Immunotherapy for prostate cancer: recent developments and future challenges

Abstract

Since the approval of sipuleucel-T for men with metastatic castrate resistant prostate cancer in 2010, great strides in the development of anti-cancer immunotherapies have been made. Current drug development in this area has focused primarily on antigen-specific (i.e. cancer vaccines and antibody based therapies) or checkpoint inhibitor therapies, with the checkpoint inhibitors perhaps gaining the most attention as of late. Indeed, drugs blocking the inhibitory signal generated by the engagement of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) found on T-cells has emerged as potent means to combat the immunosuppressive milieu. The anti-CTLA-4 monoclonal antibody ipilimumab has already been approved in advanced melanoma and two phase III trials evaluating ipilimumab in men with metastatic castrate-resistant prostate cancer are underway. A phase III trial evaluating ProstVac-VF, a poxvirus-based therapeutic prostate cancer vaccine, is also underway. While there has been reason for encouragement over the past few years, many questions regarding the use of immunotherapies remain. Namely, it is unclear what stage of disease is most likely to benefit from these approaches, how best to incorporate said treatments with each other and into our current treatment regimens and which therapy is most appropriate for which disease. Herein we review some of the recent advances in immunotherapy as related to the treatment of prostate cancer and outline some of the challenges that lie ahead.

Figure 1

Immune editing hypothesis. Abbreviations: APC, antigen presenting cell; NK, natural killer cell.

Figure 2

Increase in relative density of immune cells within the prostate following androgen deprivation [49]. After neo-adjuvant androgen deprivation CD3+ T-cells had a 1.87-fold increase in relative density, CD8+ T-cells had approximately 2-fold increase in relative density and macrophages had a 1.78-fold increase in relative density. There was no significant increase in CD20+ B-cells, natural killer cells or T-regulatory cells.