Current Urology Reports

, Volume 11, Issue 3, pp 202–207

Update: Immunological Strategies for Prostate Cancer

Article

Abstract

Prostate cancer is the second most common cause of cancer-related death in US men. Along with initial therapy using surgery, radiotherapy, or cryotherapy, hormonal therapy is the mainstay of treatment. For men with advanced (metastatic) disease, docetaxel-based chemotherapy is US Food and Drug Administration (FDA)-approved, and provides a significant survival advantage. This relative paucity of treatment options drives an ongoing quest for additional treatment modalities; among these is immunotherapy. The concept that prostate cancer is a malignancy that can be targeted by the immune system may seem counterintuitive; certainly kidney cancer and melanoma are more traditionally thought of as immune responsive cancers. However, prostate cancer arises in a relatively unique organ and may express a number of proteins (antigens) against which an immune response can be generated. More importantly, several of these agents have now demonstrated a significant survival benefit in randomized controlled clinical trials, and one agent in particular (Sipuleucel-T, Dendreon Corporation, Seattle, WA) could be FDA-approved in 2010. This update summarizes recent clinical developments in the field of prostate cancer immunotherapy, with a focus on dendritic cell vaccines, virus-based vaccines, DNA-based vaccines, and cell-based vaccines. In addition, the notion of agents that target immune checkpoints is introduced. Enthusiasm for prostate cancer immunotherapy is founded upon its potential to mediate targeted, specific, tumor cell destruction without significant systemic toxicity; however, this has yet to be fully realized in the clinical arena.

