Immunotherapy for castration-resistant prostate cancer: Progress and new paradigms

Background: The approval of sipuleucel-T in conjunction with data from other immunotherapeutic trials for prostate cancer and other solid tumors demonstrates the potential of harnessing the patients' immune system for long-term survival. Thus, a range of therapeutic approaches are under evaluation. This review describes the rationale for immunotherapy for prostate cancer, summarizes the approaches under evaluation, and discusses sequencing options for immunotherapy in the current treatment paradigm.

Design: References for this review were identified through searches of PubMed with the search terms "prostate cancer," "immune system," "vaccine," "immunotherapy," and "T cells." Articles were also identified through searches of the authors' own files. The final reference list was generated based on originality and relevance.

Results: The immune system can recognize and respond to prostate tumor antigens, effected through tumor-associated antigens and tumor infiltration of immune effector cells. However, evidence also suggests that prostate tumors are adept at escaping immunological recognition, thus hypothesizing multiple therapeutic strategies. Therapeutic approaches could include vaccination and modulation of T-cell function via the blockade of checkpoint receptors such as cytotoxic T-lymphocyte antigen-4 and programmed death 1. In phase III trials, sipuleucel-T improved overall survival for an M1 patient population with castration-resistant prostate cancer and ipilimumab also did so when given after radiotherapy in a subset of better risk patients. In randomized phase II trials, prostate-specific antigen-TRICOM improved overall survival and tasquinimod improved progression-free survival.

Conclusion: Although immunotherapy has the potential to affect advanced prostate cancer, additional research is needed to (1) identify predictive or surrogate markers of activity, (2) understand which agents are clinically effective alone or in combination with other therapies, and (3) define the optimal timing for an immunotherapy to achieve maximal benefit.