Skip to main content

Advertisement

SpringerLink
Log in

Combining radiotherapy and immunotherapy for prostate cancer: two decades of research from preclinical to clinical trials

  • Review
  • Published:
Journal of Radiation Oncology

Abstract

The combination of radiation therapy and immunotherapy is a novel therapeutic approach for prostate cancer. Preclinical evidence has shown that ionizing radiation can have immunostimulatory effects. Ionizing radiation can also affect the tumor microenvironment, enhance infiltration of activated T cells, and trigger an inflammatory process. Together, the combined radio-immunotherapy can enhance cancer cell kill and stimulate the host immune system, providing improved local and systemic control as well as prolongation of survival. The goal of combining radiation therapy with immunotherapy is also to improve cancer cure without an increase in treatment-related toxicity. The combined approach offers a new paradigm, whereby two local therapies, i.e., radiotherapy and in situ immunotherapy, are combined to elicit both local and systemic effects. Herein, we review the rationale for combining radiation and different immunotherapies, the interactions between tumors and the immune system, as well as immunological and abscopal effects of ionizing radiation. The preclinical and clinical trials of combined radiation therapy and immunotherapy for prostate cancer are reviewed. This combined approach holds promise in the management of prostate cancer.

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

Similar content being viewed by others

References

  1. Pollack A, Zagars GK (1997) External beam radiotherapy dose response of prostate cancer. Int J Radiat Oncol Biol Phys 39(5):1011–1018. doi:10.1016/S0360-3016(97)00508-7

    Article  PubMed  CAS  Google Scholar 

  2. Pollack A, Zagars GK, Starkschall G, Antolak JA, Lee JJ, Huang E, von Eschenbach AC, Kuban DA, Rosen I (2002) Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 53(5):1097–1105. doi:10.1016/S0360-3016(02)02829-8

    Article  PubMed  Google Scholar 

  3. Zelefsky MJ, Fuks Z, Leibel SA (2002) Intensity-modulated radiation therapy for prostate cancer. Semin Radiat Oncol 12(3):229–237. doi:10.1053/srao.2002.00000

    Article  PubMed  Google Scholar 

  4. Hanlon AL, Schultheiss TE, Hunt MA, Movsas B, Peter RS, Hanks GE (1997) Chronic rectal bleeding after high-dose conformal treatment of prostate cancer warrants modification of existing morbidity scales. Int J Radiat Oncol Biol Phys 38(1):59–63. doi:10.1016/S0360-3016(97)00234-4

    Article  PubMed  CAS  Google Scholar 

  5. Zelefsky MJ, Cowen D, Fuks Z, Shike M, Burman C, Jackson A, Venkatramen ES, Leibel SA (1999) Long term tolerance of high dose three-dimensional conformal radiotherapy in patients with localized prostate carcinoma. Cancer 85(11):2460–2468. doi:10.1002/(SICI)1097-0142(19990601)85:11<2460::AID-CNCR23>3.0.CO;2-N

    Article  PubMed  CAS  Google Scholar 

  6. Gao Y, Ishiyama H, Sun M, Brinkman KL, Wang X, Zhu J, Mai W, Huang Y, Floryk D, Ittmann M, Thompson TC, Butler EB, Xu B, Teh BS (2011) The alkylphospholipid, perifosine, radiosensitizes prostate cancer cells both in vitro and in vivo. Radiat Oncol 6:39. doi:10.1186/1748-717x-6-39

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. Timme TL, Satoh T, Tahir SA, Wang H, Teh BS, Butler EB, Miles BJ, Amato RJ, Kadmon D, Thompson TC (2003) Therapeutic targets for metastatic prostate cancer. Curr Drug Targets 4(3):251–261

    Article  PubMed  CAS  Google Scholar 

  8. Formenti SC, Demaria S (2009) Systemic effects of local radiotherapy. Lancet Oncol 10(7):718–726. doi:10.1016/S1470-2045(09)70082-8

    Article  PubMed Central  PubMed  Google Scholar 

  9. Demaria S, Bhardwaj N, McBride WH, Formenti SC (2005) Combining radiotherapy and immunotherapy: a revived partnership. Int J Radiat Oncol Biol Phys 63(3):655–666. doi:10.1016/j.ijrobp.2005.06.032

