Chemistry:Sipuleucel-T

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Sipuleucel-T, sold under the brand name Provenge, developed by Dendreon Pharmaceuticals, LLC, is a cell-based cancer immunotherapy for prostate cancer (CaP).[1][2][3] It is an autologous cellular immunotherapy.[1]

Medical uses

Sipuleucel-T is indicated for the treatment of metastatic, asymptomatic or minimally symptomatic, metastatic castrate-resistant 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]

Treatment method

A course of treatment consists of three basic steps:

  • The patient's white blood cells, primarily dendritic cells, a type of antigen-presenting cells (APCs), are extracted in a leukapheresis procedure.
  • The blood product is sent to a production facility and incubated with a fusion protein (PA2024) consisting of two parts:
    • The antigen prostatic acid phosphatase (PAP), which is present in 95% of prostate cancer cells and
    • An immune signaling factor granulocyte-macrophage colony stimulating factor (GM-CSF) that helps the APCs to mature.
  • The activated blood product (APC8015) is returned from the production facility to the infusion center and reinfused into the patient.[4][5]

Premedication with acetaminophen and antihistamine is recommended to minimize side effects.[4]

Side effects

Common side effects include: bladder pain; bloating or swelling of the face, arms, hands, lower legs, or feet; bloody or cloudy urine; body aches or pain; chest pain; chills; confusion; cough; diarrhea; difficult, burning, or painful urination; difficulty with breathing; difficulty with speaking up to inability to speak; double vision; sleeplessness; and inability to move the arms, legs, or facial muscles.[7][8]

Society and culture

Sipuleucel-T was approved by the US Food and Drug Administration (FDA) in April 2010, to treat asymptomatic or minimally symptomatic metastatic HRPC.[9][10][11][12][1]

Sipuleucel-T was added to the compendium of cancer treatments as a "category 1" (highest recommendation) treatment for HRPC.[13][14] The National Comprehensive Cancer Network (NCCN) Compendium is used by Medicare and major health care insurance providers to decide whether a treatment should be reimbursed.[13][14]

Research

Clinical trials

Completed

Sipuleucel-T showed overall survival (OS) benefit to patients in three double-blind randomized phase III clinical trials, D9901,[5] D9902a,[15][16] and IMPACT.[4]

The IMPACT trial[4] served as the basis for FDA licensing. 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, an increase of 4.1 months.[17] 31.7% of treated patients survived for 36 months vs. 23.0% in the control arm.[4]

Ongoing

As of August 2014, the PRO Treatment and Early Cancer Treatment (PROTECT) trial, a phase IIIB clinical trial started in 2001, was tracking subjects but no longer enrolling new subjects.[18] 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).[19]

As of August 2014, a clinical trial administering sipuleucel-T in conjunction with ipilimumab (Yervoy) was tracking subjects but no longer enrolling new subjects; the trial evaluates the clinical safety and anti-cancer effects (quantified in PSA, radiographic and T cell response) of the combination therapy in patients with advanced prostate cancer.[20]

Results from the large PROCEED registry, which enrolled men between 2011 and 2017, showed that men with metastatic castration-resistant prostate cancer had a median overall survival of approximately 30.7 months from the date of treatment, and that people with lower PSA levels had longer survival.[21] Research also found that African American men treated with Sipuleucel-T had similar or sometimes better survival than non-African American men, along with stronger immune activity, including higher levels of immune markers like ICOS, GM-CSF, CCL4 and CCL5.[22][23] These immune markers fit with the treatment's ability to stimulate antigen-presenting cells and downstream T-cell activity.[23]

