Immunotherapy for prostate cancer: biology and therapeutic approaches

Abstract

Although prostate cancer was not historically considered to be a particularly immune-responsive cancer, recent clinical trials have demonstrated that immunotherapy for prostate cancer can lead to improvements in overall survival (OS). These studies include randomized controlled trials with sipuleucel-T and another with PROSTVAC-VF, both of which rely on stimulating the immune system to target prostate proteins. This review discusses the most promising developments over the past year in immune-based therapy for prostate cancer and the opportunities that lie ahead. Recent randomized immunotherapy trials in prostate cancer have demonstrated improvements in OS but without the concomitant improvements in progression-free survival. This uncoupling of survival from clinical response poses challenges to clinical management, because conventional measures of objective response cannot be used to identify patients benefiting from treatment. There is a significant need to identify immunologic or clinical surrogates for survival so that clinical benefit can be assessed in a timely manner. Immunotherapy is now an established treatment approach for prostate cancer, with multiple clinical trials demonstrating improvements in OS. Significant challenges to this modality remain, including determining best clinical setting for immunotherapy, identifying patients who benefit, and defining relevant clinical and immunologic end points. Nevertheless, the broader availability of novel immunotherapies will provide opportunities not only to target different components of the immune system but also to combine immunotherapies with other treatments for improved clinical efficacy.

Fig 1.

Overview of tumor-specific immune response and components targeted by individual immunotherapies. Dendritic cell (DC) activation normally requires uptake, processing, and presentation of tumor antigens by immature DCs. Triggering of Toll-like receptors (TLRs) on DCs also leads to DC activation. When T cells receive two signals—first, from binding of antigen–major histocompatibility complex (MHC) to T-cell receptor (TCR), and second, from B7 binding to CD28—T cells proliferate in interleukin-2 (IL-2) –dependent manner, migrate to tumor, and directly lyse tumor cells. PROSTVAC-VF is a poxvirus vaccine that delivers prostate-specific antigen (PSA). It activates immature DCs with uptake of encoded tumor antigens released from infected cells and has three costimulation signals encoded in virus to enhance DC-to–T-cell interaction. Sipuleucel-T consists of harvested antigen-presenting cells (APCs) cultured with fused protein consisting of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). This product is reinfused into patients. In vitro manipulation of cells as well as GM-CSF presumably enhances antigen presentation. Anti–cytotoxic T lymphocyte–associated receptor 4 (CTLA4) monoclonal antibodies (anti-CTLA4 mAb) target CTLA4 coreceptors, which negatively regulates T-cell activation. Anti–programmed death 1 (PD-1) monoclonal antibodies (anti–PD-1 mAb) target PD-1 receptors, which negatively regulates function of memory T cells. PD-1 can be expressed on tumor infiltrating lymphocytes, whereas ligands for PD-1 (PD-L) are often expressed by tumors. Cytotoxic effects of radiation therapy and docetaxel can also modulate immune responses with release of proinflammatory signals from dying cells (eg, high-mobility group protein B1 [HMGB1] is a TLR4 agonist). In addition, docetaxel can also act as a TLR agonist.

Fig 2.

Overview of cytotoxic T lymphocyte–associated antigen 4 (CTLA4) blockade. After T-cell activation, CTLA4 receptors are recruited to the T-cell surface and compete with CD28 for binding to B7. (A) When CTLA4 binds to B7, it inactivates T cells, resulting in downregulation of T-cell immune response. (B) Anti-CTLA4 antibodies (anti-CTLA4 mAb) can block this interaction by binding to CTLA4, resulting in augmented T-cell activation. MHC II, major histocompatibility complex II; TCR, T-cell receptor.