surgical resection. Tumors responding to anti–PD-1 contained a baseline population of ZNF683+CD8+ T cells expressing genes associated with T cell exhaustion, tissue resident memory, and cytotoxicity. In paired pre- and post-treatment biopsies, ZNF683+CD8+ T cells were clonally expanded and exhibited the strongest change in patients responding to ICB. These findings identify reinvigoration of cytotoxicity among ZNF683+CD8+ T cells as a likely mechanism underlying response to neoadjuvant anti–PD-1 in head and neck cancer. —Claire Olingy [ABSTRACT FROM AUTHOR]

Objective: To demonstrate feasibility of a recently developed preoperative assessment tool, the Vulnerable Elders Surgical Pathways and Outcomes Analysis (VESPA), to characterize the baseline functional status of patients undergoing major head and neck surgery and to examine the relationship between preoperative functional status and postoperative outcomes. Study Design: Case series with planned data collection. Setting: Two tertiary care academic hospitals. Methods: The VESPA was administered prospectively in the preoperative setting. Data on patient demographics, ablative and reconstructive procedures, and outcomes including total length of stay, discharge disposition, delay in discharge, or complex discharge planning (delay or change in disposition) were collected via retrospective chart review. VESPA scores were calculated and risk categories were used to estimate risk of adverse postoperative outcomes using multivariate logistic regression for categorical outcomes and linear regression for continuous variables. Results: Fifty-eight patients met study inclusion criteria. The mean (SD) age was 66.4 (11.9) years, and 58.4% of patients were male. Nearly one-fourth described preoperative difficulty in either a basic or instrumental activity of daily living, and 17% were classified as low functional status (ie, high risk) according to the VESPA. Low functional status did not independently predict length of stay but was associated with delayed discharge (odds ratio [OR], 5.0; 95% CI, 1.2-21.3; P =.030) and complex discharge planning (OR, 5.7; 95% CI, 1.34-24.2; P =.018). Conclusion: The VESPA can identify major head and neck surgical patients with low preoperative functional status who may be at risk for delayed or complex discharge planning. These patients may benefit from enhanced preoperative counseling and more comprehensive discharge preparation. [ABSTRACT FROM AUTHOR]