Sipuleucel-T

Sipuleucel-T (APC8015, trade name Provenge), manufactured by Dendreon Corporation, is a therapeutic cancer vaccine for prostate cancer (CaP). It must be prepared specifically for each patient. In metastatic prostate cancer, it has extended survival by median 4.1 months (IMPACT Phase III trial data). The treatment costs $93,000.

Cancer immunotherapeutic history
Sipuleucel-T is the first therapeutic cellular immunotherapy to demonstrate effectiveness in Phase III clinical trials by prolonging the life of patients who have advanced to the late stage of the disease, metastatic, asymptomatic, hormone-refractory prostate cancer (HRPC).

Other names for this stage are metastatic castrate-resistant (mCRPC) and androgen independent (AI) or (AIPC). This stage leads to mCRPC with lymph node involvement and distal (distant) tumors; this is the lethal stage of CaP. The prostate cancer staging designation is T4,N1,M1c.

First FDA-approved therapeutic cancer vaccine
Sipuleucel-T was approved by the U.S. Food and Drug Administration (FDA) on April 29, 2010, to treat asymptomatic or minimally symptomatic metastatic HRPC.

Shortly afterward, sipuleucel-T was added to the compendium of cancer treatments published by the National Comprehensive Cancer Network (NCCN) as a "category 1" (highest recommendation) treatment for HRPC. The NCCN Compendium is used by Medicare and major health care insurance providers to decide whether a treatment should be reimbursed.

While referred to as a therapeutic vaccine that treats the cancer, as compared to a preventive vaccine, which prevents infectious disease, sipuleucel-T is an immunostimulant. As of 2013, there are three approved preventive vaccines which attack the cancer-causing viruses human papillomavirus, hepatitis A virus and hepatitis B virus.

Treatment method
A course of sipuleucel-T treatment consists of three basic steps:


 * 1) A patient's own white blood cells, primarily antigen-presenting cells (APCs), also called dendritic cells, are extracted in a leukapheresis procedure.
 * 2) The blood product is sent to the factory and incubated with a fusion protein (PA2024) consisting of two parts,
 * 3) the antigen prostatic acid phosphatase (PAP), which is present in 95% of prostate cancer cells, and
 * 4) an immune signaling factor granulocyte-macrophage colony stimulating factor (GM-CSF) that helps the APCs to mature.
 * 5) The activated blood product (APC8015) is returned from the factory to the infusion center and re-infused into the patient to cause an immune response against cancer cells carrying the PAP antigen.

A complete sipuleucel-T treatment repeats three courses over the span of a month, with two weeks between successive courses.

Survival difference
Sipuleucel-T showed overall survival (OS) benefit to patients in three double-blind randomized phase III clinical trials, D9901, D9902a, and IMPACT.

An editorial in the New England Journal of Medicine concluded that, "It is... uncertain what role sipuleucel-T will ultimately play in the treatment of prostate cancer, given the other promising treatments in development".

The IMPACT trial served as the basis for licensing approval of sipuleucel-T by the FDA. This trial enrolled 512 patients with asymptomatic or minimally symptomatic metastatic HRPC randomized in a 2:1 ratio. The median survival time for sipuleucel-T patients was 25.8 months comparing to 21.7 months for placebo-treated patients. Overall survival was statistically significant (P=0.032). However, a better control group would have included patients receiving white blood cells incubated with GM-CSF alone, so that the main difference between the two groups would have been the tumor antigen. Furthermore, the longer survival without tumor shrinkage of change in progression is surprising. This may suggest the effect of an unmeasured variable.

The D9901 trial enrolled 127 patients with asymptomatic metastatic HRPC randomized in a 2:1 ratio. The median survival time for patients treated with sipuleucel-T was 25.9 months comparing to 21.4 months for placebo-treated patients. Overall survival was statistically significant (P=0.01).

The D9902a trial was designed like the D9901 trial but enrolled 98 patients. The median survival time for patients treated with sipuleucel-T was 19.0 months comparing to 15.3 months for placebo-treated patients, but did not reach statistical significance.

However, according to Huber, in the Journal of the National Cancer Institute, Dendreon's original statistical analysis plan would analyze the difference in effectiveness between patients <65 or ≥65 years of age. The published IMPACT trial used 71 years as the cut-off point, not 65. The New England Journal of Medicine printed a correction after inquiries by Reuters. According to Reuters, an FDA review found that men over 65 had a 41% greater chance of dying with Provenge. According to Huber, older men in the placebo group had a higher chance of dying, because removing white cells was harmful. Aggregating the younger and older men made Provenge look better. Huber's contentions were ultimately exposed as a scheme to profit from speculation in put option contracts in the underlying security of Dendreon Corporation, which would have produced enrichment in the event the stock price were to have declined; the SEC accordingly found in November 2013 that in their reporting of Provenge, she and a colleague, via the dissemination of untrue statements and omissions of fact as a means to obtain money or property, violated Section 17(a)(2) of the Securities Act of 1933 (Securities Act), and imposed against each of them a six-month suspension, a $25,000 civil penalty, and a cease-and-desist order. - See more at: http://pubmemo.com/i/federal-government/2013/securities-and-exchange-commission-wed-27-nov-2013-issue_1206545.html#sthash.ksB7rcs4.Uh8V5LId.dpuf, cease-and-desist order: http://www.sec.gov/litigation/admin/2013/33-9488.pdf

Huber's analysis as published Journal of National Cancer Institute heavily speculates on the potential negative effects of Aph on placebo patients, this was later addressed by papers by James Gulley et al arriving at the conclusion that "data provides evidence that Aph inflicts negligible effects on a pts immune system, rejecting the hypothesis that pts immune competence is impacted by the procedure in a meaningful way." http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3086&sKey=8dc35a86-d973-4f4b-abdd-717b8e5c4096&cKey=26207d5b-db55-4851-95fc-17c7ba2446e2&mKey=%7b9B2D28E7-24A0-466F-A3C9-07C21F6E9BC9%7d

Side effects
The side effects of sipuleucel-T were mostly limited to chills, fever, fatigue, nausea and headache which usually occurred within the first few days of treatment. In addition, more serious cardiovascular events were observed at a rate of 2.4% in patients treated with sipuleucel-T vs 1.8% in placebo-treated patients.

Additional clinical trials
The PRO Treatment and Early Cancer Treatment (PROTECT) trial, a phase IIIB clinical trial started in 2003, is ongoing. Its purpose is to test efficacy for patients whose CaP is still controlled by either suppression of testosterone by hormone treatment or by surgical castration. Such patients have usually failed primary treatment of either surgical removal of the prostate, (EBRT), internal radiation, BNCT or (HIFU) for curative intent. Such failure is called biochemical failure and is defined as a PSA reading of 2.0 ng/mL above nadir (the lowest reading taken post primary treatment).

Clinical trials administering sipuleucel-T in conjunction with ipilimumab (Yervoy) are being conducted to evaluate for clinical safety and increased anti-cancer effects (quantified in PSA, radiographic, and T cell response) in patients with advanced prostate cancer.