Skip to main content

Advertisement

SpringerLink
Log in

The androgen receptor: a biologically relevant vaccine target for the treatment of prostate cancer

  • Original article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The androgen receptor (AR) plays an essential role in the development and progression of prostate cancer. However, while it has long been the primary molecular target of metastatic prostate cancer therapies, it has not been explored as an immunotherapeutic target. In particular, the AR ligand-binding domain (LBD) is a potentially attractive target, as it has an identical sequence among humans as well as among multiple species, providing a logical candidate for preclinical evaluation. In this report, we evaluated the immune and anti-tumor efficacy of a DNA vaccine targeting the AR LBD (pTVG-AR) in relevant rodent preclinical models. We found immunization of HHDII-DR1 mice, which express human HLA-A2 and HLA-DR1, with pTVG-AR augmented AR LBD HLA-A2-restricted peptide-specific, cytotoxic immune responses in vivo that could lyse human prostate cancer cells. Using an HLA-A2-expressing autochthonous model of prostate cancer, immunization with pTVG-AR augmented HLA-A2-restricted immune responses that could lyse syngeneic prostate tumor cells and led to a decrease in tumor burden and an increase in overall survival of tumor-bearing animals. Finally, immunization decreased prostate tumor growth in Copenhagen rats that was associated with a Th1-type immune response. These data show that the AR is as a prostate cancer immunological target antigen and that a DNA vaccine targeting the AR LBD is an attractive candidate for clinical evaluation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

AR:

Androgen receptor

LBD:

Ligand-binding domain

MDC:

Moderately differentiated carcinoma

PDC:

Poorly differentiated carcinoma

PIN:

Prostatic intraepithelial neoplasia

TRAMP:

Transgenic adenocarcinoma of the mouse prostate

WDC:

Well-differentiated carcinoma

References

  1. Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61(4):212–236

    Article  PubMed  Google Scholar 

  2. Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, Manson K, Panicali DL, Laus R, Schlom J, Dahut WL, Arlen PM, Gulley JL, Godfrey WR (2010) 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(7):1099–1105

    Article  PubMed  CAS  Google Scholar 

  3. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363(5):411–422

    Article  PubMed  CAS  Google Scholar 

  4. Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, Mellman I, Prindiville SA, Viner JL, Weiner LM, Matrisian LM (2009) The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res 15(17):5323–5337

    Article  PubMed  Google Scholar 

  5. Agoulnik IU, Weigel NL (2006) Androgen receptor action in hormone-dependent and recurrent prostate cancer. J Cell Biochem 99(2):362–372

    Article  PubMed  CAS  Google Scholar 

  6. Culig Z, Klocket H, Bartsch G, Hobisch A (2002) Androgen receptors in prostate cancer. Endocrine Relat Cancer 9:155–170

    Article  CAS  Google Scholar 

  7. Heinlein CA, Chang C (2004) Androgen receptor in prostate cancer. Endocr Rev 25(2):276–308

    Article  PubMed  CAS  Google Scholar 

  8. Edwards J, Krishna NS, Grigor KM, Bartlett JM (2003) Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer 89(3):552–556

    Article  PubMed  CAS  Google Scholar 

  9. Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL, Visakorpi T (2001) Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 61(9):3550–3555

    PubMed  CAS  Google Scholar 

  10. Hendriksen PJ, Dits NF, Kokame K, Veldhoven A, van Weerden WM, Bangma CH, Trapman J, Jenster G (2006) Evolution of the androgen receptor pathway during progression of prostate cancer. Cancer Res 66(10):5012–5020

    Article  PubMed  CAS  Google Scholar 

  11. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Flechon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364(21):1995–2005

    Article  PubMed  Google Scholar 

  12. Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, Nelson PS, Montgomery RB (2011) Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res 17(18):5913–5925

    Article  PubMed  CAS  Google Scholar 

  13. Kawata H, Ishikura N, Watanabe M, Nishimoto A, Tsunenari T, Aoki Y (2010) Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity. Prostate 70(7):745–754

    Article  PubMed  CAS  Google Scholar 

  14. Olson BM, McNeel DG (2007) Antibody and T-cell responses specific for the androgen receptor in patients with prostate cancer. Prostate 67(16):1729–1739

    Article  PubMed  CAS  Google Scholar 

  15. Olson BM, McNeel DG (2011) CD8+ T cells specific for the androgen receptor are common in patients with prostate cancer and are able to lyse prostate tumor cells. Cancer Immunol Immunother 60:781–792

    Article  PubMed  CAS  Google Scholar 

  16. Pajot A, Michel ML, Fazilleau N, Pancre V, Auriault C, Ojcius DM, Lemonnier FA, Lone YC (2004) A mouse model of human adaptive immune functions: HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice. Eur J Immunol 34(11):3060–3069

    Article  PubMed  CAS  Google Scholar 

  17. Mathieu MG, Knights AJ, Pawelec G, Riley CL, Wernet D, Lemonnier FA, Straten PT, Mueller L, Rees RC, McArdle SE (2007) HAGE, a cancer/testis antigen with potential for melanoma immunotherapy: identification of several MHC class I/II HAGE-derived immunogenic peptides. Cancer Immunol Immunother 56(12):1885–1895

