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Proposed mechanisms of action for prostate cancer vaccines

Nature Reviews Urology volume 10, pages 149–160 (2013)Cite this article

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Abstract

Prostate cancer is responsible for the deaths of more than 33,000 American men every year. Once this disease has become metastatic, there is no curative treatment. Alternative therapies to chemotherapy and radical prostatectomy are being increasingly explored. Prostate cancer vaccines—which trigger a tumour-specific cytotoxic-T-lymphocyte-mediated immune attack by the patient's immune system—have been investigated in clinical trials with modest, yet encouraging, results. When developing and administering prostate cancer vaccines, it is critical to consider how vital parameters, such as the stage of disease progression and the nature of adjuvant therapies, could influence treatment outcome. Of particular interest are current and future strategies for diminishing the activity of regulatory T lymphocytes.

Key Points

  • There is currently no effective cure for prostate cancer

  • Clinical trials have demonstrated the safety of prostate cancer vaccines

  • Prostate cancer vaccines are capable of breaking immune tolerance to tumour-associated antigens

  • Therapy with prostate cancer vaccines is likely to be of particular benefit to patients with less advanced or minimal residual disease

  • Combinatorial therapies that enhance prostate cancer vaccine therapy efficacy warrant further clinical investigation

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Figure 1: Proposed mechanisms of PROSTVAC® VF action.
Figure 2: Proposed mechanism of Ad5-PSA action.
Figure 3: Proposed mechanism of sipuleucel-T action.
Figure 4: Proposed mechanism of GVAX-PCa action.

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References

  1. Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin. 62, 10–29 (2012).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Beltran, H. et al. New therapies for castration-resistant prostate cancer: efficacy and safety. Eur. Urol. 60, 279–290 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Karan, D., Holzbeierlein, J. M., Van Veldhuizen, P. & Thrasher, J. B. Cancer immunotherapy: a paradigm shift for prostate cancer treatment. Nat. Rev. Urol. 9, 376–385 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Coffey, D. S. & Isaacs, J. T. Prostate tumor biology and cell kinetics—theory. Urology 17, 40–53 (1981).

    CAS  PubMed  Google Scholar 

  7. Drake, C. G. et al. Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. Cancer Cell 7, 239–249 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kiessling, A. et al. Advances in specific immunotherapy for prostate cancer. Eur. Urol. 53, 694–708 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Steinman, R. M. Lasker Basic Medical Research Award. Dendritic cells: versatile controllers of the immune system. Nat. Med. 13, 1155–1159 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Banchereau, J. & Palucka, A. K. Dendritic cells as therapeutic vaccines against cancer. Nat. Rev. Immunol. 5, 296–306 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Mellman, I. & Steinman, R. M. Dendritic cells: specialized and regulated antigen processing machines. Cell 106, 255–258 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Gallucci, S. & Matzinger, P. Danger signals: SOS to the immune system. Curr. Opin. Immunol. 13, 114–119 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Aderem, A. & Ulevitch, R. J. Toll-like receptors in the induction of the innate immune response. Nature 406, 782–787 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. West, A. P., Koblansky, A. A. & Ghosh, S. Recognition and signaling by toll-like receptors. Ann. Rev. Cell Dev. Biol. 22, 409–437 (2006).

    Article  CAS  Google Scholar 

  15. Cheng, C. et al. Mechanism of ad5 vaccine immunity and toxicity: fiber shaft targeting of dendritic cells. PLoS Pathog. 3, e25 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Miller, G., Lahrs, S., Pillarisetty, V. G., Shah, A. B. & DeMatteo, R. P. Adenovirus infection enhances dendritic cell immunostimulatory properties and induces natural killer and T-cell-mediated tumor protection. Cancer Res. 62, 5260–5266 (2002).

    CAS  PubMed  Google Scholar 

  17. Locher, C. et al. Desirable cell death during anticancer chemotherapy. Ann. NY Acad. Sci. 1209, 99–108 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Kaufman, H. L. 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. 22, 2122–2132 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  20. Kantoff, P. W. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gulley, J. L. 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).

