HPV Vaccine Induces CIN2/3 Histopathological Regression, Virus Clearance

Vaccine may reduce the need for surgery in women with intraepithelial pre-invasive human papillomavirus-related lesions

medwireNews: A therapeutic vaccine against human papillomavirus (HPV)-16 and -18 has shown efficacy in women with grade 2 or 3 cervical intraepithelial neoplasia (CIN) in a phase IIb randomised, double-blind trial.

The VGX-3100 vaccine contains synthetic plasmids against the HPV-16 and -18 E6 and E7 proteins and is delivered by electroporation, explain Cornelia Trimble, from Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, and team.

“Although a subset of CIN2/3 lesions does undergo spontaneous regression, in 2015, all women with the diagnosis have only a surgical treatment option because prognostic tissue biomarkers that can distinguish the likelihood of regression are unavailable”, they write in The Lancet.

“Our data suggest that VGX-3100 provides a non-surgical option for the treatment of CIN2/3 that could change the approach to care for this very common disease.”

Per-protocol analysis demonstrated histopathological regression – defined as regression to CIN1 or normal pathology at 36 weeks – in 49.5% of the 107 women who received three intramuscular doses of VGX-3100 6 mg at 0, 4 and 12 weeks compared with 30.6% of 36 patients given placebo, a significant 18.9 percentage point difference.

And this result was supported by the modified intention-to-treat analysis where a significant 18.2 percentage point difference in the rate of histopathological regression was detected between the 114 VGX-3100-treated patients and the 40 controls, at 48.2% versus 30.0%.

Furthermore, the per-protocol analysis showed the secondary endpoint of histopathological regression plus viral clearance of HPV-16 and/or HPV-18 was achieved by 40.2% of 107 VGX-3100-treated patients compared with 14.3% of 35 controls, a significant 25.9 percentage point difference. The modified intention-to-treat result was 39.5% of 114 patients given VGX-3100 versus 15.4% of 39 placebo-treated patients, giving a significant 24.1 percentage point difference.

The vaccine was well tolerated, with most trial participants developing grade 1 or 2 injection-site reactions; Erythema was the only adverse event significantly more common in women given VGX-3100 than placebo (78.4 vs 57.1%).

Mark Schiffman and Nicolas Wentzensen, from the National Cancer Institute in Bethesda, Maryland, USA, describe the trial findings in an accompanying comment as a “a major breakthrough and proof-of-principle that therapeutic HPV vaccination is feasible.”

“More broadly, the trial shows that it is possible to boost immune clearance of HPV among women who initially failed to control infection”, they write, hypothesising that the vaccine could be targeted to women with HPV persistence regardless of their precancer status.

However, the commentators acknowledge that the vaccine has relatively low efficacy compared with immediate surgery and that its use will require careful clinical monitoring for invasive disease.

Nevertheless, Mark Schiffman and Nicolas Wentzensen encourage further research into the use of immunotherapy for patients with HPV infection associated with anogenital and oropharyngeal cancer. “Therapeutic vaccination could be a very welcome alternative to surgery in patients with anal precancer”, they believe.

References

Trimble CL, Morrow MP, Kraynyak KA, et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015; Advance online publication 16 September. DOI: http://dx.doi.org/10.1016/S0140-6736(15)00239-1

Schiffman M, Wentzensen N. Towards therapeutic vaccination against cervical precancer? Lancet 2015; Advance online publication 16 September. DOI: http://dx.doi.org/10.1016/S0140-6736(15)00240-8

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