Prostate cancer immunotherapy

Abstract

The interaction between the immune system and prostate cancer has been an area of research interest for several decades. The recent U.S. Food and Drug Administration approval of 2 first-in-class proof-of-concept immunotherapies (sipuleucel-T and ipilimumab) has stimulated broader interest in manipulating immunity to fight cancer. In the context of prostate cancer, the immunotherapy strategies that have garnered the most interest are the therapeutic vaccination strategies, exemplified by sipuleucel-T and PROSTVAC-VF, and immune checkpoint blockade of CTLA-4 and PD-1. Improved understanding of the immune responses generated by these strategies and development of predictive biomarkers for patient selection will guide rational combinations of these treatments and provide building blocks for future immunotherapies.

Figure 1

Immunotherapies augment anti-tumor immunity against prostate cancer. Sipuleucel-T vaccination (Provenge) (upper left corner) is generated by first removing peripheral blood mononuclear cells (PBMC) from the patient via leukopheresis. PBMC including antigen-presenting cells (APC) are incubated ex vivo with a fusion protein composed of prostatic acid phosphatase (PAP) and GM-CSF, then re-infused into the patient. Activated APC present the PAP antigen to CD8 and CD4 T cells, causing activation and prostate cancer cytolysis. PROSTVAC-VF vaccination (lower left corner) consists of poxvirus vectors engineered to express PSA antigen and the costimulatory molecules B7.1, ICAM-1, and LFA-3. PROSTVAC-VF vaccinations are given subcutaneously in conjunction with GM-CSF, which either are taken up by skin-resident APC, or infect and lyse skin epithelium or fibroblasts, thereby creating cell debris for APC to ingest. In either case, APC express and present the antigen PSA in conjunction with costimulatory molecules to activate CD8 and CD4 T cells. Immune checkpoint blockade (upper right corner) is illustrated by monoclonal antibody-mediated blockade of CTLA-4 (by ipilimumab) or PD-1 (by anti-PD-1 antibody) expressed by CD8 or CD4 effector T cells. This blockade of inhibitory signals allows for unrestrained T cell attack on cancer cells. CTLA-4 blockade may also affect regulatory T cells (Treg), which also express CTLA-4, though the effect of blockade on this suppressive cell type is less clear. Stimulation of helper CD4 T cells can also subsequently stimulate humoral immunity by B cells secreting natural antibodies to tumor proteins such as PSA and PAP. Androgen ablation enhances T cell anti-tumor immunity by a variety of mechanisms, including increasing prostatic infiltration by T cells, restoring T cell output from the thymus, and mitigation of T cell tolerance.