TriVax-HPV: an improved peptide-based therapeutic vaccination strategy against human papillomavirus-induced cancers
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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.
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.
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.
KeywordsPeptide vaccines HPV Cervical cancer CD8 T cells PIVAC 11
- αCD40 mAb
Anti-CD40 monoclonal antibodies
Major histocompatibility complex I
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.
- 4.Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon D, Bratti MC, Schiller JT, Gonzalez P, Dubin G, Porras C, Jimenez SE, Lowy DR (2007) Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA 298:743–753PubMedCrossRefGoogle Scholar
- 5.FUTURE II Study Group (2007) Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 356:1915–1927Google Scholar
- 6.Kaufmann AM, Nieland JD, Jochmus I, Baur S, Friese K, Gabelsberger J, Gieseking F, Gissmann L, Glasschroder B, Grubert T, Hillemanns P, Hopfl R, Ikenberg H, Schwarz J, Karrasch M, Knoll A, Kuppers V, Lechmann M, Lelle RJ, Meissner H, Muller RT, Pawlita M, Petry KU, Pilch H, Walek E, Schneider A (2007) Vaccination trial with HPV16 L1E7 chimeric virus-like particles in women suffering from high grade cervical intraepithelial neoplasia (CIN 2/3). Int J Cancer 121:2794–2800PubMedCrossRefGoogle Scholar
- 10.Yee C, Thompson JA, Byrd D, Riddell SR, Roche P, Celis E, Greenberg PD (2002) Adoptive T cell therapy using antigen-specific CD8 + T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T cells. Proc Natl Acad Sci U S A 99:16168–16173PubMedCrossRefGoogle Scholar
- 11.Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850–854PubMedCrossRefGoogle Scholar
- 14.Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, Essahsah F, Fathers LM, Offringa R, Drijfhout JW, Wafelman AR, Oostendorp J, Fleuren GJ, van der Burg SH, Melief CJ (2009) Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med 361:1838–1847PubMedCrossRefGoogle Scholar
- 19.Feltkamp MC, Smits HL, Vierboom MP, Minnaar RP, de Jongh BM, Drijfhout JW, ter Schegget J, Melief CJ, Kast WM (1993) Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells. Eur J Immunol 23:2242–2249PubMedCrossRefGoogle Scholar
- 21.van Driel WJ, Ressing ME, Kenter GG, Brandt RM, Krul EJ, van Rossum AB, Schuuring E, Offringa R, Bauknecht T, Tamm-Hermelink A, van Dam PA, Fleuren GJ, Kast WM, Melief CJ, Trimbos JB (1999) Vaccination with HPV16 peptides of patients with advanced cervical carcinoma: clinical evaluation of a phase I-II trial. Eur J Cancer 35:946–952PubMedCrossRefGoogle Scholar
- 29.Hu G, Liu W, Hanania EG, Fu S, Wang T, Deisseroth AB (1995) Suppression of tumorigenesis by transcription units expressing the antisense E6 and E7 messenger RNA (mRNA) for the transforming proteins of the human papilloma virus and the sense mRNA for the retinoblastoma gene in cervical carcinoma cells. Cancer Gene Ther 2:19–32PubMedGoogle Scholar
- 33.Borrow P, Tough DF, Eto D, Tishon A, Grewal IS, Sprent J, Flavell RA, Oldstone MB (1998) CD40 ligand-mediated interactions are involved in the generation of memory CD8(+) cytotoxic T lymphocytes (CTL) but are not required for the maintenance of CTL memory following virus infection. J Virol 72:7440–7449PubMedGoogle Scholar