References

  1. ↑ 1.0 1.1 1.2 Cite error: Invalid <ref> tag; no text was provided for refs named Provenge FDA label
  2. ↑ "Sipuleucel-T: in metastatic castration-resistant prostate cancer". Drugs 71 (1): 101–108. January 2011. doi:10.2165/11206840-000000000-00000. PMID 21175243. 
  3. ↑ Laus R, Ruegg CL, Wu H, "Immunostimulatory composition", US patent 6210662
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "Sipuleucel-T immunotherapy for castration-resistant prostate cancer". The New England Journal of Medicine 363 (5): 411–422. July 2010. doi:10.1056/NEJMoa1001294. PMID 20818862. 
  5. ↑ 5.0 5.1 5.2 "Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer". Journal of Clinical Oncology 24 (19): 3089–3094. July 2006. doi:10.1200/JCO.2005.04.5252. PMID 16809734. 
  6. ↑ "New therapies for castration-resistant prostate cancer". The New England Journal of Medicine 363 (5): 479–481. July 2010. doi:10.1056/NEJMe1006300. PMID 20818868. 
  7. ↑ "Sipuleucel-T (Intravenous Route) - Side Effects". Mayo Clinic. https://www.mayoclinic.org/drugs-supplements/sipuleucel-t-intravenous-route/side-effects/drg-20074285. 
  8. ↑ "Package Insert and Patient Information - Provenge (PDF - 157KB)". U.S. Food and Drug Administration (FDA). https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM210031.pdf. 
  9. ↑ "U.S. FDA OKs Dendreon's prostate cancer vaccine". Reuters. 29 April 2010. https://www.reuters.com/article/idUSN2919838820100429. 
  10. ↑ "Approval Letter - Provenge". Food and Drug Administration. 29 April 2010. https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm210215.htm. 
  11. ↑ "Provenge (sipuleucel-T)". 22 July 2017. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/provenge-sipuleucel-t. 
  12. ↑ "Provenge (sipuleucel-T)". 14 July 2017. https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm210012.htm. 
  13. ↑ 13.0 13.1 "NCCN Guidelines and NCCN Compendium Updated". National Comprehensive Cancer Network (NCCN). http://www.nccn.org/about/news/international_ebulletin/2010-07-26/guidelines_compendium.asp. 
  14. ↑ 14.0 14.1 "NCCN Drugs & Biologics Compendium". National Comprehensive Cancer Network (NCCN). http://www.nccn.org/professionals/drug_compendium/content/contents.asp. 
  15. ↑ "Immunotherapy (APC8015) for androgen independent prostate cancer (AIPC): final progression and survival data from a second Phase 3 trial". 13th European Cancer Conference. Paris. October 2005. 
  16. ↑ "New treatment options for patients with prostate cancer". ECCO-the European CanCer Organisation. 2 November 2005. https://www.eurekalert.org/news-releases/848464. 
  17. ↑ Targeted Therapies in Cancer. Hauppauge, NY: Nova Sciences Publishers. 2014. ISBN 978-1-63321-687-7. https://www.novapublishers.com/catalog/product_info.php?products_id=50994. Retrieved 20 July 2014. 
  18. ↑ Clinical trial number NCT00779402 for "Provenge Treatment and Early Cancer Treatment (PROTECT)" at ClinicalTrials.gov
  19. ↑ "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". International Journal of Radiation Oncology, Biology, Physics 65 (4): 965–974. July 2006. doi:10.1016/j.ijrobp.2006.04.029. PMID 16798415. 
  20. ↑ "Sipuleucel-T and Ipilimumab for Advanced Prostate Cancer". Clinicaltrials.gov (US National Institutes of Health). 23 August 2017. https://clinicaltrials.gov/study/NCT01832870. 
  21. ↑ "Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer". Cancer 125 (23): 4172–4180. 2019. doi:10.1002/cncr.32445. PMID 31483485. 
  22. ↑ "Survival of African-American and Caucasian men after Sipuleucel-T immunotherapy: Outcomes from the PROCEED registry". Prostate Cancer and Prostatic Diseases 23 (3): 517–526. Sep 2020. doi:10.1038/s41391-020-0213-7. PMID 32111923. 
  23. ↑ 23.0 23.1 "Race-Related Differences in Sipuleucel-T Response among Men with Metastatic Castrate–Resistant Prostate Cancer". Cancer Research Communications 4 (7): 1715–1725. 2024. doi:10.1158/2767-9764.CRC-24-0112. PMID 38856749. 

 This article incorporates public domain material from the U.S. National Cancer Institute document "Dictionary of Cancer Terms".

Further reading



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