Assessment of a novel mutated Prostatic Acid Phosphatase-derived vaccine for the treatment of prostate cancer

Le Vu, P., 2019. Assessment of a novel mutated Prostatic Acid Phosphatase-derived vaccine for the treatment of prostate cancer. PhD, Nottingham Trent University.

N0635113 Pauline Le Vu PhD thesis- Final corrected version 2021.pdf - Published version

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Prostate cancer is the second most frequent cancer in men. Patients with a localized disease are treated with local therapies such as prostatectomy or radiation therapy whereas patients with a metastatic disease are treated with androgen deprivation therapies (ADT). However, patients ultimately develop resistance to ADT, thereby leading to a castrate resistant prostate cancer (CRPC). The treatment options for such disease are limited and not curative, with a median survival from diagnosis of 14 months. Among these treatments, the Sipuleucel-T based vaccine, FDA approved in 2010, has been shown to prolong the overall survival by 4 months. However, while this approach demonstrated the efficacy of targeting the Prostatic Acid Phosphatase (PAP) antigen, overexpressed in prostate cancer, to stimulate the patient's immune system to treat CRPC, it remains extremely expensive and limited in its efficacy.

The aim of the study was to develop a new, less expensive and more effective PAP-based vaccine for the treatment of advanced prostate cancer. A 15mer PAP-derived vaccine, when injected as a DNA vaccine, was previously shown to induce PAP-specific T-cell responses and to reduce tumour growth in a syngeneic heterotopic murine prostate cancer model. A new form of the vaccine was subsequently developed by elongating (to 42mer) and introducing a single mutation to the PAP-derived peptide.

Two pre-clinical murine models (C57Bl/6 mice and HHDII/DR1 transgenic) were used to assess the efficacy of the vaccine. The mutated PAP42mer sequence was the most immunogenic sequence in both models when administered as a peptide-based vaccine, as demonstrated by the higher number of IFNγ-releasing splenocytes following in vitro stimulation with PAP-derived class-I and class-II epitopes and by the higher functional avidity obtained. The vaccine immunogenicty was further enhanced by using stronger adjuvants and delivery systems. CAF09 adjuvant and ImmunoBody® DNA vaccine were superior to CpG adjuvant in inducing PAP-specific immune responses. This was demonstrated by the expression of activation and inhibitory markers, by the induction of a memory response and by the functional phenotype (cytokines release, proliferation, and degranulation) of CD8+ T cells following in vitro stimulation with shorter-vaccine-derived peptides. Splenocytes from vaccinated mice were capable of lysing target cells in a PAP-dependant manner in vitro. Vaccination slowed down the growth of human-PAP+ expressing tumours implanted in the HHDII/DR1 model but no anti-tumour effect was observed against TRAMP-C1 tumours in the C57Bl/6 model. Finally, circulating PAP42mer derived-specific CD8+ T cells were detected in the blood of patients with prostate cancer.

In summary, this study demonstrated that a unique vaccine strategy could induce a robust anti-PAP immunity but with little effect on the growth of implanted PAP-expressing cancer cell-derived tumours in vivo. The presence of PAP-specific CD8+ T cells in the periphery of patients with advanced prostate cancer suggests that these patients could benefit from this new approach.

Item Type: Thesis
Creators: Le Vu, P.
Date: September 2019
Rights: This work is the intellectual property of the author and may also be owned by the research sponsor(s) and/or Nottingham Trent University. 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 owner(s) of the Intellectual Property Rights.
Divisions: Schools > School of Science and Technology
Record created by: Linda Sullivan
Date Added: 04 Jun 2021 10:04
Last Modified: 04 Jun 2021 10:04

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