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 -E7 are ideal candidates to elicit strong immune responses without generating autoimmunity because: i) these products are not expressed in normal cells; and ii) 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 antitumor 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.

The Road Ahead for Cervical Cancer Prevention and Control

“…For example, if a second generation of hpv vaccines that extend protection to other hr-hpv types comes to market, policymakers might once again need to readjust screening guidelines 76 , reinforcing the need for an innovative risk-assessment strategy that is flexible with respect to the growth of the new technologies 42 . Recently, ground-breaking discoveries have also occurred in the field of hpv microbicides and therapeutic vaccines research that might once again transform the landscape of cervical cancer prevention and control strategies to include novel treatment options for hpv and associated malignancies [76][77][78] . Since introduction of the first clinical hpv tests roughly 20 years ago, the field of hpv research has experienced tremendous growth (reflected by a 400% increase in the annual number of articles on papillomavirus in Medline's PubMed database over that time period) marked by all the key events outlined here and ultimately capped with a Nobel prize to Dr. zur Hausen in 2008 for his pioneering role in establishing hpv as the main causal agent in cervical cancer 75 .…”

Novel Cell-Penetrating Peptide-Based Vaccine Induces Robust CD4+ and CD8+ T Cell–Mediated Antitumor Immunity

“…2B). This longterm persistence of OVA 257-264 -specific T cells without anti-CD40 is particularly noteworthy, because although vaccination with the OVA 257-264 short synthetic peptide can be efficient, the response was reported to be short lived without anti-CD40 antibody (31). In our experiments, there was a reduction of the frequency of these OVA-specific CD8 þ T cells in blood when anti-CD40 antibody was combined with Hiltonol ( Fig.…”

CD70 encoded by modified vaccinia virus Ankara enhances CD8 T‐cell‐dependent protective immunity in MHC class II‐deficient mice

“…This is in line with enhanced therapeutic anti‐tumour effects after i.v. injection not only of an MVA encoding MUC160 but also of peptide + pIC and anti‐CD40 (TriVax) 61, 62. The CD8 T‐cell‐enhancing effect of rMVA‐CD40L was also dependent on the i.v.…”