Indian Journal of Urology
UROSCAN
Year
: 2011  |  Volume : 27  |  Issue : 1  |  Page : 148--149

Prostate cancer vaccine: A new paradigm for prostate cancer treatment


Amod Kumar Dwivedi, Vengetesh K Sengottayan, Apul Goel 
 Department of Urology, CSM Medical University (Upgraded King George's Medical College), Lucknow, Uttar Pradesh, India

Correspondence Address:
Apul Goel
Department of Urology, CSM Medical University (Upgraded King George«SQ»s Medical College), Lucknow, Uttar Pradesh
India




How to cite this article:
Dwivedi AK, Sengottayan VK, Goel A. Prostate cancer vaccine: A new paradigm for prostate cancer treatment.Indian J Urol 2011;27:148-149


How to cite this URL:
Dwivedi AK, Sengottayan VK, Goel A. Prostate cancer vaccine: A new paradigm for prostate cancer treatment. Indian J Urol [serial online] 2011 [cited 2020 Apr 10 ];27:148-149
Available from: http://www.indianjurol.com/text.asp?2011/27/1/148/78403


Full Text

 Summary



Management of metastatic castration-resistant carcinoma prostate (CRPC) is a challenge. Docetaxel is the only therapy that improves survival to some extent. [1] Vaccine therapy is one of the many novel therapies tried for this condition and is based on the concept of sensitizing or reactivating patient's immune system, particularly the T-cell against prostate cell membrane antigen and thereby selectively destroy prostatic cancer cells. Sipuleucel-T is an autologous active cellular vaccine, and has been found to be effective in a previous smaller multicenter placebo-controlled randomized trial. [2],[3]

The present study is a phase-3 multicenter, double-blind, randomized, placebo-controlled trial of sipuleucel-T evaluated in 512 patients of asymptomatic or minimally symptomatic CRPC. [4] Patients were randomly assigned in a 2:1 ratio to receive either sipuleucel-T or placebo every 2 weeks, for a total of three infusions. Objective disease progression was monitored with serial CT scans, bone scans, and PSA. Patients found to have clinical progression in vaccine-receiving group were switched to docetaxel, while in placebo group, they were either switched to docetaxel or vaccine, depending on physician's discretion and after informing the patient. Overall survival and progression-free survival were the primary and secondary end-points, respectively. Up to study data cut-off date, a total of 331 patients had died: 210 of 341 patients in the sipuleucel-T group (61.6%) and 121 of the 171 patients in the placebo group (70.8%). The median follow-up duration was 34.1 months. For men in the sipuleucel-T group, as compared with those in the placebo group, the adjusted hazard ratio for death was 0.78 (95% CI, 0.61-0.98), representing a relative reduction in the risk of death of 22% (P = 0.03). The median survival was 4.1 months longer in the sipuleucel-T group (25.8 months) than in the placebo group (21.7 months). The estimated probability of survival 36 months after randomization was 31.7% in the sipuleucel-T group and 23.0% in the placebo group. The median time to objective disease progression was not different in both groups (14.6 weeks in sipuleucel-T group versus 14.4 in placebo). Subgroup analysis based on 20 survival interfering variables also found better survival for sipuleucel-T group in comparison to placebo. Influence of post-therapy docetaxel use on overall survival was adjusted in both groups and not found to alter results of sipuleucel-T. Immune response against this vaccine was also measured in certain number of patients. Patient who mounted higher titer of antibodies against PAP (prostatic acid phosphatase) or fusion protein PA2024 were found to have better survival in comparison to those with lesser titer of antibodies.

 Comments



Cancer cells survive in the body as they escape from immune surveillance and subsequent destruction. Few possible mechanisms of tumor-immune escape phenomenon are immunosuppressive cytokines secretion and defective antigen presentation from cancer cells. Sipuleucel-T is an active cellular vaccine and boosts the patient's immunity against prostatic cancer cells. The vaccine is individually prepared for each patient in two steps. First, leukapheresis from patient's blood is done to extract peripheral blood mononuclear cells (PBMC) as antigen-presenting cells. Next, these cells are cultured in a media containing a recombinant fusion protein (PA2024). PA2024 consists of PAP, which is fused to granulocyte-macrophage colony-stimulating factor and it acts as an immune-cell activator. PBMC engulf PA2024 to get activated and thereby present PAP at cell membranes. These activated antigen-presenting cells are infused intravenously to patient with prostate cancer. Antigen-presenting cells that express PAP are recognized by T-cells of the patient and an immune response is mounted against prostate cancer cells. [4]

This vaccine has been tested only in prostate cancer patients who have became castration-resistant. In this study, it is very surprising that overall survival advantage has been found without any effect in progression-free survival. This may be due to the delayed onset of antitumor responses after active immunotherapy, relative to objective disease progression.

Sipuleucel-T does not have the significant side-effects associated with highly potent chemotherapeutic agents like docetaxel. This drug has been found to provide median survival advantage of 4.2 months, which is not quite different from docetaxel used for similar indications. At the same time, present cost of sipuleucel-T is too high in comparison to docetaxel. The manufacturer has set the cost of a 1-month course of sipuleucel-T at $93,000, or $23,000 per month of survival advantage.

Inclusion criteria of study were limited and excluded metastatic CRPC patients with moderate symptoms, poor performance status, pathological fractures and history of recent surgery, radiation, or chemotherapy. Results of this study cannot be extrapolated to patients with such presentation. As vaccine is individually tailored and requires sophisticated technology to manufacture, reach of drug to every patient could be an uphill task.

Due to this study, sipuleucel-T got FDA approval for the management of asymptomatic or minimally symptomatic CRPC patient with Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. [5] Treatment of this condition is evolving and these newer approaches hold promises in the future.

References

1Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 2008;26:242-5.
2Small 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;24:3089-94.
3Higano 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;115:3670-9.
4Kantoff 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;363:411-22.
5Available from: http://www.fda.gov Washington, DC: Draft Guidance for Industry: Clinical considerations for therapeutic cancer vaccines. Department of Health and Human Services, Food and Drug Administration, Centre for Biologics Evaluation and Research; 2009.