Pharmacology Update

Sipuleucel-T Suspension for Intravenous Infusion (Provenge®)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

The first immunotherapy has been approved by the FDA for the treatment of hormone-resistant prostate cancer. This vaccine, containing autologous CD54+ cells, is tailored for each patient and is marketed by Dendrion as Provenge®.

Indications

Sipuleucel-T is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer.1

Dosage

The vaccine is administered as intravenous infusion in 3 doses at approximately 2-week intervals. The patient should be premedicated with acetaminophen and an antihistamine (e.g., diphenhydramine) 30 minutes prior to administration to reduce acute infusion-related adverse events (e.g., chills and fever).

Each dose of sipuleucel-T contains a minimum of 50 million autologous CD54+ cells activated granulocyte-microphage colony-stimulating factor (PAP-GM-CSF) suspended in 350 mL of Lactated Ringer's Injection.

Potential Advantages

Sipuleucel-T prolongs overall survival by about 4 months compared to placebo.1

Potential Disadvantages

Approximately 70% of patients experience acute infusion reactions. These include chills (53%), fever (31%), fatigue (41%), back pain (30%), and nausea (22%).1 Sipuleucel-T requires donation of the patient's blood from which dendritic cells are harvested. They are shipped to Dendreon in New Jersey where they are incubated with prostatic acid phosphatase (PAP) linked to PAP-GM-CSF fusion protein. PAP is an antigen commonly found on prostate cancer cells. The autologous product is then infused in 3 doses 2 weeks apart.

Comments

Sipuleucel-T consists of dendritic cells that are activated with a recombinant human protein, PAP-GM-CSF.1 In addition, the vaccine contains T cells, B cells, natural killer cells, and other cells. The therapeutic goal is to enable the vaccine to target the prostate cancer cells by recognizing PAP antigen and stimulate the patient's immune system against the cancer. The effectiveness of the vaccine was evaluated in patients with metastatic castrate-resistant prostatic cancer in 2 randomized, double-blind, placebo-controlled studies. Participants were randomized 2:1 to 3 infusions of the activated vaccine or placebo, which was autologous peripheral mononuclear cells that were not activated. There were 512 in the first study and 127 in the second study. The time to disease progression was not statistically different; however, overall survival was longer with sipuleucel-T. The median survival for study 1 was 25.8 months vs 21.7 months and 25.9 and 21.4 for the second study. The hazard ratios (95% confidence interval) were 0.775 (0.614-0.979) and 0.586 (0.388-0.884). At the 3-year survival analysis, 34% of the participants who received the vaccine were alive compared to 11% for placebo.2 The vaccine is generally well tolerated with low-grade fever and rigor the most common adverse events.2

Clinical Implications

This is the first autologous cellular immunotherapy to be approved by the FDA. Interestingly, analyses of time to disease progression did not reach statistical significance but survival was improved with sipuleucel-T. This provides a treatment option for patients with metastatic hormone-refractory prostate cancer.

References

1. Provenge Product Labeling. Seattle, WA: Dendreon Corporations; April 2010.

2. Sonpavde G, et al. Emerging vaccine therapy approaches for prostate cancer. Rev Urol 2010;12:25-34.