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TriVax-HPV: an improved peptide-based therapeutic vaccination strategy against human papillomavirus-induced cancers

Abstract

Background

Therapeutic vaccines for cancer are an attractive alternative to conventional therapies, since the later result in serious adverse effects and in most cases are not effective against advanced disease. Human papillomavirus (HPV) is responsible for several malignancies such as cervical carcinoma. Vaccines targeting oncogenic viral proteins like HPV16-E6 and HPV16-E7 are ideal candidates to elicit strong immune responses without generating autoimmunity because: (1) these products are not expressed in normal cells and (2) their expression is required to maintain the malignant phenotype. Our group has developed peptide vaccination strategy called TriVax, which is effective in generating vast numbers of antigen-specific T cells in mice capable of persisting for long time periods.

Materials and methods

We have used two HPV-induced mouse cancer models (TC-1 and C3.43) to evaluate the immunogenicity and therapeutic efficacy of TriVax prepared with the immunodominant CD8 T-cell epitope HPV16-E749-57, mixed with poly-IC adjuvant and costimulatory anti-CD40 antibodies.

Results

TriVax using HPV16-E749-57 induced large and persistent T-cell responses that were therapeutically effective against established HPV16-E7 expressing tumors. In most cases, TriVax was successful in attaining complete rejections of 6–11-day established tumors. In addition, TriVax induced long-term immunological memory, which prevented tumor recurrences. The anti-tumor effects of TriVax were independent of NK and CD4 T cells and, surprisingly, did not rely to a great extent on type-I or type-II interferon.

Conclusions

These findings indicate that the TriVax strategy is an appealing immunotherapeutic approach for the treatment of established viral-induced tumors. We believe that these studies may help to launch more effective and less invasive therapeutic vaccines for HPV-mediated malignancies.

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Abbreviations

αCD40 mAb:

Anti-CD40 monoclonal antibodies

CC:

Cervical carcinoma

DC:

Dendritic cell

HPV:

Human papillomavirus

MHC-I:

Major histocompatibility complex I

IFNγ:

Interferon-gamma

IFNαβR:

Interferon-alpha/beta receptor

KO:

Knockout

TAA:

Tumor-associated antigen

TLR:

Toll-like receptor

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Acknowledgments

We gratefully acknowledge Dr. T-C Wu and Dr. W. M. Kast for providing us with the tumor cell lines and are indebted to Dr. A. Salazar for providing large amounts of Poly-ICLC. We also thank Moffitt Cancer Center Flow Cytometry Core, especially J. Kroger for her help in flow cytometer training. This work was supported by NIH grants R01CA136828 and R01CA157303 to EC.

Conflict of interest

Esteban Celis has filed a patent application based on the use of synthetic peptides and poly-IC combinatorial complexes for vaccination. The rights of the patent application have been transferred to the Moffitt Cancer Center. Kelly Barrios declares no conflict of interest.

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Correspondence to Esteban Celis.

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Barrios, K., Celis, E. TriVax-HPV: an improved peptide-based therapeutic vaccination strategy against human papillomavirus-induced cancers. Cancer Immunol Immunother 61, 1307–1317 (2012). https://doi.org/10.1007/s00262-012-1259-8

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Keywords

  • Peptide vaccines
  • HPV
  • Cervical cancer
  • CD8 T cells
  • PIVAC 11