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Induction of Tumor-Specific CD4+ and CD8+ T-Cell Immunity in Cervical Cancer Patients by a Human Papillomavirus Type 16 E6 and E7 Long Peptides Vaccine

Authors' Affiliations: Departments of ¹ Immunohematology and Blood Transfusion, ² Gynaecology, ³ Clinical Pharmacy and Toxicology, ⁴ Pathology, and ⁵ Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands

Requests for reprints: S.H. van der Burg, Department of Clinical Oncology, Building 1, K1-P, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands. Phone: 31-71-5261180; Fax: 31-71-5266760; E-mail: shvdburg{at}lumc.nl.

Purpose: The study aims to evaluate the effect of a human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides vaccine on the antigen-specific T-cell response in cervical cancer patients.

Experimental Design: Patients with resected HPV16-positive cervical cancer were vaccinated with an overlapping set of long peptides comprising the sequences of the HPV16 E6 and E7 oncoproteins emulsified in Montanide ISA-51. HPV16-specific T-cell immune responses were analyzed by evaluating the magnitude, breadth, type, and polarization by proliferation assays, IFN-ELISPOT, and cytokine production and phenotyped by the T-cell markers CD4, CD8, CD25, and Foxp3.

Results: Vaccine-induced T-cell responses against HPV16 E6 and E7 were detected in six of six and five of six patients, respectively. These responses were broad, involved both CD4⁺ and CD8⁺ T cells, and could be detected up to 12 months after the last vaccination. The vaccine-induced responses were dominated by effector type CD4⁺CD25⁺Foxp3^– type 1 cytokine IFN-producing T cells but also included the expansion of T cells with a CD4⁺CD25⁺Foxp3⁺ phenotype.

Conclusions: The HPV16 E6 and E7 synthetic long peptides vaccine is highly immunogenic, in that it increases the number and activity of HPV16-specific CD4⁺ and CD8⁺ T cells to a broad array of epitopes in all patients. The expansion of CD4⁺ and CD8⁺ tumor-specific T cells, both considered to be important in the antitumor response, indicates the immunotherapeutic potential of this vaccine. Notably, part of the vaccine-induced T cells display a CD4⁺CD25⁺Foxp3⁺ phenotype that is frequently associated with regulatory T-cell function, suggesting that strategies to disarm this subset of T cells should be considered as components of immunotherapeutic modalities against HPV-induced cancers.

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