    Article  PubMed  CAS  Google Scholar 

  18. Olson BM, Frye TP, Johnson LE, Fong L, Knutson KL, Disis ML, McNeel DG (2010) HLA-A2-restricted T-cell epitopes specific for prostatic acid phosphatase. Cancer Immunol Immunother 59(6):943–953

    Article  PubMed  CAS  Google Scholar 

  19. Foster BA, Gingrich JR, Kwon ED, Madias C, Greenberg NM (1997) Characterization of prostatic epithelial cell lines derived from transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Cancer Res 57(16):3325–3330

    PubMed  CAS  Google Scholar 

  20. Johnson LE, Frye TP, Arnot AR, Marquette C, Couture LA, Gendron-Fitzpatrick A, McNeel DG (2006) Safety and immunological efficacy of a prostate cancer plasmid DNA vaccine encoding prostatic acid phosphatase (PAP). Vaccine 24:293–303

    Article  PubMed  CAS  Google Scholar 

  21. Sauma S, Gammon M, Bednarek M, Cunningham B, Biddison W, Hermes J, Porter G, Tamhankar S, Hawkins J, Bush B et al (1993) Recognition by HLA-A2-restricted cytotoxic T lymphocytes of endogenously generated and exogenously provided synthetic peptide analogues of the influenza A virus matrix protein. Hum Immunol 37(4):252–258

    Article  PubMed  CAS  Google Scholar 

  22. Kaplan-Lefko PJ, Chen TM, Ittmann MM, Barrios RJ, Ayala GE, Huss WJ, Maddison LA, Foster BA, Greenberg NM (2003) Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate 55(3):219–237

    Article  PubMed  Google Scholar 

  23. McNeel DG, Dunphy EJ, Davies JG, Frye TP, Johnson LE, Staab MJ, Horvath DL, Straus J, Alberti D, Marnocha R, Liu G, Eickhoff JC, Wilding G (2009) Safety and immunological efficacy of a DNA vaccine encoding prostatic acid phosphatase in patients with stage D0 prostate cancer. J Clin Oncol 27(25):4047–4054

    Article  PubMed  CAS  Google Scholar 

  24. Morse MA, Hall JR, Plate JM (2009) Countering tumor-induced immunosuppression during immunotherapy for pancreatic cancer. Expert Opin Biol Ther 9(3):331–339

    Article  PubMed  CAS  Google Scholar 

  25. Ostrand-Rosenberg S, Sinha P, Danna EA, Miller S, Davis C, Dissanayake SK (2004) Antagonists of tumor-specific immunity: tumor-induced immune suppression and host genes that co-opt the anti-tumor immune response. Breast disease 20:127–135

    PubMed  CAS  Google Scholar 

  26. de Souza AP, Bonorino C (2009) Tumor immunosuppressive environment: effects on tumor-specific and nontumor antigen immune responses. Expert Rev Anticancer Ther 9(9):1317–1332

    Article  PubMed  Google Scholar 

  27. Park JW, Melisko ME, Esserman LJ, Jones LA, Wollan JB, Sims R (2007) Treatment with autologous antigen-presenting cells activated with the HER-2 based antigen Lapuleucel-T: results of a phase I study in immunologic and clinical activity in HER-2 overexpressing breast cancer. J Clin Oncol 25(24):3680–3687. doi:10.1200/JCO.2006.10.5718

    Article  PubMed  CAS  Google Scholar 

  28. Disis ML, Wallace DR, Gooley TA, Dang Y, Slota M, Lu H, Coveler AL, Childs JS, Higgins DM, Fintak PA, dela Rosa C, Tietje K, Link J, Waisman J, Salazar LG (2009) Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. J Clin Oncol 27(28):4685–4692

    Article  PubMed  CAS  Google Scholar 

  29. Baxevanis CN, Sotiriadou NN, Gritzapis AD, Sotiropoulou PA, Perez SA, Cacoullos NT, Papamichail M (2006) Immunogenic HER-2/neu peptides as tumor vaccines. Cancer Immunol Immunother 55(1):85–95

    Article  PubMed  CAS  Google Scholar 

  30. Kaufman HL, Lenz HJ, Marshall J, Singh D, Garett C, Cripps C, Moore M, von Mehren M, Dalfen R, Heim WJ, Conry RM, Urba WJ, Benson AB III, Yu M, Caterini J, Kim-Schulze S, Debenedette M, Salha D, Vogel T, Elias I, Berinstein NL (2008) Combination chemotherapy and ALVAC-CEA/B7.1 vaccine in patients with metastatic colorectal cancer. Clin Cancer Res 14(15):4843–4849

    Article  PubMed  CAS  Google Scholar 

  31. Huang EH, Kaufman HL (2002) CEA-based vaccines. Expert Rev Vaccines 1(1):49–63

    Article  PubMed  CAS  Google Scholar 

  32. Gulley JL, Arlen PM, Tsang KY, Yokokawa J, Palena C, Poole DJ, Remondo C, Cereda V, Jones JL, Pazdur MP, Higgins JP, Hodge JW, Steinberg SM, Kotz H, Dahut WL, Schlom J (2008) Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma. Clin Cancer Res 14(10):3060–3069