    Article  CAS  PubMed  Google Scholar 

  22. Gulley, J. L., Madan, R. A. & Schlom, J. Impact of tumour volume on the potential efficacy of therapeutic vaccines. Curr. Oncol. 18, e150–e157 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. McFadden, G. Smallpox: an ancient disease enters the modern era of virogenomics. Proc. Natl Acad. Sci. USA 101, 14994–14995 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Smith, G. L., Symons, J. A., Khanna, A., Vanderplasschen, A. & Alcami, A. Vaccinia virus immune evasion. Immunol. Rev. 159, 137–154 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Engelmayer, J. et al. Vaccinia virus inhibits the maturation of human dendritic cells: a novel mechanism of immune evasion. J. Immunol. 163, 6762–6768 (1999).

    CAS  PubMed  Google Scholar 

  26. Yao, Y. et al. Vaccinia virus infection induces dendritic cell maturation but inhibits antigen presentation by MHC class II. Cell. Immunol. 246, 92–102 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yates, N. L. & Alexander-Miller, M. A. Vaccinia virus infection of mature dendritic cells results in activation of virus-specific naive CD8+ T cells: a potential mechanism for direct presentation. Virology 359, 349–361 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Mercer, J. & Helenius, A. Vaccinia virus uses macropinocytosis and apoptotic mimicry to enter host cells. Science 320, 531–535 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Chisholm, S. E. & Reyburn, H. T. Recognition of vaccinia virus-infected cells by human natural killer cells depends on natural cytotoxicity receptors. J. Virol. 80, 2225–2233 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Seet, B. T. et al. Poxviruses and immune evasion. Ann. Rev. Immunol. 21, 377–423 (2003).

    Article  CAS  Google Scholar 

  31. Deng, L. et al. Vaccinia virus subverts a mitochondrial antiviral signaling protein-dependent innate immune response in keratinocytes through its double-stranded RNA binding protein, E3. J. Virol. 82, 10735–10746 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Aarts, W. M., Schlom, J. & Hodge, J. W. Vector-based vaccine/cytokine combination therapy to enhance induction of immune responses to a self-antigen and antitumor activity. Cancer Res. 62, 5770–5777 (2002).

