HPV-16 Vaccine Might Boost Nivolumab Efficacy Against HPV-16-Positive Cancer

Phase II findings support further investigation of a combined vaccine and PD-1 inhibitor strategy against recurrent HPV-16-positive tumours

medwireNews: Preliminary research suggests that patients with incurable, recurrent human papillomavirus-16 (HPV-16)-positive cancer may benefit from a combined treatment approach of vaccination and programmed cell death 1 (PD-1) inhibitor therapy. 

The single-arm phase II trial, published in JAMA Oncology, included 22 patients with recurrent oropharyngeal cancer and two individuals with recurrent cervical and anal cancer, all of whom tested positive for HPV-16 infection. 

The participants were given the ISA101 synthetic long-peptide vaccine, designed to induce HPV-specific T cells, on days 1, 22 and 50 of the study, alongside nivolumab 3 mg/kg every 2 weeks from day 8, for up to a year. 

The regimen met the study’s primary endpoint of response in at least six patients, report Bonnie Glisson, from The University of Texas MD Anderson Cancer Center in Houston, USA, and co-investigators. 

Indeed, the overall response rate (ORR) was 33%, including two complete and six partial RECIST responses. The median duration of these responses was 10.3 months, with five of the responses ongoing at data cutoff.  

This ORR is numerically higher than that achieved among three reference trials of HPV-positive oropharyngeal cancer, namely the Keynote-012 and Keynote-055 trials of pembrolizumab and the CheckMate 141 trial of nivolumab, the authors remark. 

After a median follow-up of 12.2 months, the median durations of progression-free and overall survival were 2.7 and 17.5 months, respectively. The corresponding 6-month rates for these endpoints were 37% and 75%, falling to 25% and 70% at 12 months. 

The investigators describe the ISA101 and nivolumab regimen as “very well tolerated”, emphasizing that the “absence of synergistic toxic effects is integral to building rational combination immunotherapy on the anti-PD-1- platform”. 

The ISA101 vaccine provoked the expected injection site reactions and fever, while nivolumab was most commonly associated with fatigue, diarrhoea and hepatoxicity. Treatment was discontinued in one patient with asymptomatic grade 3 transaminase elevation and a second patient who developed grade 4 lipase and amylase elevations. 

IFN-γ release as a marker of HPV-16-specific immune response was assessed in a subset of patients but there was no correlation between reactivity or number of HPV-specific T cells and clinical response.  

However, the researchers did detect a significant correlation between PD-L1 expression and response, with an ORR of 43% for the seven patients with tumour expression of at least 1% versus 18% for the 11 patients whose tumours tested negative.  

“More comprehensive immunophenotyping and gene expression profiling are ongoing and may provide further insight as to biomarkers associated with benefit from combined HPV vaccination and PD-1 inhibition”, they comment. 

Bonnie Glisson et al conclude that the “results of the our trial are among the first clinical data to support the general concept of combining cancer vaccination with immune checkpoint blockade to enhance efficacy of vaccine-activated T cells in the immunosuppressive tumor environment.” 

“A randomized clinical trial testing the contribution of ISA101 to PD-1 inhibition, in patients with platin-resistant HPV-16-positive recurrent [oropharyngeal cancer] is planned”, they say. 



Massarelli E, William W, Johnson F, et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer. A phase 2 clinical trial . JAMA Oncol; Advance online publication 27 September 2018.
DOI: 10.1001/jamaoncol.2018.4051

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