While viral antigens in HPV-related oropharyngeal cancer (HPVOPC) are attractive targets for immunotherapy, the effects of existing standard-of-care therapies on immune responses to HPV are poorly understood. We serially sampled blood from stage III–IV OPC patients undergoing concomitant chemoradiotherapy (CRT) with or without induction chemotherapy. Circulating immunocytes including CD4+ and CD8+ T cells, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) were profiled by flow cytometry. Antigen-specific T cell responses were measured in response to HPV16 E6 and E7 peptide pools. The role of PD-1 signaling in treatment-related immunosuppression was functionally defined by performing HPV-specific T cell assays in the presence of blocking antibody. While HPV-specific T cell responses were present in 13/18 patients prior to treatment, 10/13 patients lost these responses within 3 months after CRT. CRT decreased circulating T cells and markedly elevated MDSC. PD-1 expression on CD4+ T cells increased by nearly 2.5-fold after CRT, and ex-vivo culture with PD-1 blocking antibody enhanced HPV-specific T cell responses in 8/18 samples tested. CRT suppresses circulating immune responses in HPVOPC patients by unfavorably altering effector:suppressor immunocyte ratios and upregulating PD-1 expression on CD4+ T cells. These data strongly support testing of PD-1-blocking agents in combination with standard-of-care CRT for HPVOPC.

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BACKGROUND: Concurrent inhibition of epidermal growth factor receptor (EGFR) and cyclooxygenase‐2 (COX‐2) is an active and well tolerated regimen in recurrent head and neck cancer (HNC). In the current phase 1 trial, the authors sought to determine the maximum tolerated dose (MTD) and efficacy of concurrent erlotinib and celecoxib as a radiosensitizing regimen. METHODS: Fourteen patients with previously irradiated HNC with no distant metastases who required reirradiation were eligible. Treatment consisted of daily erlotinib 150 mg and twice daily celecoxib (escalated from 200 mg to 600 mg using a 3 + 3 design with an expanded cohort at the MTD) starting on Day 1 and was continued during radiation. Daily radiation was started on Day 15, and maintenance erlotinib was recommended. RESULTS: The recommended phase 2 dose of celecoxib was 400 mg. Three dose‐limiting toxicities included late in‐field orocutaneous fistula (Dose Level 2), osteonecrosis (Dose Level 3), and trismus (Dose Level 3). Acute grade ≥3 toxicities were uncommon and included mucositis (21%) and dermatitis (14%). At a median follow‐up of 11 months, the 1‐year locoregional control, progression‐free survival, and overall survival rates were 60%, 37%, and 55%, respectively. CONCLUSIONS: Concurrent erlotinib, celecoxib, and reirradiation was a feasible and clinically active regimen in a population of patients with recurrent HNC who had a poor prognosis. Cancer 2011. © 2011 American Cancer Society.

Background Treatment of human papillomavirus‐related oropharyngeal squamous cell carcinoma (HPVOPC) results in unprecedented high survival rates but possibly unnecessary toxicity. We hypothesized that upfront surgery and neck dissection followed by reduced‐dose adjuvant therapy for early and intermediate HPVOPC would ultimately result in equivalent progression‐free survival (PFS) and overall survival while reducing toxicity. Methods This study was a nonrandomized phase II trial for early‐stage HPVOPC treated with transoral robotic surgery (TORS) followed by reduced‐dose radiotherapy. Patients with previously untreated p16‐positive HPVOPC and <20 pack years’ smoking history were enrolled. After robotic surgery, patients were assigned to group 1 (no poor risk features; surveillance), group 2 (intermediate pathologic risk factors [perineural invasion, lymphovascular invasion]; 50‐Gy radiotherapy), or group 3 (poor prognostic pathologic factors [extranodal extension [ENE], more than three positive lymph nodes and positive margin]; concurrent 56‐Gy chemoradiotherapy with weekly cisplatin). Results Fifty‐four patients were evaluable; there were 25 in group 1, 15 in group 2, and 14 in group 3. Median follow‐up was 43.9 months (9.6–75.8). Disease‐specific survival was 98.1%, and PFS was 90.7%. PFS probability via Kaplan‐Meier was 91.3% for group 1, 86.7% for group 2, and 93.3% for group 3. There were five locoregional failures (LRFs), including one distant metastasis and one contralateral second primary. Average time to LRF was 18.9 months (9.6–59.0); four LRFs were successfully salvaged, and the patients remain disease free (11.0–42.7 months); one subject remains alive with disease. Conclusion The results indicate that upfront surgery with neck dissection with reduced‐dose radiation for T1–2, N1 stage (by the eighth edition American Joint Committee on Cancer staging manual) HPVOPC results in favorable survival with excellent function in this population. These results support radiation dose reduction after TORS as a de‐escalation strategy in HPVOPC. Implications for Practice Transoral robotic surgery can provide a safe platform for de‐escalation in carefully selected patients with early‐stage human papillomavirus‐related oropharyngeal cancer. In this clinical trial, disease‐specific survival was 100%, over 90% of the cohort had a reduction of therapy from standard of care with excellent functional results, and the five patients with observed locoregional failures were successfully salvaged.

