Review Article | Published:

Immunotherapy for the treatment of prostate cancer

Nature Reviews Clinical Oncology volume 8, pages 551561 (2011) | Download Citation

Abstract

Failure of immune surveillance has a prominent role in tumorigenesis. Cancerous cells can evade T-cell responses to tumor-associated antigens by multiple mechanisms. Active immunotherapy aims to stimulate the immune response against cancer cells. Unlike normal prostate tissue, prostate cancer is not ignored by the immune system, as shown by the presence of tumor infiltrating lymphocytes. This characteristic renders prostate cancer particularly suitable for immunotherapy. The existence of well-defined antigens, largely limited to prostate tissue, allows prostate cancer cells to be targeted without the risk of systemic autoimmune reactions, as autoimmunity specifically directed at the prostate is the goal of prostate cancer immunotherapy. Active immunotherapy directed towards prostate cancer can be conducted using multiple strategies, involving dendritic cells, whole-cell vaccines, viral vectors, DNA-based and peptide-based agents, as well as immunostimulatory agents. The only FDA-approved immunotherapy for prostate cancer is the dendritic-cell-based agent Sipuleucel-T, which yielded an advantage in overall survival, but not in progression-free survival in a phase III trial. We present the clinical developments in the field of immunotherapy and critically analyze methodological issues related to the evaluation of tumor responses to immunotherapy, trial design, and surrogate end points.

Key points

  • The existence of well-defined antigens provides a strong biological rationale for immunotherapy of prostate cancer and encouraging treatment results have been achieved in the past year

  • Active immunotherapy stimulates an immune response against cancer tissue and includes the use of autologous dendritic-cell-based, DNA-based, and peptide-based agents, whole-cell vaccines, viral vectors, and immunostimulatory substances

  • Sipuleucel-T is the only FDA-approved active immunotherapy; in a phase III trial conducted in patients with metastatic castration-resistant prostate cancer (CRPC), Sipuleucel-T improved overall survival by 4 months compared with placebo

  • PROSTVAC®–VF/TRICOM consists of Vaccinia and Fowlpox viral vectors, and enhanced survival of patients with CRPC by 8.5 months in a placebo-controlled phase II trial

  • Neither Sipuleucel-T, nor PROSTVAC®–VF/TRICOM, however, improved progression-free survival or the prostate-specific-antigen response rate in the respective phase II and phase III trials

  • The lack of positive effects when using these standard surrogate end points underlines the need for innovative methodological criteria that assess efficacy of immunotherapy in clinical trials

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , & Cancer statistics, 2010. CA Cancer J. Clin. 60, 277–300 (2010).

  2. 2.

    , , , & Castration-resistant prostate cancer: current and emerging treatment strategies. Drugs 70, 983–1000 (2010).

  3. 3.

    et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

  4. 4.

    Prostate cancer as a model for tumour immunotherapy. Nat. Rev. Immunol. 10, 580–593 (2010).

  5. 5.

    Immunotherapy for prostate cancer: an emerging treatment modality. Urol. Clin. North Am. 37, 121–129 (2010).

  6. 6.

    et al. Anti-prostate-specific membrane antigen-based radioimmunotherapy for prostate cancer. Cancer 116, 1075–1083 (2010).

  7. 7.

    & Studies on the prostate and testis as immunologically privileged sites. Cancer Treat. Rep. 61, 217–222 (1977).

  8. 8.

    et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc. Natl Acad. Sci. USA 98, 14565–14570 (2001).

  9. 9.

    , , & Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma. Eur. J. Cancer 30, 1797–1803 (1994).

  10. 10.

    et al. The relationship between T-lymphocyte subset infiltration and survival in patients with prostate cancer. Br. J. Cancer 91, 541–543 (2004).

  11. 11.

    , & Mechanisms of immune evasion by tumors. Adv. Immunol. 90, 51–81 (2006).

  12. 12.

    et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281, 1591–1597 (1999).

  13. 13.

    et al. Activation of thymic regeneration in mice and humans following androgen blockade. J. Immunol. 175, 2741–2753 (2005).

  14. 14.

    , , , & Androgen deprivation boosts prostatic infiltration of cytotoxic and regulatory T lymphocytes and has no effect on disease-free survival in prostate cancer patients. Clin. Cancer Res. 17, 1571–1581 (2010).

  15. 15.

