Compound Name:Sipuleucel-TMolecular Target:Prostate acid phosphatase expressing cellsMolecular Structure:Prostate acid phosphatase stimulated autologous peripheral blood mononuclear cellsLicensed Indication:Metastatic prostate cancer that is minimally symptomatic and hormone refractoryManufacturer and/or Distributor:DendreonInitial FDA Approval:2010Summary:Sipuleucel-T (Provenge) is currently the only FDA approved cellular cancer therapy for prostate cancer. The treatment consists of three steps: 1) leukopheresis of peripheral blood mononuclear cells from the patient; 2) in vitro culture of the leukopheresed cells over approximately two days with a recombinant protein construct consisting of human prostate acid phosphatase (PAP; an antigen present in ~95% of prostate cells) linked to granulocyte macrophage colony-stimulating factor (GM-CSF); 3) adoptive transfer of these autologous cells back into the patient via three transfusions at two week intervals. The culture predominantly contains antigen-presenting cells such as dendritic cells (DCs), but may contain T cells, B cells and NK cells. It is believed that the GM-CSCF-activated DCs efficiently present PAP antigen to the host’s lymphocytes upon re-infusion, thereby allowing for directed priming of T cells in vivo. In clinical trials, treated patients subsequently demonstrated long-term immune responses (over 2 years) to the PAP antigen by both T cell and B cells, including hu moral antoigen spreading Sipuleucel-T was approved by the FDA in 2010 for treatment of asymptomatic or minimally symptomatic, metastatic, hormone-refractory prostate cancer on the basis of three randomized, double-blind, placebo-controlled clinical trials. Patients entered into the studies had metastatic prostate cancer with evidence of progression. The placebo group received reinfusions of autologous cells that had not been pre-activated. Although no improvement in time to disease progression was seen, the studies consistently showed that sipuleucel-T treatment led to a lengthening of median survival by more than 4 months and an increase in 3-year survival from 25% to 33%, compared to the placebo (i.e, reinfusion of autologous cells that were not pre-activated). A recent phase II clinical trial also indicates that sipleucel–T and abiraterone acetate (an androgen synthesis inhibitor) may be used in combination without affecting the efficacy of the anti-PAP T cell manufacturing process or the ensuing immune responses in men with metastatic castration-resistant prostate cancer. Major safety concerns center around acute infusion reactions, including chills, fever, and fatigue. Premedication with oral acetaminophen and an oral antihistamine 30 minutes prior to reinfusion is recommended in the package insert. More severe (Grade 3) reactions (including respiratory events, hypertension, dizziness, asthenia, headache, and nausea and vomiting) were seen at an increased frequency after the 2nd (2.1%) reinfusion, as opposed to the 1st (0.8%) or 3rd (1.3%) reinfusion. This cellular immunotherapy regimen is estimated to cost over $100,000 per patient and recent evidence review group appraisals did not recommend sipleucel-T for the treatment of asymptomatic or minimally symptomatic patients with metastatic hormone-relapsed prostate cancer.References

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1. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006 Jul 1;24(19):3089-3094.

2. Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009 Aug 15;115(16):3670-3679.

3. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010 Jul 29;363(5):411-422.

4. Higano CS, Small EJ, Schellhammer P, Yasothan U, Gubernick S, Kirkpatrick P, et al. Sipuleucel-T. Nat Rev Drug Discov. 2010 Jul;9(7):513-514.

5. Goozner M. Concerns about Provenge simmer as CMS ponders coverage. J Natl Cancer Inst. 2011 Feb 16;103(4):288-289.

6. Carballido E, Fishman M. Sipuleucel-T: Prototype for development of anti-tumor vaccines. Curr Oncol Rep. 2011 Apr;13(2):112-119.

7. Sonpavde G, Di Lorenzo G, Higano CS, Kantoff PW, Madan R, Shore ND. The role of sipuleucel-T in therapy for castration-resistant prostate cancer: a critical analysis of the literature. Eur Urol. 2012 Apr;61(4):639-647.

8. Kawalec P, Paszulewicz A, Holko P, Pilc A. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. A systematic review and meta-analysis. Arch Med Sci. 2012 Nov 9;8(5):767-75.

9. Dawson NA, Roesch EE. Sipuleucel-T and immunotherapy in the treatment of prostate cancer. Expert Opin Biol Ther. 2014 May;14(5):709-19.

10. Antonarakis ES, Kibel AS, Adams GW, Karsh LI, Elfiky A, Shore ND, Vogelzang NJ, Corman JM, Tyler RC, McCoy C, DeVries T, Sheikh N, Drake CG. Antigen-specific immune responses through 24 months in the STAND trial: a randomized phase 2 study evaluating optimal sequencing of sipleucel-T (sip-T) and androgen deprivation therapy (ADT) in biochemically-recurrent prostate cancer (BRPC). J Cln Oncol. 2015 33(Suppl 7; abstr 171)

11. GuhaThakurta D, Sheikh NA, Fan LQ, Kandadi H, Meagher TC, Hall SJ, Kantoff PW, Higano CS, Small EJ, Gardner TA, Bailey K, Vu T, DeVries T, Whitmore JB, Frohlich MW, Trager JB, Drake CG. Humoral immune response against nontargeted tumor antigens after treatment with sipuleucel-T and its association with improved clinical outcomes. Clin Cancer Res. 2015 Aug; 21(16):3619-30.

12. Small EJ, Lance RS, Gardner TA, Karsh LI, Fong L, McCoy C, DeVries T, Sheikh NA, GuhaThakurta D, Chang N, Redfern CH, Shore ND. A randomized phase II trial of sipleucel-T with concurrent versus sequential abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2015 Sep 1;21(17):3862-9.

13. Simpson EL, Davis S, Thokala P, Breeze PR, Pryden P, Wong R. Sipleucel-T for the treatment of metastatic hormone-relapsed prostate cancer: a NICE single technology appraisal; an evidence review group perspective. Pharmacoeconomics. 2015 Nov; 33(11):1187-94.

14. Lovett R, George E, Adler A. NICE guidance on sipleucel-T for asymptomatic or minimally symptomatic metastatic hormone-relapsed prostate cancer. Lancet Oncol 2015 Apr:16(4):369-70.

15. Crawford ED, Petrylak, DP, Higano CS, Kibel AS, Kantoff PW, Samll EJ, Shore ND, Ferrari, A. Optimal timing of sipleucel-T treatment in metastatic castration-resistant prostate cancer. Can J Urol. 2015 Dec; 22(6): 8048-55.