    Article  PubMed Central  PubMed  Google Scholar 

  10. Gulley JL, Arlen PM, Bastian A, Morin S, Marte J, Beetham P, Tsang KY, Yokokawa J, Hodge JW, Menard C, Camphausen K, Coleman CN, Sullivan F, Steinberg SM, Schlom J, Dahut W (2005) Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with localized prostate cancer. Clin Cancer Res 11(9):3353–3362. doi:10.1158/1078-0432.ccr-04-2062

    Article  PubMed  CAS  Google Scholar 

  11. Wersäll PJ, Blomgren H, Pisa P, Lax I, Kälkner K-M, Svedman C (2006) Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma. Acta Oncol 45(4):493–497. doi:10.1080/02841860600604611

    Article  PubMed  Google Scholar 

  12. Tang C, Wang X, Soh H, Seyedin S, Cortez MA, Krishnan S, Massarelli E, Hong D, Naing A, Diab A, Gomez D, Ye H, Heymach J, Komaki R, Allison JP, Sharma P, Welsh JW (2014) Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol Res 2(9):831–838. doi:10.1158/2326-6066.cir-14-0069

    Article  PubMed  CAS  Google Scholar 

  13. Reynders K, Illidge T, Siva S, Chang JY, De Ruysscher D (2015) The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev 41(6):503–510. doi:10.1016/j.ctrv.2015.03.011

    Article  PubMed  Google Scholar 

  14. Chhikara M, Huang H, Vlachaki MT, Zhu X, Teh B, Chiu KJ, Woo S, Berner B, Smith EO, Oberg KC, Aguilar LK, Thompson TC, Butler EB, Aguilar-Cordova E (2001) Enhanced therapeutic effect of HSV-tk + GCV gene therapy and ionizing radiation for prostate cancer. Mol Ther 3(4):536–542. doi:10.1006/mthe.2001.0298

    Article  PubMed  CAS  Google Scholar 

  15. Teh BS, Aguilar-Cordova E, Vlachaki MT, Aguilar L, Mai WY, Caillouet J, Davis M, Miles B, Kadmon D, Ayala G, Lu HH, Chiu JK, Carpenter LS, Woo SY, Grant 3rd WH, Wheeler T, Thompson TC, Butler EB (2002) Combining radiotherapy with gene therapy (from the bench to the bedside): a novel treatment strategy for prostate cancer. Oncologist 7(5):458–466

    Article  PubMed  CAS  Google Scholar 

  16. Vlachaki MT, Chhikara M, Aguilar L, Zhu X, Chiu KJ, Woo S, Teh BS, Thompson TC, Butler EB, Aguilar-Cordova E (2001) Enhanced therapeutic effect of multiple injections of HSV-TK + GCV gene therapy in combination with ionizing radiation in a mouse mammary tumor model. Int J Radiat Oncol Biol Phys 51(4):1008–1017

    Article  PubMed  CAS  Google Scholar 

  17. Fujita T, Timme TL, Tabata K, Naruishi K, Kusaka N, Watanabe M, Abdelfattah E, Zhu JX, Ren C, Ren C, Yang G, Goltsov A, Wang H, Vlachaki MT, Teh BS, Butler EB, Thompson TC (2007) Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer. Gene Ther 14(3):227–236. doi:10.1038/sj.gt.3302788

    Article  PubMed  CAS  Google Scholar 

  18. Fujita T, Satoh T, Timme TL, Hirayama T, Zhu JX, Kusaka N, Naruishi K, Yang G, Goltsov A, Wang J, Vlachaki MT, Teh BS, Brian Butler E, Thompson TC (2014) Combined therapeutic effects of adenoviral vector-mediated GLIPR1 gene therapy and radiotherapy in prostate and bladder cancer models. Urol Oncol 32(2):92–100. doi:10.1016/j.urolonc.2012.10.007

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Harris TJ, Hipkiss EL, Borzillary S, Wada S, Grosso JF, Yen HR, Getnet D, Bruno TC, Goldberg MV, Pardoll DM, DeWeese TL, Drake CG (2008) Radiotherapy augments the immune response to prostate cancer in a time-dependent manner. Prostate 68(12):1319–1329. doi:10.1002/pros.20794

