Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy.

Neoadjuvant immune checkpoint blockade has shown promising clinical activity. Here, we characterized early kinetics in tumor-infiltrating and circulating immune cells in oral cancer patients treated with neoadjuvant anti-PD-1 or anti-PD-1/CTLA-4 in a clinical trial (NCT02919683). Tumor-infiltrating CD8 T cells that clonally expanded during immunotherapy expressed elevated tissue-resident memory and cytotoxicity programs, which were already active prior to therapy, supporting the capacity for rapid response. Systematic target discovery revealed that treatment-expanded tumor T cell clones in responding patients recognized several self-antigens, including the cancer-specific antigen MAGEA1. Treatment also induced a systemic immune response characterized by expansion of activated T cells enriched for tumor-infiltrating T cell clonotypes, including both pre-existing and emergent clonotypes undetectable prior to therapy. The frequency of activated blood CD8 T cells, notably pre-treatment PD-1-positive KLRG1-negative T cells, was strongly associated with intra-tumoral pathological response. These results demonstrate how neoadjuvant checkpoint blockade induces local and systemic tumor immunity.

Managing the experience of breathlessness with Tai Chi: A qualitative analysis from a randomized controlled trial in COPD.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is associated with dyspnea, decreased physical activity, and reduced quality-of-life. While pulmonary rehabilitation is helpful, maintenance of physical activity afterwards is problematic. We sought to explore qualitatively the multi-dimensional, biopsychosocial experience of patients with COPD who participated in Tai Chi (TC) vs. group walking to facilitate physical activity after pulmonary rehabilitation). METHODS: We analyzed semi-structured qualitative exit interviews (N = 81) from a randomized controlled trial comparing 6-months TC with a time-matched group walking intervention and usual care control (UC). Transcripts were reviewed by at least 2 independent reviewers utilizing a social constructivist framework and theoretical sampling approach. An in-depth analysis of an exemplar subset was performed to thematic saturation and captured emergent themes within and between groups. RESULTS: Focused analysis was conducted on 54 transcripts (N = 21 TC, N = 16 Walking, N = 17 UC). Participants were characterized by mean age 68.5 (±8.3) years, GOLD Stage = 3.0 (IQR 2.0-3.0), baseline FEV1 percent predicted 48.8% (±16.4), and 48.2% female. We identified predominant themes of breathlessness, and associated fear and embarrassment that limited physical activity across all groups. In both TC and walking, participants reported improvements in energy and endurance. Those in TC additionally shared improvements in breathing, mobility, and capacity for daily activities facilitated by body and breath awareness, emotional control and regulation of breathing, and an adaptive reframing of breathlessness. CONCLUSION: TC promoted physical and mental wellbeing by diminishing fear and embarrassment associated with breathlessness. Results highlight the multimodal characteristics of TC that may facilitate continued physical activity and improvement in quality of life.

Patient reported outcomes in patients with head and neck cancer treated with concurrent chemoradiation with weekly versus bolus cisplatin.

BACKGROUND: Patient Reported Outcome (PRO) data comparing bolus (B-CP) with weekly (W-CP) cisplatin concurrent with radiation are lacking. METHODS: We performed a retrospective study comparing PRO among 99 patients with head and neck radiation, 26% who received concurrent B-CP and 73% treated with W-CP. RESULTS: W-CP patients had a higher Charlson comorbidity index (CCI) (P = .004). There were no differences in median cisplatin dose, PROs, percutaneous endoscopic gastrostomy (PEG) dependence or hospitalization between arms. Patients with a greater decline in their self-reported dysphagia score were more often PEG dependent at the end of radiation therapy (P = .03). There was also a trend toward PEG dependence with a higher maximum dysphagia score and greater change in aspiration score (P = .06). The maximum decline in white cell count and absolute neutrophil count were greater in the W-CP group (P = .04, P = .01). CONCLUSION: Both B-CP and W-CP are well tolerated. PROs do not suggest a benefit to W-CP.

Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial.

Importance: Novel approaches are needed to improve outcomes in patients with squamous cell carcinoma of the oral cavity. Neoadjuvant immunotherapy given prior to surgery and combining programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immune checkpoint inhibitors are 2 strategies to enhance antitumor immune responses that could be of benefit. Design, Setting, and Participants: In this randomized phase 2 clinical trial conducted at 1 academic center, 29 patients with untreated squamous cell carcinoma of the oral cavity (≥T2, or clinically node positive) were enrolled between 2016 to 2019. Interventions: Treatment was administered with nivolumab, 3 mg/kg, weeks 1 and 3, or nivolumab and ipilimumab (ipilimumab, 1 mg/kg, given week 1 only). Patients had surgery 3 to 7 days following cycle 2. Main Outcomes and Measures: Safety and volumetric response determined using bidirectional measurements. Secondary end points included pathologic and objective response, progression-free survival (PFS), and overall survival. Multiplex immunofluorescence was used to evaluate primary tumor immune markers. Results: Fourteen patients were randomized to nivolumab (N) and 15 patients to nivolumab/ipilimumab (N+I) (mean [SD] age, 62 [12] years; 18 men [62%] and 11 women [38%]). The most common subsite was oral tongue (n = 16). Baseline clinical staging included patients with T2 (n = 20) or greater (n = 9) T stage and 17 patients (59%) with node-positive disease. Median time from cycle 1 to surgery was 19 days (range, 7-21 days); there were no surgical delays. There were toxic effects at least possibly related to study treatment in 21 patients, including grade 3 to 4 events in 2 (N), and 5 (N+I) patients. One patient died of conditions thought unrelated to study treatment (postoperative flap failure, stroke). There was evidence of response in both the N and N+I arms (volumetric response 50%, 53%; pathologic downstaging 53%, 69%; RECIST response 13%, 38%; and pathologic response 54%, 73%, respectively). Four patients had major/complete pathologic response greater than 90% (N, n = 1; N+I, n = 3). With 14.2 months median follow-up, 1-year progression-free survival was 85% and overall survival was 89%. Conclusions and Relevance: Treatment with N and N+I was feasible prior to surgical resection. We observed promising rates of response in both arms, supporting further neoadjuvant studies with these agents. Trial Registration: ClinicalTrials.gov Identifier: NCT02919683.