Immuno-gene Therapy for Metastatic Prostate Cancer

  • Takefumi Satoh
  • Terry L. Timme
  • Yehoshua Gdor
  • Brian J. Miles
  • Robert J. Amato
  • Dov Kadmon
  • Timothy C. Thompson
Part of the Cancer Metastasis – Biology and Treatment book series (CMBT, volume 10)


It has long been appreciated that a significant number of prostate cancers will not progress to clinical significance, yet some prostate cancers disseminate rapidly leading to lethal metastatic disease. Therefore, a reasonable goal of prostate cancer research is to develop novel alternative interventions and adjuvant therapeutic approaches that would suppress local tumor growth and/or impact pre-existing metastatic disease. This chapter will describe the potential for gene therapy to achieve this goal. We will review both pre-clinical and clinical studies using in situ gene therapy to generate a systemic immune response. These therapeutic strategies include a cytotoxic approach using the HSV-tk gene combined with the prodrug ganciclovir, the immune modulator gene for interleukin-12, and a novel gene that is both cytotoxic and immunomodulatory, Related to Testes-specific, Vespid and Pathogenesis proteins-1 (RTVP-1).


gene therapy prostate cancer immune therapy metastasis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001, 51:15–36.PubMedCrossRefGoogle Scholar
  2. 2.
    Ohori M, Wheeler TM, Kattan MW, Goto Y, Scardino PT. Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 1995, 154:1818–24.PubMedCrossRefGoogle Scholar
  3. 3.
    Zietman AL, Edelstein RA, Coen JJ, Babayan RK, Krane RJ. Radical prostatectomy for adenocarcinoma of the prostate: The influence of preoperative and pathologic findings on biochemical disease-free outcome. Urology 1994, 43:828–33.PubMedCrossRefGoogle Scholar
  4. 4.
    Sakr WA, Macoska JA, Benson P, Grignon DJ, Wolman SR, Pontes JE, Crissman JD. Allelic loss in locally metastatic, multisampled prostate cancer. Cancer Res 1994, 54:3273–7.PubMedGoogle Scholar
  5. 5.
    Qian J, Bostwick DG, Takahashi S, Borell TJ, Herath JF, Lieber MM, Jenkins RB. Chromosomal anomalies in prostatic intraepithelial neoplasia and carcinoma detected by fluorescence in situ hybridization. Cancer Res 1995, 55:5408–14.PubMedGoogle Scholar
  6. 6.
    Thompson TC, Park SH, Timme TL, Ren C, Eastham JA, Donehower LA et al. Loss of P53 function leads to metastasis in ras+myc-initiated mouse prostate cancer. Oncogene 1995, 10:869–79.PubMedGoogle Scholar
  7. 7.
    Stamey TA, Freiha FS, McNeal JE, Redwine EA, Whittemore AS, Schmid HP. Localized prostate cancer. Relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 1993, 71:933–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Franks LM. Latent carcinoma of the prostate. J Pathol Bacteriol 1954, 68:603–16.PubMedCrossRefGoogle Scholar
  9. 9.
    Epstein JI, Carmichael MJ, Partin AW, Walsh PC. Small high grade adenocarcinoma of the prostate in radical prostatectomy specimens performed for nonpalpable disease: Pathogenetic and clinical implications. J Urol 1994, 151:1587–92.PubMedGoogle Scholar
  10. 10.
    Ohori M, Wheeler TM, Dunn JK, Stamey TA, Scardino PT. The pathological features and prognosis of prostate cancer detectable with current diagnostic tests. J Urol 1994, 152:1714–20.PubMedGoogle Scholar
  11. 11.
    Goto Y, Ohori M, Arakawa A, Kattan MW, Wheeler TM, Scardino PT. Distinguishing clinically important from unimportant prostate cancers before treatment: Value of systematic biopsies. J Urol 1996, 156:1059–63.PubMedCrossRefGoogle Scholar
  12. 12.
    Noguchi M, Stamey TA, McNeal JE, Yemoto CM. Relationship between systematic biopsies and histological features of 222 radical prostatectomy specimens: Lack of prediction of tumor significance for men with nonpalpable prostate cancer. J Urol 2001, 166:104–109; discussion 109–110.Google Scholar
  13. 13.
    Rodriguez R, Schuur ER, Lim HY, Henderson GA, Simons JW, Henderson DR. Prostate attenuated replication competent adenovirus (ARCA) CN706: A selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res 1997, 57:2559–63.PubMedGoogle Scholar
  14. 14.
    Yu DC, Chen Y, Seng M, Dilley J, Henderson DR. The addition of adenovirus type 5 region E3 enables calydon virus 787 to eliminate distant prostate tumor xenografts. Cancer Res 1999, 59:4200–3.PubMedGoogle Scholar
  15. 15.
    Walker JR, McGeagh KG, Sundaresan P, Jorgensen TJ, Rabkin SD, Martuza RL. Local and systemic therapy of human prostate adenocarcinoma with the conditionally replicating herpes simplex virus vector G207. Hum Gene Ther 1999, 10:2237–43.PubMedCrossRefGoogle Scholar
  16. 16.
    Koeneman KS, Kao C, Ko SC, Yang L, Wada Y, Kallmes DF et al. Osteocalcin-directed gene therapy for prostate-cancer bone metastasis. World J Urol 2000, 18:102–10.PubMedCrossRefGoogle Scholar
  17. 17.
    Galanis E, Vile R, Russell SJ. Delivery systems intended for in vivo gene therapy of cancer: Targeting and replication competent viral vectors. Crit Rev Oncol Hematol 2001, 38:177–92.PubMedCrossRefGoogle Scholar
  18. 18.
    Uchida A, O’Keefe DS, Bacich DJ, Molloy PL, Heston WD. In vivo suicide gene therapy model using a newly discovered prostate-specific membrane antigen promoter/enhancer: A potential alternative approach to androgen deprivation therapy. Urology 2001, 58:132–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Nasto B. Questions about systemic adenovirus delivery. Mol Ther 2002, 5:652–3.PubMedCrossRefGoogle Scholar
  20. 20.
    Templeton NS. In liposomal gene delivery systems. Expert Opin Biol Ther Dev 2001, 1:567–70.CrossRefGoogle Scholar
  21. 21.
    Pirollo KF, Xu L, Chang EH. Non-viral gene delivery for P53. Curr Opin Mol Ther 2000, 2:168–75.PubMedGoogle Scholar
  22. 22.
    Sanda MG, Ayyagari SR, Jaffee EM, Epstein JI, Clift SL, Cohen LK et al. Demonstration of a rational strategy for human prostate cancer gene therapy. J Urol 1994, 151:622–8.PubMedGoogle Scholar
  23. 23.
    Simons JW, Mikhak B, Chang JF, DeMarzo AM, Carducci MA, Lim M et al. Induction of immunity to prostate cancer antigens: Results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer. Cancer Res 1999, 59:5160–8.PubMedGoogle Scholar
  24. 24.
    Steele FR, Aguilar-Cordova E. Cabo II: Immunology and gene therapy. Mol Ther 2002, 5:486–91.CrossRefGoogle Scholar
  25. 25.
    Eastham JA, Chen SH, Sehgal I, Yang G, Timme TL, Hall SJ et al. Prostate cancer gene therapy: Herpes simplex virus thymidine kinase gene transduction followed by ganciclovir in mouse and human prostate cancer models. Hum Gene Ther 1996, 7:515–23.PubMedGoogle Scholar
  26. 26.
    Hall SJ, Mutchnik SE, Chen SH, Woo, SL, Thompson, TC. Adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy leads to systemic activity against spontaneous and induced metastasis in an orthotopic mouse model of prostate cancer. Int J Cancer 1997:70: 183–187.PubMedCrossRefGoogle Scholar
  27. 27.
    Hall SJ, Mutchnik SE, Yang G, Timme TL, Nasu Y, Bangma CH et al. Cooperative therapeutic effects of androgen ablation and adenovirus- mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy in experimental prostate cancer. Cancer Gene Ther 1999, 6:54–63.PubMedCrossRefGoogle Scholar
  28. 28.
    Thompson TC. In situ gene therapy for prostate cancer. Oncol Res 1999, 11:1–8.PubMedGoogle Scholar
  29. 29.
    Timme TL, Hall SJ, Barrios R, Woo SL, Aguilar-Cordova E, Thompson TC. Local inflammatory response and vector spread after direct intraprostatic injection of a recombinant adenovirus containing the herpes simplex virus thymidine kinase gene and ganciclovir therapy in mice. Cancer Gene Ther 1998, 5:74–82.PubMedGoogle Scholar
  30. 30.
    Pramudji C, Shimura S, Ebara S, Yang G, Wang J, Ren C et al. In Situ prostate cancer gene therapy using a novel adenoviral vector regulated by the caveolin-1 promoter. Clin Cancer Res 2001, 7:4272–9.PubMedGoogle Scholar
  31. 31.
    Ebara S, Shimura S, Nasu Y, Kaku H, Kumon H, Yang G et al. Gene therapy for prostate cancer: Toxicological profile of four HSV-tk transducing adenoviral vectors regulated by different promoters. Prost Can Prostatic Dis, 5:316–325, 2002.CrossRefGoogle Scholar
  32. 32.
    Atkinson G, Hall SJ. Prodrug activation gene therapy and external beam irradiation in the treatment of prostate cancer. Urology 1999, 54:1098–104.PubMedCrossRefGoogle Scholar
  33. 33.
    Chhikara M, Huang H, Vlachaki MT, Zhu X, Teh B, Chiu KJ et al. Enhanced therapeutic effect of HSV-tk+GCV gene therapy and ionizing radiation for prostate cancer. Mol Ther 2001, 3:536–42.PubMedCrossRefGoogle Scholar
  34. 34.
    Hall SJ, Sanford MA, Atkinson G, Chen SH. Induction of potent antitumor natural killer cell activity by herpes simplex virus-thymidine kinase and ganciclovir therapy in an orthotopic mouse model of prostate cancer. Cancer Res 1998, 58:3221–5.PubMedGoogle Scholar
  35. 35.
    Nasu Y, Bangma C, Hull G, Yang G, Wang J, Shimura S et al. Combination gene therapy with adenoviral vector-mediated HSV-tk+GCV and IL-12 in an orthotopic mouse model for prostate cancer. Prost Cancer Prostatic Dis 2001:4: 44–55.CrossRefGoogle Scholar
  36. 36.
    Yamamoto S, Suzuki S, Hoshino A, Akimoto M, Shimada T. Herpes simplex virus thymidine kinase/ganciclovir-mediated killing of tumor cell induces tumor-specific cytotoxic T cells in mice. Cancer Gene Ther 1997, 4:91–6.PubMedGoogle Scholar
  37. 37.
    Mullen CA, Anderson L, Woods K, Nishino M, Petropoulos D. Ganciclovir chemoablation of herpes thymidine kinase suicide gene-modified tumors produces tumor necrosis and induces systemic immune responses. Hum Gene Ther 1998, 9:2019–30.PubMedCrossRefGoogle Scholar
  38. 38.
    Kuriyama S, Kikukawa M, Masui K, Okuda H, Nakatani T, Akahane T et al. Gene therapy with HSV-tk/GCV system depends on T-cell-mediated immune responses and causes apoptotic death of tumor cells in vivo. Cancer 1999, 83:374–80.Google Scholar
  39. 39.
    Herman JR, Adler HL, Aguilar-Cordova E, Rojas-Martinez A, Woo S, Timme TL et al. In situ gene therapy for adenocarcinoma of the prostate: A phase I clinical trial. Hum Gene Ther 1999, 10:1239–49.PubMedCrossRefGoogle Scholar
  40. 40.
    Shalev M, Kadmon D, Teh BS, Butler EB, Aguilar-Cordova E, Thompson TC et al. Suicide gene therapy toxicity after multiple and repeat injections in patients with localized prostate cancer. J Urol 2000, 163:1747–50.PubMedCrossRefGoogle Scholar
  41. 41.
    Miles BJ, Shalev M, Aguilar-Cordova E, Timme TL, Lee HM, Yang G et al. Prostate-specific antigen response and systemic T cell activation after in situ gene therapy in prostate cancer patients failing radiotherapy. Hum Gene Ther 2001, 12:1955–67.PubMedCrossRefGoogle Scholar
  42. 42.
    Ayala G, Wheeler TM, Shalev M, Thompson TC, Miles B, Aguilar-Cordova E et al. Cytopathic effect of in situ gene therapy in prostate cancer. Hum Pathol 2000, 31:866–70.PubMedCrossRefGoogle Scholar
  43. 43.
    Teh BS, Aguilar-Cordova E, Kernen K, Chou CC, Shalev M, Vlachaki MT et al. Phase I/II trial evaluating combined radiotherapy, in situ gene therapy with or without hormonal therapy in the treatment of prostate cancer–a preliminary report. Int J Radiat Oncol Biol Phys 2001, 51:605–13.PubMedGoogle Scholar
  44. 44.
    Nasu Y, Bangma CH, Hull GW, Lee HM, Hu J, Wang J et al. Adenovirus-mediated interleukin-12 gene therapy for prostate cancer: Suppression of orthotopic tumor growth and pre-established lung metastases in an orthotopic model. Gene Ther 1999, 6:338–49.PubMedCrossRefGoogle Scholar
  45. 45.
    Hull GW, McCurdy MA, Nasu Y, Bangma CH, Yang G, Shimura S et al. Prostate cancer gene therapy: Comparison of adenovirus-mediated expression of interleukin 12 with interleukin 12 plus B7-1 for in situ gene therapy and gene-modified, cell-based vaccines. Clin Cancer Res 2000, 6:4101–9.PubMedGoogle Scholar
  46. 46.
    Chen L, Ashe S, Brady WA, Hellstrom I, Hellstrom KE, Ledbetter JA et al. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 1992, 71:1093–102.PubMedCrossRefGoogle Scholar
  47. 47.
    Thompson T, Timme T, Bangma C, Nasu Y, Hull G, Hall S, Stapleton A. Molecular biology of prostate cancer, pp. 553–64. In: Comprehensive Textbook of Genitourinary Oncology. Coffey DS, Shipley WU, Vogelzang NJ, eds, Baltimore Md: Williams and Wilkins, 1999.Google Scholar
  48. 48.
    Thompson TC, Timme TL, Sehgal I. Oncogenes, growth factors, and hormones in prostate cancer, pp. 327–59. In: Hormones and Growth Factors in Development and Neoplasia. Dickson RB, Salomon DS, eds, New York: Wiley-Liss, Inc, 1998.Google Scholar
  49. 49.
    Eastham JA, Hall SJ, Sehgal I, Wang J, Timme TL, Yang G et al. In vivo gene therapy with P53 or P21 adenovirus for prostate cancer. Cancer Res 1995, 55:5151–5.PubMedGoogle Scholar
  50. 50.
    Ren C, Li L, Goltsov AA, Timme TL, Tahir SA, Wang J et al. MRTVP-1, a novel P53 target gene with proapoptotic activities. Mol Cell Biol 2002, 22:3345–57.PubMedCrossRefGoogle Scholar
  51. 51.
    Murphy EV, Zhang Y, Zhu W, Biggs J. The human glioma pathogenesis-related protein is structurally related to plant pathogenesis-related proteins and its gene is expressed specifically in brain tumors. Gene 1995, 159:131–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Rich T, Chen P, Furman F, Huynh N, Israel MA. RTVP-1, a novel human gene with sequence similarity to genes of diverse species, is expressed in tumor cell lines of glial but not neuronal origin. Gene 1996, 180:125–30.PubMedCrossRefGoogle Scholar
  53. 53.
    Gingras MC, Margolin JF. Differential expression of multiple unexpected genes during U937 cell and macrophage differentiation detected by suppressive subtractive hybridization. Exp Hematol 2000, 28:65–76.PubMedCrossRefGoogle Scholar
  54. 54.
    Satoh T, Timme TL, Yang G, Wang J, Ren C, Kusaka N et al. Adenoviral vector mediated mRTVP-1 gene therapy for prostate cancer. Human Gene Therapy 2003, 14:91–101.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Takefumi Satoh
    • 1
  • Terry L. Timme
    • 1
  • Yehoshua Gdor
    • 1
  • Brian J. Miles
    • 1
  • Robert J. Amato
    • 1
  • Dov Kadmon
    • 1
  • Timothy C. Thompson
    • 1
  1. 1.Scott Department of UrologyBaylor College of MedicineHoustonUSA

Personalised recommendations