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

Abstract

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-specificT-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-specificT-cell immune responses were analyzed by evaluating the magnitude, breadth, type, and polarization by proliferation assays, IFNg-ELISPOT, and cytokine production and phenotyped by theT-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 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 + Tcells 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-inducedTcells display a CD4 + CD25 + Foxp3+ phenotype that is frequently associated with regulatory T-cell function, suggesting that strategies to disarm this subset of Tcells should be considered as components of immunotherapeutic modalities against HPV-induced cancers.Cervical cancer is the second most common cancer in women worldwide (1), and it is the first cancer recognized by the WHO to be 100% attributable to the infection with a high-risk type of human papillomavirus (HPV; ref. 2). HPV type 16 (HPV16) is the most common carcinogenic type and is found in around 50% of invasive cervical tumors worldwide (3, 4).

A new era in anticancer peptide vaccines

“…14,15 In addition to those artificial polyepitope vaccines, naturally linked and usually overlapping CTL and T h epitopes also performed well as vaccines in preclinical mouse models. 16,17 Furthermore, naturally occurring, linked CTL and T h epitopes with improved immunogenicity are present in humans, such as human papillomavirus (HPV), 18,19 NY-ESO-1 (a cancer testis antigen), 20 and HER-2/neu. 21,22 One of the major mechanisms for the enhanced vaccine potency of long peptides is most likely that, unlike 8-mer to 10-mer CTL epitopes, these are not able to bind directly to MHC class I molecules, so their presentation to CTL precursors must follow processing by DCs.…”

A virosomal formulated Her-2/neu multi-peptide vaccine induces Her-2/neu-specific immune responses in patients with metastatic breast cancer: a phase I study

“…Unlike many peptide vaccines against cancers which have been designed to induce cytotoxic T cell responses using class I restricted peptides [18][19][20][21][22][23], we used putative B cell epitopes from the extracellular domain of the Her-2/ neu protein being HLA type independent. In order to induce CD4?…”

Immunotherapy: An Evolving Paradigm in the Treatment of Advanced Cervical Cancer

“…The same vaccine regimen was studied in a subset of patients with resected HPV-16-positive cervical cancer. 51 Vaccine-induced T-cell responses against HPV-16 E6 were detected in 6 of 6 patients and against E7 in 5 of 6 patients. These responses were broad, involved both CD4 þ and CD8 þ T cells, and could be detected up to 12 months after the last vaccination.…”

“…These responses were broad, involved both CD4 þ and CD8 þ T cells, and could be detected up to 12 months after the last vaccination. 51 Despite the above successes, peptide-based vaccines result in immune tolerance rather than activation and require the identification of epitopes associated with a particular MHC allele, limiting therapeutic generalizability.…”