Sipuleucel-T

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A dendritic cell under the light microscope

Sipuleucel-T (further name: APC8015 ) is an immunotherapeutic used as a therapeutic cancer vaccine that belongs to the group of gene therapeutics .

Sipuleucel-T consists of the body's own ( autologous ) dendritic cells , which were incubated outside the organism ( ex vivo ) with the fusion protein PA2024 . In PA2024 is a genetically combined protein from prostate specific acid phosphatase (PAP) and human granulocyte-macrophage colony stimulating factor ( GM-CSF ).

Sipuleucel-T was developed by the US company Dendreon and is approved as a drug under the brand name Provenge for the treatment of prostate cancer . The approval for the US -Markt by the FDA was issued in April 2010, in September 2013 was followed by the EU approval for 28 countries. On May 6, 2015, however, this approval was revoked by the European Commission at the request of the approval holder and with effect from June 30, 2015, reasons have not yet been known (as of May 19, 2015).

However, the product was assessed negatively by the Institute for Quality and Efficiency in Health Care ( IQWiG ) in a benefit assessment: “In summary, there is an additional benefit of Sipuleucel-T compared to the appropriate comparator therapy, the wait-and-see approach while maintaining the existing conventional androgen deprivation, for patients with asymptomatic or minimally symptomatic, metastatic (not visceral), castration-resistant prostate cancer, for which chemotherapy is not yet clinically indicated, not proven. "

description

Sipuleucel-T is intended to stimulate the immune system of treated patients who are already suffering from prostate cancer in order to fight the tumor. The treatment takes about one adoptive cell transfer : These patients are by leukapheresis ( "blood washing") mononuclear cells of peripheral blood (PBMC . English Peripheral blood mononuclear cell ) taken. The cells are enriched further by centrifugation and incubated with the fusion protein PA2024 for 40 hours . The cells are then washed and suspended in Ringer's lactate solution . The entire process takes about 48 hours. This suspension (Sipuleucel-T) is then infused into the patient on an outpatient basis . The maximum stimulation of the T cells is reached after three infusions within two weeks.

The fusion protein PA2024 consists of the enzyme prostate-specific acid phosphatase ( prostatic acid phosphatase , PAP), which is linked to human glycoprotein GM-CSF ( granulocyte macrophage colony-stimulating factor ). PAP is the tumor antigen . It is expressed by 95 percent of malignant prostate cells , but not healthy ones.

After incubation with PA2024, the induced T cells are directed against the tumor antigen PAP and are intended to fight the cells in the patient's body that express this tumor antigen. Ideally, these are the cells of the primary tumor and those of its metastases .

Results of clinical studies

In a study with 127 fully treated patients with metastatic and hormone-resistant tumors, the mean survival time increased from 21.4 months in the comparison group that received the placebo to 25.9 months in the group treated with sipuleucel-T. The progression-free survival was (not significant) increased from 10 months to 11.7 months. The survival rate after three years increased from 11 to 34 percent. The Food and Drug Administration (FDA), which is responsible for approval in the United States, initially refused approval in 2007. The FDA's decision was preceded by an advisory meeting. In it, 13 of the advisors had spoken out in favor and 4 against the approval. All 17 considered the drug to be safe. After the conference, two of the consultants had written to the FDA expressly against the approval of Sipuleucel-T. Ultimately, this was the decisive factor in the FDA initially refusing approval and requesting another study.

In another phase III study (IMPACT = Immunotherapy for Prostate Adeno Carcinoma Treatment ), which was carried out in a multi-center, double-blind and placebo-controlled manner with over 500 patients, the following results were published in 2009: the mean survival time was 4.1 months and the three- Annual survival rate increased by 38 percent.

Criticism of the study design

Critics criticize both the high cost of Sipuleucel-T, averaging US $ 23,000 per month “won”, and the design of the study. Sipuleucel-T was not tested in comparison to another therapeutic agent such as docetaxel . In this case, it is possible that no significant increase in the mean survival time would have been found.

A therapy cycle consists of three infusions of Sipuleucel-T. The cost of this in the United States is US $ 93,000.

Side effects

The clinical studies found that Sipuleucel-T is generally well tolerated by patients. Common side effects are fever , tremor, and feeling cold. There was no evidence of a possible autoimmune disease that could be triggered by an interaction of the PAP tumor antigen with normal tissue. In principle, this would be possible because PAP is not expressed by healthy tissue.

Individual evidence

  1. ↑ Approved Cellular and Gene Therapy Products , FDA: List of U.S. Gene Therapeutics, accessed March 7, 2019
  2. ↑ a b c A. L. Harzstark and EJ Small: Immunotherapy for prostate cancer using antigen-loaded antigen-presenting cells: APC8015 (Provenge). In: Expert Opin Biol Ther 7, 2007, pp. 1275-1280. PMID 17696825 (Review)
  3. ↑ Dendreon: Dendreon Press Release: FDA Approves PROVENGE (R) for the Treatment of Men with Advanced Prostate Cancer . April 29, 2010. Archived from the original on March 4, 2014. Retrieved on March 4, 2014.
  4. ↑ Summary of the EPAR for the public , from the website of the European Health Authority (EMA), accessed on March 4, 2014
  5. ↑ IMPLEMENTING DECISION OF THE COMMISSION of 6 May 2015 on the revocation of the authorization granted by Decision C (2013) 5841 (final) for the human medicinal product “Provenge - Autologous, mononuclear cells of the peripheral blood, activated with PAP-GM-CSF (Sipuleucel-T ) "At the request of the authorization holder , from the website of the European Commission, accessed on May 19, 2015
  6. ↑ Sipuleucel-T: Benefit assessment according to Section 35a SGB V , accessed on September 8, 2017.
  7. ^ B. Rini: Technology evaluation: APC-8015, Dendreon. In: Curr Opin Mol Ther 4, 2002, pp. 76-79. PMID 11883698 (Review)
  8. ↑ a b c Hope for therapy: Vaccination against cancer , In: Ärzteblatt from April 15, 2009
  9. ↑ Prostate Cancer: Vaccine Extends Life. ( Memento from October 20, 2011 in the Internet Archive ) In: Ärzteblatt from June 30, 2006
  10. ↑ EJ Small et al .: Placebo-Controlled Phase III Trial of Immunologic Therapy with Sipuleucel-T (APC8015) in Patients with Metastatic, Asymptomatic Hormone Refractory Prostate Cancer. In: Journal of Clinical Oncology 24, 2006, pp. 3089-3094. doi: 10.1200 / JCO.2005.04.5252 PMID 16809734
  11. ↑ Prostate Cancer Immunotherapy Significantly Prolongs Survival in Men With Advanced Prostate Cancer. In: auanet.mediaroom.com. American Urological Association, April 30, 2009, accessed May 1, 2017 .
  12. ↑ W. Caesar: Therapeutic vaccine Provenge approved. In: Deutsche Apotheker Zeitung of May 5, 2010
  13. ↑ B. Orelli: Pricey Provenge Pumps Up Dendreon. dated April 30, 2010
  14. ↑ T. Solin et al .: Gene expression and prostate specificity of human prostatic acid phosphatase (PAP): evaluation by RNA blot analyzes. In: Biochim Biophys Acta 1048, 1990, pp. 72-77. PMID 1688712

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