    , & Therapeutic vaccines for prostate cancer. Oncologist 11, 451–462 (2006).

  16. 16.

    et al. Sipuleucel-T. Nat. Rev. Drug Discov. 9, 513–514 (2010).

  17. 17.

    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. 24, 3089–3094 (2006).

  18. 18.

    et al. Elevated eosinophils following treatment with Sipuleucel-T in men with prostate cancer is associated with antigen-specific immune response and prolonged survival [abstract 1491]. 52nd ASH Annual Meeting (2010).

  19. 19.

    et al. Correlation between product parameters and overall survival in three trials of Sipuleucel-T, an autologous active cellular immunotherapy for the treatment of prostate cancer. J. Clin. Oncol. 28 (15 Suppl.), a4552 (2010).

  20. 20.

    et al. Vaccination of hormone-refractory prostate cancer patients with peptide cocktail-loaded dendritic cells: results of a phase I clinical trial. Prostate 66, 811–821 (2006).

  21. 21.

    et al. Immunotherapy of patients with hormone-refractory prostate carcinoma pre-treated with interferon-gamma and vaccinated with autologous PSA-peptide loaded dendritic cells—a pilot study. Prostate 67, 500–508 (2007).

  22. 22.

    New therapies for castration-resistant prostate cancer. N. Engl. J. Med. 363, 479–481 (2010).

  23. 23.

    Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 1966–1967 (2010).

  24. 24.

    et al. Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer. Cancer 113, 975–984 (2008).

  25. 25.

    et al. Granulocyte macrophage colony-stimulating factor--secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer. Clin. Cancer Res. 13, 3883–3891 (2007).

  26. 26.

    et al. Treatment of biochemical recurrence of prostate cancer with granulocyte-macrophage colony-stimulating factor secreting, allogeneic, cellular immunotherapy. J. Urol. 180, 2011–2018 (2008).

  27. 27.

    et al. Phase I/II trial of an allogeneic cellular immunotherapy in hormone-naive prostate cancer. Clin. Cancer Res. 12, 3394–3401 (2006).

  28. 28.

    et al. A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC) [abstract 7]. Genitourinary Cancers Symp. (2009).

  29. 29.

    et al. Therapeutic vaccination with an interleukin-2-interferon-γ-secreting allogeneic tumor vaccine in patients with progressive castration-resistant prostate cancer: a phase I/II trial. Hum. Gene Ther. 20, 1641–1651 (2009).

  30. 30.

    et al. Allogeneic retrovirally transduced, IL-2- and IFN-γ-secreting cancer cell vaccine in patients with hormone refractory prostate cancer—a phase I clinical trial. J. Gene Med. 9, 547–560 (2007).

  31. 31.

    , , , & Phase I study with an autologous tumor cell vaccine for locally advanced or metastatic prostate cancer. J. Pharm. Pharm. Sci. 10, 144–152 (2007).

  32. 32.

    et al. A phase III trial of GVAX immunotherapy for prostate cancer versus docetaxel plus prednisone in asymptomatic, castration-resistant prostate cancer (CRPC) [abstract LBA150]. Genitourinary Cancers Symp. (2009).

  33. 33.

    , , & Preliminary evidence that the allogeneic response might trigger antitumour immunity in patients with advanced prostate cancer. BJU Int. 98, 989–995 (2006).

  34. 34.

    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. 28, 1099–1105 (2010).

  35. 35.

    et al. MVA-MUC1-IL2 vaccine immunotherapy (TG4010) improves PSA doubling time in patients with prostate cancer with biochemical failure. Invest. New Drugs 27, 379–386 (2009).

  36. 36.

    et al. Vaccination of prostate cancer patients with modified vaccinia ankara delivering the tumor antigen 5T4 (TroVax): a phase 2 trial. J. Immunother. 31, 577–585 (2008).

  37. 37.

    Immunologic basis of vaccine vectors. Immunity 33, 504–515 (2010).

  38. 38.

    et al. A triad of costimulatory molecules synergize to amplify T-cell activation. Cancer Res. 59, 5800–5807 (1999).

  39. 39.

    et al. Clinical safety of a viral vector based prostate cancer vaccine strategy. J. Urol. 178, 1515–1520 (2007).

  40. 40.

    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. 59, 663–674 (2010).

  41. 41.

    et al. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin. Cancer Res. 12, 1260–1269 (2006).