    Article  PubMed Central  PubMed  Google Scholar 

  20. Wada S, Harris TJ, Tryggestad E, Yoshimura K, Zeng J, Yen HR, Getnet D, Grosso JF, Bruno TC, De Marzo AM, Netto GJ, Pardoll DM, DeWeese TL, Wong J, Drake CG (2013) Combined treatment effects of radiation and immunotherapy: studies in an autochthonous prostate cancer model. Int J Radiat Oncol Biol Phys 87(4):769–776. doi:10.1016/j.ijrobp.2013.07.015

    Article  PubMed Central  PubMed  Google Scholar 

  21. Teh BS, Aguilar-Cordova E, Kernen K, Chou CC, Shalev M, Vlachaki MT, Miles B, Kadmon D, Mai WY, Caillouet J, Davis M, Ayala G, Wheeler T, Brady J, Carpenter LS, Lu HH, Chiu JK, Woo SY, Thompson T, Butler EB (2001) Phase I/II trial evaluating combined radiotherapy and in situ gene therapy with or without hormonal therapy in the treatment of prostate cancer—a preliminary report. Int J Radiat Oncol Biol Phys 51(3):605–613

    Article  PubMed  CAS  Google Scholar 

  22. Teh BS, Ayala G, Aguilar L, Mai WY, Timme TL, Vlachaki MT, Miles B, Kadmon D, Wheeler T, Caillouet J, Davis M, Carpenter LS, Lu HH, Chiu JK, Woo SY, Thompson T, Aguilar-Cordova E, Butler EB (2004) 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(5):1520–1529. doi:10.1016/j.ijrobp.2003.09.083

    Article  PubMed  CAS  Google Scholar 

  23. Fujita T, Teh BS, Timme TL, Mai WY, Satoh T, Kusaka N, Naruishi K, Fattah EA, Aguilar-Cordova E, Butler EB, Thompson TC (2006) Sustained long-term immune responses after in situ gene therapy combined with radiotherapy and hormonal therapy in prostate cancer patients. Int J Radiat Oncol Biol Phys 65(1):84–90. doi:10.1016/j.ijrobp.2005.11.009

    Article  PubMed  CAS  Google Scholar 

  24. Satoh T, Teh BS, Timme TL, Mai WY, Gdor Y, Kusaka N, Fujita T, Pramudji CK, Vlachaki MT, Ayala G, Wheeler T, Amato R, Miles BJ, Kadmon D, Butler EB, Thompson TC (2004) Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients. Int J Radiat Oncol Biol Phys 59(2):562–571. doi:10.1016/j.ijrobp.2004.01.020

    Article  PubMed  CAS  Google Scholar 

  25. Freytag SO, Stricker H, Pegg J, Paielli D, Pradhan DG, Peabody J, DePeralta-Venturina M, Xia X, Brown S, Lu M, Kim JH (2003) Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformal radiation therapy for the treatment of newly diagnosed, intermediate- to high-risk prostate cancer. Cancer Res 63(21):7497–7506

    PubMed  CAS  Google Scholar 

  26. Dranoff G (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4(1):11–22. doi:10.1038/nrc1252

    Article  PubMed  CAS  Google Scholar 

  27. Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360. doi:10.1146/annurev.immunol.22.012703.104803

    Article  PubMed  CAS  Google Scholar 

  28. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science (New York, NY) 331(6024):1565–1570. doi:10.1126/science.1203486

    Article  CAS  Google Scholar 

  29. Gajewski TF, Meng Y, Blank C, Brown I, Kacha A, Kline J, Harlin H (2006) Immune resistance orchestrated by the tumor microenvironment. Immunol Rev 213:131–145. doi:10.1111/j.1600-065X.2006.00442.x

    Article  PubMed  CAS  Google Scholar 

  30. Gajewski TF, Fuertes M, Spaapen R, Zheng Y, Kline J (2011) Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment. Curr Opin Immunol 23(2):286–292. doi:10.1016/j.coi.2010.11.013

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  31. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3(11):991–998. doi:10.1038/ni1102-991

