Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16-Related Cancer: A Phase 2 Clinical Trial
Erminia Massarelli, William William, Faye Johnson, Merrill Kies, Renata Ferrarotto, Ming Guo, Lei Feng, J Jack Lee, Hai Tran, Young Uk Kim, Cara Haymaker, Chantale Bernatchez, Michael Curran, Tomas Zecchini Barrese, Jaime Rodriguez Canales, Ignacio Wistuba, Lerong Li, Jing Wang, Sjoerd H van der Burg, Cornelis J Melief, Bonnie Glisson, Erminia Massarelli, William William, Faye Johnson, Merrill Kies, Renata Ferrarotto, Ming Guo, Lei Feng, J Jack Lee, Hai Tran, Young Uk Kim, Cara Haymaker, Chantale Bernatchez, Michael Curran, Tomas Zecchini Barrese, Jaime Rodriguez Canales, Ignacio Wistuba, Lerong Li, Jing Wang, Sjoerd H van der Burg, Cornelis J Melief, Bonnie Glisson
Abstract
Importance: In recurrent human papilloma virus (HPV)-driven cancer, immune checkpoint blockade with anti-programmed cell death 1 (PD-1) antibodies produces tumor regression in only a minority of patients. Therapeutic HPV vaccines have produced strong immune responses to HPV-16, but vaccination alone has been ineffective for invasive cancer.
Objective: To determine whether the efficacy of nivolumab, an anti-PD-1 immune checkpoint antibody, is amplified through treatment with ISA 101, a synthetic long-peptide HPV-16 vaccine inducing HPV-specific T cells, in patients with incurable HPV-16-positive cancer.
Design, setting, and participants: In this single-arm, single-center phase 2 clinical trial, 24 patients with incurable HPV-16-positive cancer were enrolled from December 23, 2015, to December 12, 2016. Duration of follow-up for censored patients was 12.2 months through August 31, 2017.
Interventions: The vaccine ISA101, 100 μg/peptide, was given subcutaneously on days 1, 22, and 50. Nivolumab, 3 mg/kg, was given intravenously every 2 weeks beginning day 8 for up to 1 year.
Main outcomes and measures: Assessment of efficacy reflected in the overall response rate (per Response Evaluation Criteria in Solid Tumors, version 1.1).
Results: Of the 24 patients (4 women and 20 men; 22 with oropharyngeal cancer; median age, 60 years [range, 36-73 years]), the overall response rate was 33% (8 patients; 90% CI, 19%-50%). Median duration of response was 10.3 months (95% CI, 10.3 months to inestimable). Five of 8 patients remain in response. Median progression-free survival was 2.7 months (95% CI, 2.5-9.4 months). Median overall survival was 17.5 months (95% CI, 17.5 months to inestimable). Grades 3 to 4 toxicity occurred in 2 patients (asymptomatic grade 3 transaminase level elevation in 1 patient and grade 4 lipase elevation in 1 patient), requiring discontinuation of nivolumab therapy.
Conclusions and relevance: The overall response rate of 33% and median overall survival of 17.5 months is promising compared with PD-1 inhibition alone in similar patients. A randomized clinical trial to confirm the contribution of HPV-16 vaccination to tumoricidal effects of PD-1 inhibition is warranted for further study.
Trial registration: ClinicalTrials.gov identifier: NCT02426892.
Conflict of interest statement
Conflict of Interest Disclosures: Dr Rodriguez Canales reported being employed by Medimmune. Dr van der Burg reported receiving research funding from and holding patents with ISA Pharmaceuticals. Dr Melief reported being employed by; holding patents with; and receiving research funding, travel expenses, and honoraria from ISA Pharmaceuticals. Dr Massarelli reported receiving research funding from Bristol-Myers Squibb (to her institution). No other disclosures were reported.
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Source: PubMed