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Original Investigation
January 2019

Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16–Related Cancer: A Phase 2 Clinical Trial

Author Affiliations
  • 1Department of Medical Oncology, City of Hope National Medical Center, Duarte, California
  • 2Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
  • 3Department of Pathology, University of Texas MD Anderson Cancer Center, Houston
  • 4Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston
  • 5Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
  • 6Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston
  • 7Department of Immunology, University of Texas MD Anderson Cancer Center, Houston
  • 8Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston
  • 9Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands
  • 10Department of Immunohematology and Blood Tranfusion, Leiden University Medical Center, Leiden, the Netherlands
  • 11ISA Pharmaceuticals, Leiden, the Netherlands
JAMA Oncol. 2019;5(1):67-73. doi:10.1001/jamaoncol.2018.4051
Key Points

Question  Is the efficacy of programmed cell death 1 immune checkpoint inhibition increased by a tumor-specific vaccine in patients with incurable human papillomavirus 16–positive cancer?

Findings  In this phase 2 clinical trial of nivolumab and human papillomavirus 16 vaccine ISA101, the primary end point was met, with a 33% overall response rate (8 of 24 patients), compared with response rates of 16% to 22% with programmed cell death 1 inhibitors alone in similar patients. Survival data were also encouraging, with a median survival of 17.5 months.

Meaning  These data indicate that HPV-16 vaccination may augment the efficacy of programmed cell death 1 checkpoint inhibition and merit confirmation in a randomized trial.

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

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