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Thomas, JE, 2024. Development of a prostatic acid phosphatase-derived vaccine for the treatment of advanced prostate cancer. PhD, Nottingham Trent University.
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Abstract
Background: Current treatments for castrate-resistant prostate cancer (CRPC) remain limited, with a median survival from diagnosis of 23 months, the PAP-specific Sipuleucel-T vaccine, which was approved by the FDA in 2010, increases the Overall Survival by 4.1 months but is extremely expensive. Previous work in our laboratory has demonstrated that a 15mer PAP-derived peptide delayed TRAMP-C1 prostate tumours, yet this vaccine only targeted HLA A2 haplotype patients. Thereby the sequence was elongated to 42mer with an amino acid substitution to include epitopes predicted to bind to additional HLA haplotypes. The MutPAP42mer +CAF®09b vaccine has improved secretory IFNγ and PAP-specific splenic T-cells in HHDII DR mouse models, however, no CD4+ T-cell mediated responses were demonstrated. To improve the anti-tumour efficacy of MutPAP42mer by improving CD4+ T-cell mediated responses, a novel 15-mer PAP peptide was identified. MutPAP42mer with PAP15mer CPR immunogenicity was assessed using CpG ODN1826/2395+IFA and CAF®09b adjuvant.
Methods: HHDII DR/DP4 and C57BL/6J mice were immunised with MutPAP42mer+CPR or hPAP42mer WT respectively with CAF®09b or CpG ODN1826/2395+IFA adjuvants. Vaccine-induced immune responses and cytotoxic capabilities were measured by assessing the proportion and functionality of splenic PAP-specific T-cells in vitro.
Results: PAP peptide/s adjuvanted with CAF®09b was shown to have improved secretory IFN-γ and CD4+/CD8+ specific immune response in HHDII and C57BL/6J models. Moreover, the in vivo analysis of hPAP42mer WT +CAF®09b vaccine increased the percentage of IFN-γ-releasing CD8+ T-cells when applied with androgen ablation in TRAMP C2 prostate tumour bearing C57BL/6J models. However, the vaccine had no effect in reducing the tumour growth was reported to be due to the elevated levels of MDSC in the PCa tumours. Immunophenotyping of blood samples also revealed increased expression of M-MDSCs and G-MDSCs, with G-MDSCs being more prevalent in both PCa and benign patients.
Conclusions: The preclinical analysis of the PAP peptide-based vaccine concludes that administering the vaccine in conjunction with androgen deprivation and strategies to reduce MDSC-mediated suppression, will enhance the therapeutic efficacy of the vaccination. Future studies should investigate the link between MDSCs and vaccine efficacy, particularly in humanized models, to develop more effective immunotherapy strategies for CRPC.
| Item Type: | Thesis |
|---|---|
| Creators: | Thomas, J.E. |
| Contributors: | Name Role NTU ID ORCID |
| Date: | August 2024 |
| Rights: | This work is the intellectual property of the author. You may copy up to 5% of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed to the Intellectual Property Rights owner(s) |
| Divisions: | Schools > School of Science and Technology |
| Record created by: | Laura Borcherds |
| Date Added: | 10 Jun 2025 13:23 |
| Last Modified: | 10 Jun 2025 13:23 |
| URI: | https://irep.ntu.ac.uk/id/eprint/53718 |
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