Keywords

Immunotherapy Immune checkpoints Prostate cancer T cell Vaccine CTLA-4 PD-1 GVAX ProstVac VF Sipuleucel-T 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Wang X, Yu J, Sreekumar A, et al.: Autoantibody signatures in prostate cancer. N Engl J Med 2005, 353:1224–1235.CrossRefPubMedGoogle Scholar
  2. 2.
    Lin AM, Hershberg RM, Small EJ: Immunotherapy for prostate cancer using prostatic acid phosphatase loaded antigen presenting cells. Urol Oncol 2006, 24:434–441.PubMedGoogle Scholar
  3. 3.
    Fong L, Ruegg CL, Brockstedt D, et al.: Induction of tissue-specific autoimmune prostatitis with prostatic acid phosphatase immunization: implications for immunotherapy of prostate cancer. J Immunol 1997, 159:3113–3117.PubMedGoogle Scholar
  4. 4.
    Burch PA, Breen JK, Buckner JC, et al.: Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer. Clin Cancer Res 2000, 6:2175–2182.PubMedGoogle Scholar
  5. 5.
    • Small EJ, Schellhammer PF, Higano CS, 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, 24:3089–3094. This is the first randomized phase III trial to demonstrate a survival advantage for immunotherapy in men with CRPC.CrossRefPubMedGoogle Scholar
  6. 6.
    •• Schellhammer PF, Higano C, Berger ER: A randomized, double-blind, placebo-controlled, multi-center, phase III trial of Sipuleucel-T in men with metastatic, androgen independent prostatic adenocarcinoma [abstract]. Presented at the American Urological Association Annual Meeting. Chicago, IL; April 25–30, 2009. This large randomized phase III trial confirmed a survival advantage for Sipuleucel-T in men with CRPC (most likely the pivotal trial in the development of this agent). Google Scholar
  7. 7.
    Petrylak DP, Tangen CM, Hussain MH, et al.: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004, 351:1513–1520.CrossRefPubMedGoogle Scholar
  8. 8.
    Tannock IF, de Wit R, Berry WR, et al.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004, 351:1502–1512.CrossRefPubMedGoogle Scholar
  9. 9.
    Berthold DR, Pond GR, Soban F, et al.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 2008, 26:242–245.CrossRefPubMedGoogle Scholar
  10. 10.
    • Madan RA, Arlen PM, Mohebtash M, et al.: A vector-based vaccine targeting PSA in prostate cancer. Expert Opin Investig Drugs 2009, 18:1001–1011. This is an excellent up-to-date review of the ProstVac VF immunotherapy platform CrossRefPubMedGoogle Scholar
  11. 11.
    Kaufman HL, Wang W, Manola J, et al.: Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2004, 22:2122–2132.CrossRefPubMedGoogle Scholar
  12. 12.
    Hodge JW, Sabzevari H, Yafal AG, et al.: A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res 1999, 59:5800–5807.PubMedGoogle Scholar
  13. 13.
    •• Kantoff PW, Schuetz TJ, Blumenstein BA, et al.: Overall survival analysis of a phase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol 2010, 28:1099–1105. This trial shows a survival benefit for ProstVac VF in men with asymptomatic CRPC, but should be considered hypothesis-generating because OS was not the primary end point of this study Google Scholar
  14. 14.
    Gulley JL, Arlen PM, Madan RA, et al.: Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother 2010, 59:663–674.Google Scholar
  15. 15.
    • McNeel DG, Dunphy EJ, Davies JG, et al.: Safety and immunological efficacy of a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with stage D0 prostate cancer. J Clin Oncol 2009, 27:425–430. This is a phase I trial of a DNA vaccine platform in early-stage (nonmetastatic) prostate cancer.CrossRefGoogle Scholar
  16. 16.
    Dranoff G, Jaffee E, Lazenby A, et al.: Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993, 90:3539–3543.CrossRefPubMedGoogle Scholar
  17. 17.
    Simons JW, Sacks N: Granulocyte-macrophage colony-stimulating factor-transduced allogeneic cancer cellular immunotherapy: the GVAX vaccine for prostate cancer. Urol Oncol 2006, 24:419–424.PubMedGoogle Scholar
  18. 18.
    Higano CS, Corman JM, Smith DC, et al.: Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer. Cancer 2008, 113:975–984.CrossRefPubMedGoogle Scholar
  19. 19.
    Simons JW, Higano C, Corman J, et al.: A phase I/II trial of high dose allogeneic GM-CSF gene-transduced prostate cancer cell line vaccine in patients with metastatic hormone-refractory prostate cancer [abstract]. Proc Am Soc Clin Oncol 2003, 22:166.Google Scholar
  20. 20.
    • Higano C, Saad F, Somer B, et al.: A phase III trial of GVAX immunotherapy for prostate cancer versus docetaxel plus prednisone in asymptomatic, castration-resistant prostate cancer (CRPC) [abstract]. J Clin Oncol 2009, LBA. This latest published report on VITAL-1 trial results shows no evidence of a survival benefit, with 289 of 626 patient deaths reported.Google Scholar
  21. 21.
    Dunn GP, Old LJ, Schreiber RD: The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004, 21:137–148.CrossRefPubMedGoogle Scholar
  22. 22.
    Drake CG, Jaffee E, Pardoll DM: Mechanisms of immune evasion by tumors. Adv Immunol 2006, 90:51–81.CrossRefPubMedGoogle Scholar
  23. 23.
    Sfanos KS, Bruno TC, Meeker AK, et al.: Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+. Prostate 2009, 69:1694–1703.CrossRefPubMedGoogle Scholar
  24. 24.
    Weber J: Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother 2009, 58:823–830.CrossRefPubMedGoogle Scholar
  25. 25.
    • Fong L, Kwek SS, O’Brien S, et al.: Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res 2009, 69:609–615. This study and Small et al. [26•] are early studies of CTLA-4 blockade in patients with prostate cancer, in which some PSA responses were noted. CrossRefPubMedGoogle Scholar
  26. 26.
    • Small EJ, Tchekmedyian NS, Rini BI, et al.: A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res 2007, 13:1810–1815. This study and Fong et al. [25•] are early studies of CTLA-4 blockade in patients with prostate cancer, in which some PSA responses were noted.CrossRefPubMedGoogle Scholar
  27. 27.
    Beardsley EK, Chi KN: Systemic therapy after first-line docetaxel in metastatic castration-resistant prostate cancer. Curr Opin Support Palliat Care 2008, 2:161–166.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Oncology, Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins UniversityBaltimoreUSA

Personalised recommendations