    CAS  PubMed  Google Scholar 

  33. Halabi, S. et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J. Clin. Oncol. 21, 1232–1237 (2003).

    Article  PubMed  Google Scholar 

  34. Madan, R. A. et al. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 13, 501–508 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Attia, P. et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J. Clin. Oncol. 23, 6043–6053 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Brahmer, J. R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107, 4275–4280 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Torchilin, V. Tumor delivery of macromolecular drugs based on the EPR effect. Adv. Drug Deliv. Rev. 63, 131–135 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Gabizon, A. A. Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Cancer Invest. 19, 424–436 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Manolova, V. et al. Nanoparticles target distinct dendritic cell populations according to their size. Eur. J. Immunol. 38, 1404–1413 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Arlen, P. M., Pazdur, M., Skarupa, L., Rauckhorst, M. & Gulley, J. L. A randomized phase II study of docetaxel alone or in combination with PANVAC-V (vaccinia) and PANVAC-F (fowlpox) in patients with metastatic breast cancer (NCI 05-C-0229). Clin. Breast Cancer 7, 176–179 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Garnett, C. T., Schlom, J. & Hodge, J. W. Combination of docetaxel and recombinant vaccine enhances T-cell responses and antitumor activity: effects of docetaxel on immune enhancement. Clin. Cancer Res. 14, 3536–3544 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Vincent, J. et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res. 70, 3052–3061 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Matsushima, H. & Takashima, A. Cyclophosphamide, DCs, and Tregs. Blood 115, 4322–4324 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tongu, M., Harashima, N., Yamada, T., Harada, T. & Harada, M. Immunogenic chemotherapy with cyclophosphamide and doxorubicin against established murine carcinoma. Cancer Immunol. Immunother. 59, 769–777 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Liniger, M., Zuniga, A. & Naim, H. Y. Use of viral vectors for the development of vaccines. Expert Rev. Vaccines 6, 255–266 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Siemens, D. R. et al. Cutting edge: restoration of the ability to generate CTL in mice immune to adenovirus by delivery of virus in a collagen-based matrix. J. Immunol. 166, 731–735 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Lubaroff, D. M. et al. Clinical protocol: phase I study of an adenovirus/prostate-specific antigen vaccine in men with metastatic prostate cancer. Hum. Gene Ther. 17, 220–229 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Lubaroff, D. M. et al. Phase I clinical trial of an adenovirus/prostate-specific antigen vaccine for prostate cancer: safety and immunologic results. Clin. Cancer Res. 15, 7375–7380 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Elzey, B. D., Siemens, D. R., Ratliff, T. L. & Lubaroff, D. M. Immunization with type 5 adenovirus recombinant for a tumor antigen in combination with recombinant canarypox virus (ALVAC) cytokine gene delivery induces destruction of established prostate tumors. Int. J. Cancer 94, 842–849 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Zhu, J., Huang, X. & Yang, Y. NKG2D is required for NK cell activation and function in response to E1-deleted adenovirus. J. Immunol. 185, 7480–7486 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Cao, H. et al. Innate immune response of human plasmacytoid dendritic cells to poxvirus infection is subverted by vaccinia E3 via its Z-DNA/RNA binding domain. PLoS ONE 7, e36823 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Geary, S. M., Lemke, C. D., Lubaroff, D. M. & Salem, A. K. Tumor immunotherapy using adenovirus vaccines in combination with intratumoral doses of CpG ODN. Cancer Immunol. Immunother. 60, 1309–1317 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lubaroff, D. M. et al. Decreased cytotoxic T cell activity generated by co-administration of PSA vaccine and CpG ODN is associated with increased tumor protection in a mouse model of prostate cancer. Vaccine 24, 6155–6162 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Karan, D., Krieg, A. M. & Lubaroff, D. M. Paradoxical enhancement of CD8 T cell-dependent anti-tumor protection despite reduced CD8 T cell responses with addition of a TLR9 agonist to a tumor vaccine. Int. J. Cancer 121, 1520–1528 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Le, D. T., Pardoll, D. M. & Jaffee, E. M. Cellular vaccine approaches. Cancer J. 16, 304–310 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Higano, C. S. 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 115, 3670–3679 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Sonpavde, G. et al. The role of sipuleucel-T in therapy for castration-resistant prostate cancer: a critical analysis of the literature. Eur. Urol. 61, 639–647 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Burch, P. A. et al. Immunotherapy (APC8015, Provenge) targeting prostatic acid phosphatase can induce durable remission of metastatic androgen-independent prostate cancer: a phase 2 trial. Prostate 60, 197–204 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Laus, R. et al. Dendritic cell immunotherapy of prostate cancer: preclinical models and early clinical experience. Can. Res. Ther. Control 11, 1–10 (2001).

    Google Scholar 

  62. Huber, M. L., Haynes, L., Parker, C. & Iversen, P. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer. J. Natl Cancer Inst. 104, 273–279 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Burns, E. A., Lum, L. G., L'Hommedieu, G. & Goodwin, J. S. Specific humoral immunity in the elderly: in vivo and in vitro response to vaccination. J. Gerontol. 48, B231–B236 (1993).

    Article  CAS  PubMed  Google Scholar 

  64. Grubeck-Loebenstein, B. Fading immune protection in old age: vaccination in the elderly. J. Comp. Pathol. 142 (Suppl. 1), S116–S119 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Pawelec, G., Lustgarten, J., Ruby, C. & Gravekamp, C. Impact of aging on cancer immunity and immunotherapy. Cancer Immunol. Immunother. 58, 1907–1908 (2009).