  42. 42.

    et al. A phase II study of PROSTVAC-V (vaccinia)/TRICOM and PROSTVAC-F (fowlpox)/TRICOM with GM-CSF in patients with PSA progression after local therapy for prostate cancer: results of ECOG 9802 [abstract 108]. Genitourinary Cancers Symp. (2009).

  43. 43.

    et al. Analysis of overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilutamide, and combination therapy. Clin. Cancer Res. 14, 4526–4531 (2008).

  44. 44.

    et al. A randomized phase II study of flutamide with or without PSA-TRICOM in nonmetastatic castration-resistant prostate cancer (CRPC) [abstract 163]. Genitourinary Cancers Symp. (2011).

  45. 45.

    , & DNA vaccines: precision tools for activating effective immunity against cancer. Nat. Rev. Cancer 8, 108–120 (2008).

  46. 46.

    et al. Safety and immunological efficacy of a DNA vaccine encoding prostatic acid phosphatase in patients with stage D0 prostate cancer. J. Clin. Oncol. 27, 4047–4054 (2009).

  47. 47.

    et al. DNA vaccine encoding prostatic acid phosphatase (PAP) elicits long-term T-cell responses in patients with recurrent prostate cancer. J. Immunother. 33, 639–647 (2010).

  48. 48.

    et al. DNA vaccination with electroporation induces increased antibody responses in patients with prostate cancer. Hum. Gene Ther. 20, 1269–1278 (2009).

  49. 49.

    et al. Induction of specific T cell immunity in patients with prostate cancer by vaccination with PSA146–154 peptide. Cancer Immunol. Immunother. 55, 1033–1042 (2006).

  50. 50.

    et al. A polyvalent vaccine for high-risk prostate patients: “are more antigens better?”. Cancer Immunol. Immunother. 56, 1921–1930 (2007).

  51. 51.

    et al. Combination therapy of personalized peptide vaccination and low-dose estramustine phosphate for metastatic hormone refractory prostate cancer patients: an analysis of prognostic factors in the treatment. Oncol. Res. 16, 341–349 (2007).

  52. 52.

    et al. Immunological evaluation of personalized peptide vaccination monotherapy in patients with castration-resistant prostate cancer. Cancer Sci. 101, 601–608 (2010).

  53. 53.

    , , , & CTLA-4 regulates induction of anergy in vivo. Immunity 14, 145–155 (2001).

  54. 54.

    et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

  55. 55.

    et al. Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res. 69, 609–615 (2009).

  56. 56.

    et al. Targeting human γδ T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res. 67, 7450–7457 (2007).

  57. 57.

    et al. Human γδ T lymphocytes induce robust NK cell-mediated antitumor cytotoxicity through CD137 engagement. Blood 116, 1726–1733 (2010).

  58. 58.

    et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J. Clin. Oncol. 26, 1148–1159 (2008).

  59. 59.

    et al. The use of a rapid ELISPOT assay to analyze peptide-specific immune responses in carcinoma patients to peptide vs. recombinant poxvirus vaccines. Cancer Immunol. Immunother. 49, 517–529 (2000).

  60. 60.

    et al. Improved endpoints for cancer immunotherapy trials. J. Natl Cancer Inst. 102, 1388–1397 (2010).

  61. 61.

    et al. Assessing oncologic benefit in clinical trials of immunotherapy agents. Ann. Oncol. 21, 1944–1951 (2010).

Download references

Author information

Affiliations

  1. Department of Endocrinology and Medical Oncology, Genitourinary Cancer Section, University Federico II, Via Pansini 5, Napoli, 80132, Italy

    • Giuseppe Di Lorenzo
    •  & Carlo Buonerba
  2.  Dana–Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, 44 Binney Street, Dana 1230, Boston, MA 02115, USA

    • Philip W. Kantoff

Authors

  1. Search for Giuseppe Di Lorenzo in:

  2. Search for Carlo Buonerba in:

  3. Search for Philip W. Kantoff in:

Contributions

G. Di Lorenzo and C. Buonerba researched the data and wrote the article. All authors provided substantial contributions to the discussion of content and reviewed/edited the manuscript before submission.

Competing interests

P. Kantoff declares that he was a consultant for Dendreon Corporation and BN Immunotherapeutics. G. Di Lorenzo and C. Buonerba declare no competing interests.

Corresponding author

Correspondence to Giuseppe Di Lorenzo.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrclinonc.2011.72

Further reading