Immune Therapy for Prostate Cancer

Abstract

Immunotherapy for castration-resistant prostate cancer has continued to be an area of active research over the last several years. The enthusiasm of this approach has been based on the assumption of better tolerability and that using the body's own immune system may be more effective than either hormonal or chemotherapy. Sipuleucel-T, a dendritic cell-based vaccine, is the only approved agent in this class for the management of castrate-resistant prostate cancer. Although sipuleucel-T increases overall survival without any significant changes in progression-free survival, other forms of immunotherapy such as PSA-TRICOM, ipilimumab, and chimeric antigen receptor T cell therapy are in advanced stages of clinical development. Immune biomarkers are being developed to assess response to these treatments and also to understand how the immune system responds to these respective therapies. Combinations of immunotherapy with androgen deprivation, radiation therapy, and chemotherapy have also been explored with varying results. This review discusses the mechanisms, key preclinical and clinical data, and perspectives for immunotherapeutic agents in the treatment scheme for castrate-resistant prostate cancer.

Figure 1

Overview of vaccine-based immune therapy. Top panel (Sipuleucel-T): Autologous peripheral mononuclear cells are co-incubated with a synthetic peptide and costimulatory molecules. APC’s capture and process the antigen and costimulatory molecules ex vivo. Upon administration back to the patient, activated APC’s engage and educate T cells. Educated T cells seek out and eradicate tumor. Bottom panel (PSA-TRICOM): The vaccine containing the tumor associated antigen and costimulatory molecules are administered to the patient. The vaccine is processed by APC’s in vivo and the antigens/costimulatory molecules are presented to T cells. Educated T cells seek out and eradicate tumor.

Figure 2

Overview of checkpoint blockade. Endogenous T cells with T cell receptors that recognize tumor antigens initially engage the tumor and become activated. After activation, CTLA-4 is translocated to the cell membrane and binds to CD80 on the tumor. This CTLA-4/CD80 engagement leads to T cell inactivation. CTLA-4 inhibitors prevent interaction with CD80 leading to persistent T cell activation and tumor eradication.

Figure 3

Overview of CAR T immune therapy. Autologous T cells collected from the patient are transduced with a retrovirus or lentivirus that contains the chimeric antigen receptor construct. Transduced T cells are infused back to the patient where they seek out and eradicate tumor cells.