Abstract and Introduction
Abstract
Background: Sipuleucel-T is an autologous cellular immunotherapy approved by the US Food and Drug Administration for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. Its mechanism of action is based on stimulation of the patient's own immune system to target prostate cancer. Peripheral blood mononuclear cells, including antigen-presenting cells and T cells, are obtained from patients via leukapheresis and treated ex vivo with PA2024, a fusion protein consisting of prostatic acid phosphatase/granulocyte-macrophage colony-stimulating factor antigen.
Methods: Data relating to the potential pharmacodynamic biomarkers associated with sipuleucel-T activity are reviewed, as well as considerations for patient selection and for sequencing sipuleucel-T with other prostate cancer treatments. Possible directions for future development are also discussed, including treatment of less advanced prostate cancer populations, combination treatment, and immune modulation.
Results: Data from three randomized, double-blind, placebo-controlled phase III clinical trials of sipuleucel-T in patients with metastatic castration-rresistant prostate cancer have shown improvement in overall survival vs control. Here, we review its developing role in prostate cancer therapy and future directions for development.
Conclusions: There is potential to build on sipuleucel-T to further advance immunotherapy of prostate cancer.
Introduction
Although mortality from prostate cancer is declining within the United States, the rate remains high, with an estimated 28,170 deaths occurring in 2012. Localized therapies for newly diagnosed prostate cancer have been successful in curing upward of 75% of patients, but novel therapies for advanced prostate cancer are needed to reduce prostate cancer mortality.
Sipuleucel-T was approved by the US Food and Drug Administration (FDA) in 2010 for asymptomatic and minimally symptomatic patients with metastatic castration-resistant prostate cancer (CRPC). Since then, a number of other treatments have been approved for metastatic CRPC. In 2010 and 2011, both abiraterone acetate and cabazitaxel were approved by the FDA for therapy after prior docetaxel treatment, and denosumab was approved for the prevention of skeletal-related events in patients with bone metastases. More recently, an overall survival (OS) benefit was shown with both radium-223 and enzalutamide in metastatic CRPC, and the latter was approved in 2012. Phase III trials of cabozantinib were initiated after phase II results showed evidence of antitumor activity. Other promising immunotherapies in late-phase development for prostate cancer include prostate-specific antigen (PSA)-TRICOM vaccine (a poxviral-based vaccine directed against PSA) and ipilimumab (an anticytotoxic T-lymphocyte antigen [CTLA-4] monoclonal antibody currently approved for the treatment of metastatic melanoma).
Among these emerging novel therapies, sipuleucel-T is the only immunotherapy with a demonstrated OS benefit for asymptomatic or minimally symptomatic metastatic CRPC. Here, we review the clinical data leading to FDA approval of sipuleucel-T and the practical aspects of treatment. We also discuss potential pharmacodynamic biomarkers associated with sipuleucel-T activity, patient selection and drug-sequencing strategies, and future directions for development.