    Article  PubMed  Google Scholar 

  66. Gravekamp, C. The importance of the age factor in cancer vaccination at older age. Cancer Immunol. Immunother. 58, 1969–1977 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Sheasley-O'Neill, S. L., Brinkman, C. C., Ferguson, A. R., Dispenza, M. C. & Engelhard, V. H. Dendritic cell immunization route determines integrin expression and lymphoid and nonlymphoid tissue distribution of CD8 T cells. J. Immunol. 178, 1512–1522 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Draube, A. et al. Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis. PLoS ONE 6, e18801 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Liu, J. Y. et al. Single administration of low dose cyclophosphamide augments the antitumor effect of dendritic cell vaccine. Cancer Immunol. Immunother. 56, 1597–1604 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  71. Higano, C. S. 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).

    Article  CAS  PubMed  Google Scholar 

  72. Nguyen, M. C. et al. Antibody responses to galectin-8, TARP and TRAP1 in prostate cancer patients treated with a GM-CSF-secreting cellular immunotherapy. Cancer Immunol. Immunother. 59, 1313–1323 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Obeid, M. et al. Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ. 14, 1848–1850 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Apetoh, L. et al. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol. Rev. 220, 47–59 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. van den Eertwegh, A. J. et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 13, 509–517 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. van Elsas, A., Hurwitz, A. A. & Allison, J. P. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J. Exp. Med. 190, 355–366 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

    Article  CAS  PubMed  Google Scholar 

  79. Davis, M. B. et al. Intratumoral administration of TLR4 agonist absorbed into a cellular vector improves antitumor responses. Clin. Cancer Res. 17, 3984–3992 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Drake, C. G. Immunotherapy for prostate cancer: walk, don't run. J. Clin. Oncol. 27, 4035–4037 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Higano, C. et al. A phase III trial of GVAX immunotherapy for prostate cancer vs docetaxel plus prednisone in asymptomatic, castration-resistant prostate cancer (CRPC). In Genitourinary Cancer Symposium abstract #LBA150 (American Society of Clinical Oncology, Alexandria, VA, USA, 2009).

    Google Scholar 

  82. Small, E. et al. A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel vs docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer (CRPC). In Genitourinary Cancer Symposium abstract #7 (American Society of Clinical Oncology, Alexandria, VA, USA, 2009).

    Google Scholar 

  83. Machiels, J. P. et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res. 61, 3689–3697 (2001).

    CAS  PubMed  Google Scholar 

  84. He, Q. et al. Low-dose paclitaxel enhances the anti-tumor efficacy of GM-CSF surface-modified whole-tumor-cell vaccine in mouse model of prostate cancer. Cancer Immunol. Immunother. 60, 715–730 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Srivastava, I. K. & Liu, M. A. Gene vaccines. Ann. Intern. Med. 138, 550–559 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. McNeel, D. G. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Becker, J. T. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Pavlenko, M. et al. A phase I trial of DNA vaccination with a plasmid expressing prostate-specific antigen in patients with hormone-refractory prostate cancer. Br. J. Cancer 91, 688–694 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Roos, A. K., Pavlenko, M., Charo, J., Egevad, L. & Pisa, P. Induction of PSA-specific CTLs and anti-tumor immunity by a genetic prostate cancer vaccine. Prostate 62, 217–223 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Peachman, K. K., Rao, M. & Alving, C. R. Immunization with DNA through the skin. Methods 31, 232–242 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Burnham, K., Robb, L., Scott, C. L., O'Keeffe, M. & Shortman, K. Effect of granulocyte-macrophage colony-stimulating factor on the generation of epidermal Langerhans cells. J. Interferon Cytokine Res. 20, 1071–1076 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Yokozeki, H. et al. Comparative analysis of CD80 and CD86 on human Langerhans cells: expression and function. Arch. Dermatol. Res. 290, 547–552 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Roos, A. K. et al. Enhancement of cellular immune response to a prostate cancer DNA vaccine by intradermal electroporation. Mol. Ther. 13, 320–327 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Kepp, O., Tesniere, A., Zitvogel, L. & Kroemer, G. The immunogenicity of tumor cell death. Curr. Opin. Oncol. 21, 71–76 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Apetoh, L., Tesniere, A., Ghiringhelli, F., Kroemer, G. & Zitvogel, L. Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res. 68, 4026–4030 (2008).

