Novel prostate acid phosphatase‐based peptide vaccination strategy induces antigen‐specific T‐cell responses and limits tumour growth in mice

Abstract

Treatment options for patients with advanced prostate cancer remain limited and rarely curative. Prostatic acid phosphatase (PAP) is a prostate-specific protein overexpressed in 95% of prostate tumours. An FDA-approved vaccine for the treatment of advanced prostate disease, PROVENGE R (sipuleucel-T), has been shown to prolong survival, however the precise sequence of the PAP protein responsible for the outcome is unknown. As the PAP antigen is one of the very few prostate-specific antigens for which there is a rodent equivalent with high homology, preclinical studies using PAP have the potential to be directly relevant to clinical setting. Here, we show three PAP epitopes naturally processed and presented in the context of HHDII/DR1 (114-128, 299-313, and 230-244). The PAP-114-128 epitope elicits CD4 + and CD8 + T-cell-specific responses in C57BL/6 mice.Furthermore, when immunised in a DNA vector format (ImmunoBody R ), PAP-114-128 prevents and reduces the growth of transgenic adenocarcinoma of mouse prostate-C1 prostate cancer cell-derived tumours in both prophylactic and therapeutic settings. This anti-tumour effect is associated with infiltration of CD8 + tumour-infiltrating lymphocytes and the generation of high avidity T cells secreting elevated levels of IFN-γ. PAP-114-128 therefore appears to be a highly relevant peptide on which to base vaccines for the treatment of prostate cancer. Keywords:Immunotherapy r Prostate acid phosphatase r Prostate cancer r Tumour-infiltrating lymphocyte r Vaccine Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionProstate cancer is the most common form of male cancer in developed countries and cases are rising among men under 50. EveryCorrespondence: Dr. Stephanie E. B. McArdle e-mail: stephanie.mcardle@ntu.ac.uk year, more than 32 000 British men are diagnosed and 10 000 die from the disease [1,2]. At present there is no standard treatment available for patients with biochemical recurrence in the absence of radiographically visible metastases [3]. A long-held dream of tumour immunologists is to harness the specificity and sensitivity of the immune response and induce specific protective anti-tumour immunity. Unfortunately, for most cancers, the specific antigenic determinants on which vaccination strategies can C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 994-1004 Cellular immune response 995 be based are weakly immunogenic self-antigens that are comparatively poor at inducing robust, protective anti-tumour responses. Developing cancer vaccines that can overcome immune evasion and the tolerogenic capacity of self-antigens and induce protective immune responses is therefore essential for the development of new immunotherapies for aggressive disease. Several tumour-associated antigens have been reported to be expressed by prostate cancer cells. These include prostate-specific membrane antigen, prostate-specific antigen and prostate acidic phosphatase (P...

Establishing the pig as a large animal model for vaccine development against human cancer

“…Vaccine efficacy can be determined in various ways, and a typical approach to evaluate Th1-inducing adjuvant systems is to measure the IFN-γ production. Importantly, the level of secreted IFN-γ has been used to evaluate the efficacy of the only FDA-approved therapeutic anti-cancer vaccine, PROVENGE® (sipuleucel-T), in a peptide-immunization study in mice (Saif et al, 2014 ). Several cell types have the ability to produce IFN-γ including Natural Killer T cells, Natural Killer cells, CD4 + and CD8 + T cells amongst others.…”

A vaccine strategy with multiple prostatic acid phosphatase-fused cytokines for prostate cancer treatment

“…A question that remains to be answered is associated with the peptide epitopes of the PAP antigen in the cellular arm of the immune response in the current C57BL/6 mouse model. Notably, other investigators recently reported that three human PAP epitopes (114–128, 299–313 and 230–244) were immunologically processed for vaccinations in mice ( 8 ). They demonstrated that the PAP (114–128) epitope, which is identical between human and mouse species at the amino acid level, elicits CD4 + and CD8 + T lymphocyte-specific responses in C57BL/6 mice.…”

“…Homologs of the human PAP gene have been identified in rats and mice, and these proteins respectively share 75 and 81% homology with the human protein at the amino acid level ( 2 ). PAP is overexpressed in 95% of prostate cancer tissues ( 8 ), and the tissue specificity of PAP makes it an attractive target antigen for immunotherapy against prostatic malignancy ( 8 , 9 ). Several vaccine candidates have been developed based on the PAP protein using cell-based medicine ( 10 , 11 ), DNA vaccines ( 12 ) or peptide antigens ( 13 , 14 ).…”

Prostate cancer

“…We have recently demonstrated the ability of a prostatic acid phosphatase (PAP)-derived 15-mer peptide (PAP-114) to reduce the growth of established TRAMP C1 tumors in a preclinical murine model. 1 Although these results are encouraging and illustrate the potential of vaccine-based immunotherapy, they were obtained using relatively young animals (maximum 12 w of age, which equates to 10–20 y in humans). Thus, our findings might not represent the responsiveness/effectiveness of anti-cancer vaccines in old mice or in prostate patients, the average age of whom is 65 y.…”

“…An example of the latter is a monoclonal antibody against CD274 (best known as PD-L1), which influences the presence and immunosuppressive activity of Treg cells (so-called “immune checkpoint blockade”). The widespread adoption of anti-cancer vaccines into clinical practice requires the development of optimized formulations and approaches that are capable of 1 breaking immunological tolerance; 2 overcoming local and systemic tumor-driven immunosuppression; 3 operate in spite of age-related immune dysfunctions; and 4 targeting metastatic disease. These issues can be investigated (and potentially addressed) using induced, engineered and spontaneous heterotopic and orthotopic mouse tumor models ( Fig.…”