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Clin Cancer Res. 2016 May 15;22(10):2342-50. doi: 10.1158/1078-0432.CCR-15-2594. Epub 2016 Jan 26.

Vaccination against Oncoproteins of HPV16 for Noninvasive Vulvar/Vaginal Lesions: Lesion Clearance Is Related to the Strength of the T-Cell Response.

Author information

1
Department of Gynaecology, Leiden University Medical Centre, Leiden, the Netherlands.
2
Department of Clinical Oncology, Leiden University Medical Centre, Leiden, the Netherlands.
3
Department of Gynaecology, University Medical Centre Groningen, Groningen, the Netherlands.
4
Department of Obstetrics and Gynaecology, Haga Teaching Hospital, the Hague, the Netherlands.
5
Netherlands Cancer Institute, Amsterdam, the Netherlands.
6
Department of Obstetrics and Gynaecology, University Medical Centre Utrecht, Utrecht, the Netherlands.
7
Department of Obstetrics and Gynaecology, Medical Centre Haaglanden, the Hague, the Netherlands.
8
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, the Netherlands.
9
Department of Medical Microbiology, University Medical Centre Groningen, Groningen, the Netherlands.
10
Department of Pathology and Medical Biology, University Medical Centre Groningen, Groningen, the Netherlands.
11
Department of Allergy, Internal Medicine, Groningen Research Institute for Asthma and COPD, University Medical Centre Groningen, Groningen, the Netherlands.
12
Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands.
13
Department of Gynaecology, Academic Medical Centre, Amsterdam, the Netherlands.
14
Department of Medical Statistics and Bioinformatics, Leiden University Medical Centre, Leiden, the Netherlands.
15
ISA Pharmaceuticals, Leiden, the Netherlands. Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, the Netherlands.
16
Department of Clinical Oncology, Leiden University Medical Centre, Leiden, the Netherlands. shvdburg@lumc.nl.

Abstract

PURPOSE:

Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides (SLP) is effective against HPV16-induced high-grade vulvar and vaginal intraepithelial neoplasia (VIN/VaIN). However, clinical nonresponders displayed weak CD8(+) T-cell reactivity. Here, we studied if imiquimod applied at the vaccine site could improve CD8(+) T-cell reactivity, clinical efficacy, and safety of HPV16-SLP (ISA101).

EXPERIMENTAL DESIGN:

A multicenter open-label, randomized controlled trial was conducted in patients with HPV16(+) high-grade VIN/VaIN. Patients received ISA101 vaccination with or without application of 5% imiquimod at the vaccine site. The primary objective was the induction of a directly ex vivo detectable HPV16-specific CD8(+) T-cell response. The secondary objectives were clinical responses (lesion size, histology, and virology) and their relation with the strength of vaccination-induced immune responses.

RESULTS:

Forty-three patients were assigned to either ISA101 with imiquimod (n = 21) or ISA101 only (n = 22). Imiquimod did not improve the outcomes of vaccination. However, vaccine-induced clinical responses were observed in 18 of 34 (53%; 95% CI, 35.1-70.2) patients at 3 months and in 15 of 29 (52%; 95% CI, 32.5-70.6) patients, 8 of whom displayed a complete histologic response, at 12 months after the last vaccination. All patients displayed vaccine-induced T-cell responses, which were significantly stronger in patients with complete responses. Importantly, viral clearance occurred in all but one of the patients with complete histologic clearance.

CONCLUSIONS:

This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16-induced high-grade VIN/VaIN. Clin Cancer Res; 22(10); 2342-50. ©2016 AACRSee related commentary by Karaki et al., p. 2317.

PMID:
26813357
DOI:
10.1158/1078-0432.CCR-15-2594
[Indexed for MEDLINE]
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