Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16–Related Cancer

Abstract

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

Targeted therapies in gynaecological cancers

“…Combination therapy of vaccines with other immune modulatory agents are ongoing. For example, ISA101 has been combined with Nivolumab in HPV‐positive cancers with an ORR of 33%, supporting the concept of combining cancer vaccination with immune check‐point blockade. Further ISA101 combination studies are recruiting, and specifically in cervix cancer, the vaccine is being trialled with Phases I/II with carboplatin, paclitaxel with or without bevacizumab (NCT02128126).…”

GRIDSS, PURPLE, LINX: Unscrambling the tumor genome via integrated analysis of structural variation and copy number

“…For example, 20kbp reads would allow an additional 6% of structural variants in the Hartwig cohort to be phased and allow a greater portion of LINE translocations to be fully resolved. Unfortunately, long reads are unable to resolve the telomeric and centromeric breakend ambiguities and still require supplementary approaches such as optical mapping [29] to fully resolve derivative chromosomes. At this time, cost and the high indel error rate of long reads makes short read technology an appropriate choice for comprehensive somatic variant determination for routine patient diagnostics and stratification towards precision medicine as well as for biomarker discovery Despite the limitations of short reads, the clinical utility of the combined toolkit is significant.…”

“…At this time, cost and the high indel error rate of long reads makes short read technology an appropriate choice for comprehensive somatic variant determination for routine patient diagnostics and stratification towards precision medicine as well as for biomarker discovery Despite the limitations of short reads, the clinical utility of the combined toolkit is significant. Detection of viral integrations, such as HPV, can directly impact treatment [29]. Base level accurate allele specific copy number in PURPLE allows more sensitive calling of regions with LOH and homozygous deletions and allow a more accurate classification of bi-allelic inactivation driven by short copy number segments.…”

Immunology‐Guided Biomaterial Design for Mucosal Cancer Vaccines

“…For example, several clinical trials have combined adjuvants with varied TAAs‐derived synthetic peptides, autologous whole tumor cells lysate or personalized genomic vaccines, whereby the resected tumor of each individual is sequenced and synthetic peptides are identified using a computational pipeline . Other trials have examined the therapeutic efficacy of vaccines in combination with immunotherapy, including the programmed death protein 1 (PD‐1) inhibitor nivolumab, programmed death‐ligand 1 (PD‐L1) inhibitor atezolizumab, and utomilumab (a monoclonal antibody against CD137) . Indeed, identifying combination, synergistic therapies, and exploration of the mucosal route for vaccination may yield further progress.…”