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Title: Development of prostrate cancer vaccine using PAP as target antigen
Author: Javad, J. M. S.
ISNI:       0000 0004 5354 6701
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2014
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Treatment options for patients with advanced prostate cancer (PC) still remain limited and rarely curative. The prostatic acid phosphatase (PAP) is prostate specific protein over-expressed in more than 90% of prostate tumours. Although an FDA-approved vaccine for the treatment of advanced prostate disease, PROVENGE® (sipuleucel-T), has been shown to prolong survival, the precise sequence of the PAP protein responsible for the outcome remains unknown. As the PAP antigen is one of the very few prostate-specific antigens for which there is a rodent equivalent with high homology, pre-clinical studies using PAP have the potential to be directly relevant to the clinical setting. The current study identified HLA-A2 and HLA-DR1 PAP-derived peptides using the transgenic HHDII/DR1 and C57Bl/6 mice. The PAP-114-128 (15-mer) peptide was shown to elicit CD4+ and CD8+ T-cell-specific responses in C57Bl/6 mice. Furthermore, when immunised in a DNA vector format (ImmunoBody), PAP-114-128 was able to prevent and reduce the growth of TRAMP C1 prostate cancer cell-derived tumours in both prophylactic and therapeutic settings. This anti-tumour effect was associated with an enhanced infiltration of CD8+ tumour-infiltrating lymphocytes (TILs) and the generation of high avidity T cells secreting elevated levels of IFNγ. Importantly, PAP-114-128 specific IFNγ response was also seen in PBMC isolated from PC patients. Also, immunisation of C57Bl/6 and HHDII/DRI mice with the analogue peptide epitope (obtained by altering the second amino acid of PAP-114-128) showed significantly enhanced IFNγ response compared to PAP-114-128 epitope. Collectively, PAP-114-128 appears to be a highly relevant peptide on which to base vaccines for the treatment of advanced PC.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available