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Sipuleucel-T

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Sipuleucel-T
Vaccine description
TargetProstate cancer
Vaccine typeProtein subunit
Clinical data
Trade namesProvenge
AHFS/Drugs.comFDA Professional Drug Information
MedlinePlusa611025
Pregnancy
category
  • N/A (only approved in men)
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem SID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
 ☒NcheckY (what is this?)  (verify)

Sipuleucel-T (APC8015, trade name Provenge),[1][2] 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.[3]

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.[4][5][6]

First FDA-approved 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.[7][8]

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.[9][10]

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 2011, there are two approved preventive vaccines which prevent the cancer-causing viruses human papillomavirus 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,
    1. the antigen prostatic acid phosphatase (PAP), which is present in 95% of prostate cancer cells, and
    2. an immune signaling factor granulocyte-macrophage colony stimulating factor (GM-CSF) that helps the APCs to mature.
  3. 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.[4][5]

A complete sipuleucel-T treatment repeats three courses over the span of a month, with two weeks between successive courses.[11]

Survival difference

Sipuleucel-T showed overall survival (OS) benefit to patients in three double-blind randomized phase III clinical trials, D9901,[5] D9902a,[12][13] and IMPACT.[4]

An editorial in the New England Journal of Medicine concluded that sipuleucel-T will probably result in a substantial improvement to the poor prognosis for castration-resistant prostate cancer.[6]

The IMPACT trial[4] 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 may suggest the effect of an unmeasured variable.[6]

The D9901 trial[5] 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[12] 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 under 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.[3][14]

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.[4]

Additional clinical trials

The PRO Treatment and Early Cancer Treatment (PROTECT) trial, a phase IIIB clinical trial started in 2003, is ongoing.[15] 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).[16]

References

  1. ^ Plosker GL (2011). "Sipuleucel-T: in metastatic castration-resistant prostate cancer". Drugs. 71 (1): 101–8. doi:10.2165/11206840-000000000-00000. PMID 21175243. {{cite journal}}: Unknown parameter |month= ignored (help)
  2. ^ Immunostimulatory composition
  3. ^ a b Exclusive: Questionable data propped up cancer drug Provenge, By Sharon Begley, Reuters, Oct 11, 2012
  4. ^ a b c d e Kantoff PW (2010). "Sipuleucel-T immunotherapy for castration-resistant prostate cancer" (PDF). N. Engl. J. Med. 363 (5): 411–22. doi:10.1056/NEJMoa1001294. PMID 20818862. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  5. ^ a b c d Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM (2006). "Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer" (PDF). J. Clin. Oncol. 24 (19): 3089–94. doi:10.1200/JCO.2005.04.5252. PMID 16809734. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ a b c Longo DL (2010). "New therapies for castration-resistant prostate cancer". N. Engl. J. Med. 363 (5): 479–81. doi:10.1056/NEJMe1006300. PMID 20818868. {{cite journal}}: Unknown parameter |month= ignored (help)
  7. ^ Richwine L (2010-04-29). "U.S. FDA OKs Dendreon's prostate cancer vaccine". Reuters. Retrieved 2010-04-30.
  8. ^ "Approval Letter - Provenge". Food and Drug Administration. 2010-04-29.
  9. ^ "NCCN Guidelines and NCCN Compendium Updated". Retrieved 2011-01-08. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  10. ^ "NCCN Drugs & Biologics Compendium". {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  11. ^ "Sipuleucel-T: APC 8015, APC-8015, prostate cancer vaccine - Dendreon". Drugs R D. 7 (3): 197–201. 2006. PMID 16752945.
  12. ^ a b Higano C, Burch P, Small E, Schellhammer P, Lemon R, Verjee S, Hershberg R (2005). Immunotherapy (APC8015) for androgen independent prostate cancer (AIPC): final progression and survival data from a second Phase 3 trial. 13th European Cancer Conference. Paris. {{cite conference}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Mason K (2005-11-02). "New treatment options for patients with prostate cancer". ECCO-the European CanCer Organisation.
  14. ^ Huber ML (2012). "Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer" (PDF). J. Natl. Cancer Inst. 104 (4): 273–9. doi:10.1093/jnci/djr514. PMC 3283534. PMID 22232132. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  15. ^ "NCT00779402: Provenge for the Treatment of Hormone Sensitive Prostate Cancer". ClinicalTrials.gov. US National Institutes of Health. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help)
  16. ^ Roach M (2006). "Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference". Int. J. Radiat. Oncol. Biol. Phys. 65 (4): 965–74. doi:10.1016/j.ijrobp.2006.04.029. PMID 16798415. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)

Public Domain This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute.

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