The development of novel immunotherapy strategies for prostrate cancer

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Parkinson, R.J., 2005. The development of novel immunotherapy strategies for prostrate cancer. PhD, Nottingham Trent University.

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Abstract

This thesis examines two separate approaches to prostate cancer immunotherapy. The first aims to employ a viral vector (DISC-HSV) for the systemic delivery of a multi-epitope vaccine in order to induce immune responses against several prostate cancer antigens simultaneously. Initially, it is intended to establish the feasibility of delivering a multi-epitope vaccine using DISC-HSV. The design and construction of a multi-epitope vaccine employing well-known cancer epitopes is described.

The succeeding chapters will describe the identification of novel prostate cancer epitopes, and the testing of their immunogenicity in both human and transgenic animal models. The discovery of an entirely novel, immunogenic, class-I epitope derived from prostate acid phosphatase, designated PAP. 135, is described. This peptide was predicted to be immunogenic by analysis of the PAP amino-acid sequence, and subsequently exhibited strong HLA-A2 binding in a T2 binding assay. Its ability to excite an immune response has been demonstrated in a transgenic mouse model, and this has been shown to be mediated through the induction of cytotoxic T- lymphocytes (CTL). Early data in a human model system, employing peripheral blood monocytes to establish CTL cultures have supported these findings.

The second approach employs the same viral vector to deliver a cytokine gene (GMCSF) to tumour cells, with the aim of inducing anti-tumour immunity. The feasibility of this approach is established by the successful testing the ability of the virus to infect prostate cancer cells in vivo and in vitro, with the expression of virally encoded gene products. The physiological effects of infection by this agent on the prostate cancer cells are examined in relation to gene expression.

Although several strands of related work are presented here in sequence, it should be remarked that the experiments are not presented in chronological order; indeed many of these experiments were undertaken concurrently. Work on the multi-epitope vaccine constructs began at the start of the project, whereas the confirmation of the immunogenicity of PAP.135 was very late in the study period. Therefore, PAP.135 was not (and indeed could not) be included in the multi-epitope construct described in chapter three.

Item Type:

Thesis

Creators:

Parkinson, R.J.

Date:

2005

ISBN:

9781369314465

Identifiers: