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ESMO 2017: Combined Therapy with Nivolumab and ISA 101 Vaccine Results in Promising Efficacy in HPV-positive Oropharyngeal Cancer

11 Sep 2017
Head and Neck Cancers

Treatment with the checkpoint inhibitor nivolumab combined with ISA 101, a synthetic long-peptide vaccine directed against human papilloma virus 16 (HPV16) improved response in patients with incurable oropharyngeal cancer, compared to historical data with nivolumab alone, according to findings presented during ESMO 2017, the Annual Congress of the European Society for Medical Oncology in Madrid, Spain.

ISA 101 comprises 13 synthetic long peptides derived from the E6 and E7 oncogenic proteins of the HPV16, which is responsible for 50% of human cervical cancers and cervical intra-epithelial neoplasias and approximately 80-90% of HPV-positive head and neck cancers, anal cancers and premalignant HPV-induced anal lesions, or anal intra-epithelial neoplasia. ISA 101 caused regression of vulvar intra-epithelial neoplasia, but is not active in invasive cervical cancer.

These findings suggest that an immunosuppressive tumour microenvironment may impose limits on efficacy of HPV vaccines.  Bonnie S. Glisson, professor at The University of Texas MD Anderson Cancer Center in Houston, USA, and colleagues reasoned that vaccine-induced T cell activity may be amplified through treatment with immune checkpoint antibodies such as nivolumab.

The researchers conducted a phase II trial of the synthetic long-peptide HPV16 vaccine, ISA 101, plus nivolumab in patients with incurable HPV16-positive cancer. The trial was open to all patients with HPV16-related cancers regardless of organ of origin and accrued 24 patients; 22 patients had oropharyngeal cancer and one patient each had anal and cervical cancer. HPV-genotype 16 was confirmed using Cervista HPV16/18 in all tumours.

The patients had ECOG performance status 0-1 and had received up to one prior regimen for recurrence; 18 (75%) patients had progressed within 6 months of receiving platin, 12 (50%) had received cetuximab, and just one patient was platin-naive.

Treatment with ISA 101 plus nivolumab was frontline for recurrence in 10 patients and second line in 14 of the 24 enrolled patients. All patients were treated with ISA 101 at 100 mcgs/peptide on days 1, 22, and 50 plus nivolumab at 3 mg/kg intravenously every 2 weeks beginning on day 8 for up to one year. Imaging was obtained at baseline, week 11 and every 6 weeks thereafter.

The primary objective was assessment of overall response rate (ORR) with a target of 30%  and the secondary objectives included tolerability, progression-free survival (PFS), and overall survival (OS).

The primary endpoint of overall response rate was met with ISA 101 and nivolumab

The ORR of 33% was higher than the target, thus meeting the primary objective. In all, 8 patients showed a response including two complete response (CR) and 8 partial responses (PR), with one unconfirmed PR. Stable disease (SD) was achieved by 3 (13%) patients and 13 (54%) patients showed progressive disease (PD). The median duration of response is not reached, 39+ weeks (range 21-59) with 5/8 remaining in response. Six of the patients achieving PR had progressed within 6 months of prior platin.


Percentage change in target lesions.

© Bonnie S. Glisson.

All responses occurred in patients with oropharyngeal cancer, where the ORR was 36% (8/22). Response was positively correlated with tumour cell PD-L1 positivity (≥1%).

Regarding the secondary endpoints, at a median follow-up of 8.6 months the median PFS was 2.7 months (95% confidence interval [CI] 2.3, 8.0 months) and median OS was not reached.

The 6-month PFS rate was 33%, (95% CI 16%, 52%) and the 6-month OS rate was 74% (95% CI 51%, 87%).

PD-L1 ≥ 1% on tumour cells was identified in 39% (7/18) of baseline tumour specimens and was associated with probability of response.   

The combination of the ISA 101 vaccine plus nivolumab was well tolerated with only grade 1 and 2 toxicity, including fever in 5 patients, injection site reaction in 6, and transaminase elevation, fatigue, and nausea which each occurred in 3 patients. Grade 3 elevated transaminase and grade 4 lipase elevation each occurred in one patient.


The authors pointed out that the ORR of 36% in patients with oropharyngeal cancer compares favourably to the ORR of 16% demonstrated for nivolumab monotherapy in patients with p16-positive platin-refractory oropharyngeal cancer participating in the in Checkmate 141 study.1

These data support the hypothesis that the efficacy of vaccine-induced T cells can be augmented by anti-PD-1 therapy, thus mitigating the influence of an immunosuppressive microenvironment. The investigators concluded that these findings merit confirmation in a larger randomised trial which is being planned.

Helen Gogas, Professor in Medical Oncology at First Department of Medicine, National and Kapodistrian University of Athens, Greece who discussed the study results said that strenghts of the study are strong rationale (HPV-positive tumour microenvironment is immunosuppressive); strong translational research component (biopsies baseline/restaging, serial blood samples, HPV-specific immune responses, exploratory biomarkers); and promising results. However, the caveats are clinical response observed in small non-randomised study, heterogeneity prior treatment; and in term of translational research skewing of data and small number of evaluable tumours. As a proof of principe, a randomised controlled trial to confirm findings is needed.


The study was supported by UT MD Anderson Cancer Center.


  1. Ferris RL, et al. N Engl J Med 2016;375:1856-1867.


1136O – Glisson B, et al. Nivolumab and ISA 101 HPV vaccine in incurable HPV-16+ cancer.

Last update: 11 Sep 2017

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