Is There a Role for Immunotherapy in Prostate Cancer?

Abstract

In the last decade, immunotherapy has revolutionized the treatment landscape of several hematological and solid malignancies, reporting unprecedented response rates. Unfortunately, this is not the case for metastatic castration-resistant prostate cancer (mCRPC), as several phase I and II trials assessing programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors have shown limited benefits. Moreover, despite sipuleucel-T representing the only cancer vaccine approved by the Food and Drug Administration (FDA) for mCRPC following the results of the IMPACT trial, the use of this agent is relatively limited in everyday clinical practice. The identification of specific histological and molecular biomarkers that could predict response to immunotherapy represents one of the current challenges, with an aim to detect subgroups of mCRPC patients who may benefit from immune checkpoint monoclonal antibodies as monotherapy or in combination with other anticancer agents. Several unanswered questions remain, including the following: is there-or will there ever be-a role for immunotherapy in prostate cancer? In this review, we aim at underlining the failures and promises of immunotherapy in prostate cancer, summarizing the current state of art regarding cancer vaccines and immune checkpoint monoclonal antibodies, and discussing future research directions in this immunologically "cold" malignancy.

Keywords: CTLA-4; combination therapy; immune checkpoint inhibitors; immunotherapy; pd-1; predictive biomarkers; prostate cancer; vaccines.

Figure 1

Sipuleucel-T in prostate cancer. Firstly, the cancer vaccine sipuleucel-T requires leukapheresis of immature immune cells; leukapheresis is then followed by incubation with specific fusion protein (PA2024), consisting of prostatic acid phosphatase (PAP) coupled with granulocyte-macrophage colony stimulating factor (GM-CSF). Subsequently, cells are re-infused allowing for APC maturation and activation of CD4+ and CD8+ T cells, which in turn are able to recognize and kill PAP presenting tumor cells.

Figure 2

PROSTVAC-VF vaccine. PROSTVAC-VF consists of a recombinant vaccinia vector followed by multiple booster vaccination using a recombinant fowlpox vector. Both vectors contain PSA and the TRIad of CO-stimulatory Molecules (TRICOM), which in turn includes B7-1, ICAM-1, and LFA-3.

Figure 3

Simplified mechanisms of action of Listeria Monocytogenes (Lm)-based vaccine in cancer. Firstly, Lm-based vectors are attenuated, with removal of one or more virulence genes. When attenuated, these vaccines are particularly rich in tumor-associated antigens; following administration, Lm-based vaccines infect antigen-presenting cells (APCs), escape phagocytosis and secrete tumor-associated antigens; these antigens are involved in the secretion of proinflammatory cytokines, the upregulation of costimulatory molecules, and the activation of tumor-specific cytolytic T lymphocytes which produce antitumor responses and cell death.