    Article  PubMed  CAS  Google Scholar 

  33. Loveland BE, Zhao A, White S, Gan H, Hamilton K, Xing PX, Pietersz GA, Apostolopoulos V, Vaughan H, Karanikas V, Kyriakou P, McKenzie IF, Mitchell PL (2006) Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma. Clin Cancer Res 12(3 Pt 1):869–877

    Article  PubMed  CAS  Google Scholar 

  34. Acres B, Limacher JM (2005) MUC1 as a target antigen for cancer immunotherapy. Expert Rev Vaccines 4(4):493–502

    Article  PubMed  CAS  Google Scholar 

  35. Garcia B, Neninger E, de la Torre A, Leonard I, Martinez R, Viada C, Gonzalez G, Mazorra Z, Lage A, Crombet T (2008) Effective inhibition of the epidermal growth factor/epidermal growth factor receptor binding by anti-epidermal growth factor antibodies is related to better survival in advanced non-small-cell lung cancer patients treated with the epidermal growth factor cancer vaccine. Clin Cancer Res 14(3):840–846

    Article  PubMed  CAS  Google Scholar 

  36. Heimberger AB, Crotty LE, Archer GE, Hess KR, Wikstrand CJ, Friedman AH, Friedman HS, Bigner DD, Sampson JH (2003) Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin Cancer Res 9(11):4247–4254

    PubMed  CAS  Google Scholar 

  37. Lu Y, Wei YQ, Tian L, Zhao X, Yang L, Hu B, Kan B, Wen YJ, Liu F, Deng HX, Li J, Mao YQ, Lei S, Huang MJ, Peng F, Jiang Y, Zhou H, Zhou LQ, Luo F (2003) Immunogene therapy of tumors with vaccine based on xenogeneic epidermal growth factor receptor. J Immunol 170(6):3162–3170

    PubMed  CAS  Google Scholar 

  38. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA Jr (2003) The influence of finasteride on the development of prostate cancer. N Engl J Med 349(3):215–224

    Article  PubMed  CAS  Google Scholar 

  39. Steinkamp MP, O’Mahony OA, Brogley M, Rehman H, Lapensee EW, Dhanasekaran S, Hofer MD, Kuefer R, Chinnaiyan A, Rubin MA, Pienta KJ, Robins DM (2009) Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res 69(10):4434–4442

    Article  PubMed  CAS  Google Scholar 

  40. Gulley JL, Drake CG (2011) Immunotherapy for prostate cancer: recent advances, lessons learned, and areas for further research. Clin Cancer Res 17(12):3884–3891

    Article  PubMed  CAS  Google Scholar 

  41. Gray A, Raff AB, Chiriva-Internati M, Chen SY, Kast WM (2008) A paradigm shift in therapeutic vaccination of cancer patients: the need to apply therapeutic vaccination strategies in the preventive setting. Immunol Rev 222:316–327. doi:10.1111/j.1600-065X.2008.00605.x

    Article  PubMed  CAS  Google Scholar 

  42. Gray A, de la Luz Garcia-Hernandez M, van West M, Kanodia S, Hubby B, Kast WM (2009) Prostate cancer immunotherapy yields superior long-term survival in TRAMP mice when administered at an early stage of carcinogenesis prior to the establishment of tumor-associated immunosuppression at later stages. Vaccine 27(Suppl 6):G52–G59

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. François Lemonnier for provision of HHDII-DR1 animals (which are property of the Institut Pasteur, 25-28 rue de Docteur Roux, Paris, France 75015), and Drs. George Wilding and Ajit Verma for TRAMP+/+ mice. We also thank Drs. Ruth Sullivan and Weixiong Zhong for pathological consultations, Dr. Joan Jorgensen for help with immunofluorescence protocols, and Dr. Wei Huang and Sally Drew for assistance with the Vectra Imaging System. We would also like to thank Dr. Glenn Liu for critical evaluation of the manuscript. Grant support was provided by the National Institutes of Health (R01 CA142608, P30 CA014520), and by the US Army Medical Research and Materiel Command Prostate Cancer Research Program (W81XWH-05-1-0404, W81XWH-08-1-0341, and W81XWH-11-1-0196).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. University of Wisconsin Carbone Cancer Center, 1111 Highland Avenue, Madison, WI, 53705, USA

    Brian M. Olson, Laura E. Johnson & Douglas G. McNeel

  2. 7007 Wisconsin Institutes for Medical Research, 1111 Highland Avenue, Madison, WI, 53705, USA

    Douglas G. McNeel

Authors
  1. Brian M. Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura E. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Douglas G. McNeel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Douglas G. McNeel.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Olson, B.M., Johnson, L.E. & McNeel, D.G. The androgen receptor: a biologically relevant vaccine target for the treatment of prostate cancer. Cancer Immunol Immunother 62, 585–596 (2013). https://doi.org/10.1007/s00262-012-1363-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-012-1363-9

Keywords

Search

Navigation