Human papilloma virus-associated oropharyngeal cancer (HPVOPC), which accounts for almost 75% of newly diagnosed OPC, is an appealing target for immunotherapy due to the expression of viral antigens. ADXS11-001, a live attenuated Listeria monocytogenes listeriolysin O (LLO) immunotherapeutic agent expressing an HPV16-E7 fusion protein, has been shown to induce HPV-specific T cell responses in animal models, and to have clinical activity in cervical cancer. A phase II “window of opportunity” trial was designed to evaluate the effect of ADXS11-001 on anti-tumor immunity in peripheral blood and the tumor immune microenvironment (TIME) of patients with HPVOPC. Previously untreated, surgically resectable, stage II-IV, HPVOPC patients received two doses of ADXS11-001 over 5 weeks prior to transoral robotic surgery. Formalin-fixed paraffin embedded (FFPE) pre-treatment biopsies and post-treatment surgical resection specimens were banked for studies of the TIME. Peripheral blood samples were collected at multiple time points before, during and after ADXS11-001 administration and after surgery. The TIME was profiled by quantitative multiplex immunofluorescence (qIF) microscopy and conventional H&E histopathology. T cell immune responses in the peripheral blood were monitored by ELISPOT of IFN-γ and TNF-α expressing T cells. Serum expression of 38 cytokines was measured using the Luminex multiplex analysis platform. So far 8 patients have completed treatment, of which 5 showed increased E6 or E7-specific IFN-γ responses on the day of surgery or 5 weeks post-surgery, compared to pre-treatment responses. Serum cytokines CCL22 and CXCL10 showed a trend towards increase after ADXS11-001 delivery (p = 0.067, p = 0.070) and drop following surgery (p = 0.069, p = 0.016). CCL22 levels were correlated with E6-specific T cell response after immunotherapy treatment (R2 = 0.6303, p = 0.019). qIF results demonstrated increased post-treatment CD8 and CD4 intratumoral T cell infiltration in 4/8 patients, and correlations between intra-tumoral pre- and post-treatment CD8 numbers (R2 = 0.6481, p = 0.0167). Also, post-treatment PD-1 expression strongly correlated with PD-L1 expression (R2 = 0.8803, p = 0.0007) in the tumor. Tumor infiltrating lymphocytes at the tumor host interface tended to increase after treatment (p = 0.188) and correlated with pre-treatment numbers (R2 = 0.772, p = 0.042). Antigen-specific peripheral blood T cell responses are increased post-treatment with ADXS11-001 and correlate with increased serum CCL22 levels. In this small patient sample (n = 8), the intratumoral qIF and H&E results present an overall suggestion of positive treatment-induced effects in the TIME, which must be confirmed as additional patients are accrued. Citation Format: Rosemarie Krupar, Naoko Imai, Brett Miles, Eric Genden, Krzys Misiukiewicz, Yvonne Saenger, Elizabeth G. Demicco, Jigneshkumar Patel, Phapichaya Chaoprang Herrera, Falguni Parikh, Michael Donovan, Seunghee Kim-Schulze, Marshall Posner, Sacha Gnjatic, Andrew G. Sikora. HPV E7 antigen-expressing Listeria-based immunotherapy (ADXS11-001) prior to robotic surgery for HPV-positive oropharyngeal cancer enhances HPV-specific T cell immunity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-095.