Abstract and Introduction
Abstract
This review presents important information about the current state of the art for vaccine immunotherapy of prostate cancer. It includes important preclinical research for each of the important prostate cancer vaccines to have reached clinical trials. To date, the only prostate cancer vaccine that has completed Phase III trials and has been approved and licensed by the US FDA is Sipuleucel-T, which immunizes patients against the prostate-associated antigen prostatic acid phosphatase. The benefits and concerns associated with the vaccine are presented. A current Phase III trial is currently underway using the vaccinia-based prostate-specific antigen vaccine Prostvac-TRICOM. Other immunotherapeutic vaccines in trials include the Ad/prostate-specific antigen vaccine Ad5-prostate-specific antigen and the DNA/prostatic acid phosphatase vaccine. A cellular vaccine, GVAX, has been in clinical trials but has not seen continuous study. This review also delves into the multiple immune regulatory elements that must be overcome in order to obtain strong antitumor-associated antigen immune responses capable of effectively destroying prostate tumor cells.
Introduction
Prostate cancer is the second leading cause of cancer death among men in the USA. There will be an estimated 241,740 new diagnoses of prostate cancer made in the USA in the year 2012 with a predicted 28,170 deaths from the disease. First-line treatments for organ-confined prostate cancer include radical prostatectomy and radiation therapy, either external beam or brachytherapy. When the cancer recurs, either in the original prostate bed or at a metastatic site, patients are treated by elimination of androgens, the so-called androgen-deprivation therapy (ADT), previously referred to as hormone therapy. Early ADT used surgical castration to eliminate testicular testosterone, but chemical castration is the current treatment, using luteinizing-hormone-releasing hormone or gonadotropin-releasing hormone agonists. The absence of testosterone results in the death of cells dependent upon the hormone for their growth. However, within a mean of 2 years from the initiation of ADT, cells that are able to proliferate in the absence of testosterone begin to grow. This stage of tumor progression is termed castrate-resistant prostate cancer (CRPC) and ultimately results in the death of the patient. Treatment options for CRPC are currently limited to further hormonal manipulation or the use of a few chemotherapeutic agents. Although surgical or chemical castration prevents the production of testicular androgens, it has no effect on the production of these steroid hormones from other sites. One such site, known for many years, is the adrenal glands. More recently, there is a strong evidence that androgens are also produced in situ within prostate tumors by the tumor cells. Only recently developed, tested and licensed, a CYP-17 inhibitor has been demonstrated to have an effect on what is now termed CRPC. In a Phase II study, the effect of the latter agent on survival was determined to be an increase in overall survival (OS) of 3.9 months. An additional drug, MDV3100, that acts as an oral nonsteroidal anti-androgen agent is being tested in this same population of men with recurrent and refractory prostate cancer. In data recently presented at the 2012 ASCO GU Symposium (San Francisco, CA, USA, 2–4 February 2012), the drug demonstrated an increased survival of patients of 4.8 months. The data presented at the same conference also showed an increase in median survival of 4.5 months of patients treated with a radium-223 drug Alpharadin®. Thus, although some therapies have demonstrated a prolongation of survival for few months, no cure for recurrent prostate cancer exists at present.
In the past 15–20 years, basic scientists and clinicians have been investigating the use of vaccine immunotherapy as a means to treat men with recurrent prostate cancer. These vaccines are not meant to be prophylactic, that is, to prevent the development of prostate cancer, but to be therapeutic with the ultimate goal of killing prostate antigen-expressing tumor cells by immune mechanisms. A number of antigens have been studied that includes prostate-specific antigen (PSA), fowlpox virus, liposomes, plasmids and chemical conjugates. Noncarrier immunogens such as DNA vaccines have also been used, particularly in studies in which investigators have targeted PAP. The overwhelming majority of both preclinical and research and clinical trials have attempted to induce antigen-specific CD8 cytotoxic T lymphocytes (CTLs), although studies using antibody therapy against PSCA and an immunotoxin against PSMA were reported.