    Article  CAS  PubMed  Google Scholar 

  96. Fucikova, J. et al. Human tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer Res. 71, 4821–4833 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Aymeric, L. et al. Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity. Cancer Res. 70, 855–858 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Aguilar, L. K., Guzik, B. W. & Aguilar-Cordova, E. Cytotoxic immunotherapy strategies for cancer: mechanisms and clinical development. J. Cell Biochem. 112, 1969–1977 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Fyfe, J. A., Keller, P. M., Furman, P. A., Miller, R. L. & Elion, G. B. Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxyethoxymethyl)guanine. J. Biol. Chem. 253, 8721–8727 (1978).

    CAS  PubMed  Google Scholar 

  100. Eastham, J. A. 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. 7, 515–523 (1996).

    Article  CAS  PubMed  Google Scholar 

  101. Freeman, S. M. et al. The “bystander effect”: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res. 53, 5274–5283 (1993).

    CAS  PubMed  Google Scholar 

  102. Fick, J. et al. The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro. Proc. Natl Acad. Sci. USA 92, 11071–11075 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Vile, R. G., Nelson, J. A., Castleden, S., Chong, H. & Hart, I. R. Systemic gene therapy of murine melanoma using tissue specific expression of the HSVtk gene involves an immune component. Cancer Res. 54, 6228–6234 (1994).

    CAS  PubMed  Google Scholar 

  104. Hall, S. J., Mutchnik, S. E., Chen, S. H., Woo, S. L. & Thompson, T. C. 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 70, 183–187 (1997).

    Article  CAS  PubMed  Google Scholar 

  105. Kuriyama, S. et al. Cancer gene therapy with HSV-tk/GCV system depends on T-cell-mediated immune responses and causes apoptotic death of tumor cells in vivo. Int. J. Cancer 83, 374–380 (1999).

    Article  CAS  PubMed  Google Scholar 

  106. Ayala, G. et al. Biological response determinants in HSV-tk + ganciclovir gene therapy for prostate cancer. Mol. Ther. 13, 716–728 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Teh, B. S. et al. Phase I-II trial evaluating combined intensity-modulated radiotherapy and in situ gene therapy with or without hormonal therapy in treatment of prostate cancer-interim report on PSA response and biopsy data. Int. J. Radiat. Oncol. Biol. Phys. 58, 1520–1529 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Liakou, C. I. et al. CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc. Natl Acad. Sci. USA 105, 14987–14992 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Fizazi, K. et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 13, 983–992 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Choudhury, A. D. & Kantoff, P. W. New agents in metastatic prostate cancer. J. Natl Compr. Canc. Netw. 10, 1403–1409 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. D'Amico, A. V. et al. Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J. Natl Cancer Inst. 95, 1376–1383 (2003).

    Article  PubMed  Google Scholar 

  112. Hamilton, R. J. et al. Limitations of prostate specific antigen doubling time following biochemical recurrence after radical prostatectomy: results from the SEARCH database. J. Urol. 179, 1785–1790 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Small, E. J. 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).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We gratefully acknowledge financial support from the American Cancer Society (grant RSG-09-015-01-CDD) and the National Cancer Institute at the National Institutes of Health (grant 1R21CA13345-01/UI Mayo Clinic Lymphoma SPORE/ P50CA09727411).

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Authors and Affiliations

  1. Division of Pharmaceutics, College of Pharmacy, University of Iowa, Iowa City, 52242, IA, USA

    Sean M. Geary, Caitlin D. Lemke & Aliasger K. Salem

  2. Department of Urology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, 52242, IA, USA

    David M. Lubaroff

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  1. Sean M. Geary
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  2. Caitlin D. Lemke
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  3. David M. Lubaroff
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  4. Aliasger K. Salem
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All authors contributed towards researching, writing, discussing, reviewing, and editing the manuscript.

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Correspondence to Aliasger K. Salem.

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The authors declare no competing financial interests.

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Geary, S., Lemke, C., Lubaroff, D. et al. Proposed mechanisms of action for prostate cancer vaccines. Nat Rev Urol 10, 149–160 (2013). https://doi.org/10.1038/nrurol.2013.8

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