Advances in prostate cancer immunotherapies
ABSTRACT
Prostate cancer is a major cause of mortality in men in the Western world. Although treatment of early stage prostate cancer with radiation therapy or prostatectomy is efficient in most cases, some patients develop a fatal hormone-refractory disease. Treatments in this case are limited to aggressive chemotherapies, which can reduce serum prostate-specific antigen (PSA) levels in some patients. Taxane- and platinum-compound-based chemotherapies produce a survival benefit of only a few months. Therefore, it is crucial to develop novel, well tolerated treatment strategies. Over the past years, immunotherapy of hormone-refractory prostate cancer has been studied in numerous clinical trials. The fact that the prostate is a non-essential organ makes prostate cancer an excellent target for immunotherapy. Administration of antibodies targeting the human epidermal growth factor receptor-2 or the prostate-specific membrane antigen led to stabilisation of PSA levels in several patients. Vaccination of prostate cancer patients with irradiated allogeneic prostate cell lines has demonstrated that whole cell-based vaccines can significantly attenuate increases in PSA. Two different recombinant viral expression vectors have been applied in prostate cancer treatment: poxvirus and adenovirus vectors. Both vaccines have the advantages of using a natural method to induce immune responses and achieving high levels of transgene expression. Vaccinia viruses in combination with recombinant fowlpox or canarypox virus have been used to express recombinant PSA. Several studies demonstrated that this approach is safe and can lead to stabilisation of PSA values. A very promising approach in prostate cancer immunotherapy is vaccination of patients with dendritic cells. Thereby, peptides, recombinant proteins, tumour lysates or messenger RNA have been used to deliver antigens to autologous dendritic cells. Loading of dendritic cells with up to five different peptides derived from multiple proteins expressed in prostate cancer demonstrated that cytotoxic T-cell responses could be elicited in prostate cancer patients. Sipuleucel-T (APC8015), an immunotherapy product consisting of antigen-presenting cells, loaded ex vivo with a recombinant fusion protein consisting of prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor, demonstrated in a phase III, placebo-controlled trial an improvement in median time to disease progression. The improvement in overall survival was 4.5 months for sipuleucel-T-treated patients compared with the placebo group. Although there is a minor increase in overall survival of metastatic prostate cancer patients with some approaches, more effective therapeutic strategies need to be developed.