Graduation Year

2012

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Medicine

Major Professor

Esteban Celis

Keywords

adjuvants, CD8 T cells, cervical cancer, vaccine, virus

Abstract

There is an urgent need for the development of an effective therapeutic vaccine against cancer caused by human papilloma virus (HPV). We focused on HPV-induced malignancies because of their high worldwide prevalence (e.g., cervical carcinoma and head & neck cancer). A successful therapeutic vaccine could prevent the 250 000 deaths/year worldwide and the 2.25 billion dollars that

are expended in related care in the US.

We used an HPV-induced mouse cancer model to test vaccines

composed of a CD8 T cell peptide epitope administered with potent adjuvants designed to generate vast numbers of high avidity cytotoxic T lymphocytes specific for the HPV16-E7 antigen. One vaccination strategy (TriVax) consists of intravenous administration of synthetic peptide HPV16-E749-57 administered together with a Poly-IC (a TLR3 agonist) and anti-CD40 monoclonal antibody(αCD40 mAb) while the second more simple strategy (BiVax) comprises solely of peptide plus Poly-IC. We used an E7 peptide as antigen in the vaccination strategies because expression of the viral E6 and E7 proteins is required to maintain oncogenic phenotype and because normal cells do not express E6/E7, therefore a therapeutic vaccine targeting these proteins has several advantages:

a) a strong immune response can be induced since immune tolerance to these foreign antigens does not exist and b) the strong immune response should not inflict damage to normal cells.

TriVax and BiVax generate a high number of antigen specific CD8 T cells capable clear subcutaneous tumors and prevent recurrences, both vaccines are efficient through the i.v. and i.m. route. TriVax (prime-boost) clears tumor in 100% of mice while BiVax clears tumor in 50% of mice, this differential effect is due to the number of antigen specific CD8 T cells and increasing the number of booster shot makes BiVax as immunogenic and efficient in clearing tumors. In the absence of type-I IFN signaling (in IFNαΒR KO mice), TriVax is less effective in generating sufficient numbers of CD8 T cells that could be necessary for total disease eradication. We observed a significant anti-tumor effect of TriVax in the absence of interferon gamma, however the cytokine may play some role in the overall effectiveness of TriVax to completely reject the tumors. Immune responses produced by BiVax are highly dependent on the simultaneous administration of peptide and Poly-IC, on the peptide composition, vaccine formulation and route of administration. The magnitude of the response is dependent on the expression of the Poly-IC receptors TLR3 and melanoma differentiation-associated protein 5 (MDA5). Interestingly, the magnitude and duration of the CD8 T cell responses generated by peptide and Poly-IC mixtures does not rely on the presence of CD4 T cells, scavenger receptor-A (SR-A) or type-I IFN signals and was minimally affected by the absence of CD40 signaling.

The present findings could facilitate the development of simple and effective subunit vaccines for diseases where CD8 T cells may hold a therapeutic benefit.

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