    Article  PubMed  CAS  Google Scholar 

  32. Watts C (2004) The exogenous pathway for antigen presentation on major histocompatibility complex class II and CD1 molecules. Nat Immunol 5(7):685–692. doi:10.1038/ni1088

    Article  PubMed  CAS  Google Scholar 

  33. Rock KL, Goldberg AL (1999) Degradation of cell proteins and the generation of MHC class I-presented peptides. Annu Rev Immunol 17:739–779. doi:10.1146/annurev.immunol.17.1.739

    Article  PubMed  CAS  Google Scholar 

  34. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273

    Article  PubMed  CAS  Google Scholar 

  35. Ferris RL, Jaffee EM, Ferrone S (2010) Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J Clin Oncol Off J Am Soc Clin Oncol 28(28):4390–4399. doi:10.1200/jco.2009.27.6360

    Article  CAS  Google Scholar 

  36. Levy A, Chargari C, Cheminant M, Simon N, Bourgier C, Deutsch E (2013) Radiation therapy and immunotherapy: implications for a combined cancer treatment. Crit Rev Oncol Hematol 85(3):278–287. doi:10.1016/j.critrevonc.2012.09.001

    Article  PubMed  Google Scholar 

  37. Raval RR, Sharabi AB, Walker AJ, Drake CG, Sharma P (2014) Tumor immunology and cancer immunotherapy: summary of the 2013 SITC primer. J Immunother Cancer 2:14. doi:10.1186/2051-1426-2-14

    Article  PubMed Central  PubMed  Google Scholar 

  38. Zitvogel L, Kepp O, Kroemer G (2010) Decoding cell death signals in inflammation and immunity. Cell 140(6):798–804. doi:10.1016/j.cell.2010.02.015

    Article  PubMed  CAS  Google Scholar 

  39. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3(1):23–35. doi:10.1038/nri978

    Article  PubMed  CAS  Google Scholar 

  40. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122(3):787–795. doi:10.1172/jci59643

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  41. Ostrand-Rosenberg S, Sinha P, Beury DW, Clements VK (2012) Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression. Semin Cancer Biol 22(4):275–281. doi:10.1016/j.semcancer.2012.01.011

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  42. Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022. doi:10.1038/ni.2703

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  43. Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD (2007) Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450(7171):903–907. doi:10.1038/nature06309

    Article  PubMed  CAS  Google Scholar 

  44. Demaria S, Golden EB, Formenti SC (2015) Role of local radiation therapy in cancer immunotherapy. JAMA Oncology. doi:10.1001/jamaoncol.2015.2756

    PubMed  Google Scholar 

  45. Eriksson D, Stigbrand T (2010) Radiation-induced cell death mechanisms. Tumour Biol 31(4):363–372. doi:10.1007/s13277-010-0042-8

    Article  PubMed  Google Scholar 

  46. Gudkov AV, Komarova EA (2003) The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer 3(2):117–129. doi:10.1038/nrc992

    Article  PubMed  CAS  Google Scholar 

  47. Ferrara TA, Hodge JW, Gulley JL (2009) Combining radiation and immunotherapy for synergistic antitumor therapy. Curr Opin Mol Ther 11(1):37–42

    PubMed Central  PubMed  CAS  Google Scholar 

  48. Golden EB, Pellicciotta I, Demaria S, Barcellos-Hoff MH, Formenti SC (2012) The convergence of radiation and immunogenic cell death signaling pathways. Front Oncol 2:88. doi:10.3389/fonc.2012.00088

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  49. McBride WH, Chiang CS, Olson JL, Wang CC, Hong JH, Pajonk F, Dougherty GJ, Iwamoto KS, Pervan M, Liao YP (2004) A sense of danger from radiation. Radiat Res 162(1):1–19

    Article  PubMed  CAS  Google Scholar 

  50. Formenti SC, Demaria S (2013) Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst 105(4):256–265. doi:10.1093/jnci/djs629

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  51. Formenti SC, Demaria S (2012) Radiation therapy to convert the tumor into an in situ vaccine. Int J Radiat Oncol Biol Phys 84(4):879–880. doi:10.1016/j.ijrobp.2012.06.020

    Article  PubMed  Google Scholar 

  52. Shiao SL, Coussens LM (2010) The tumor-immune microenvironment and response to radiation therapy. J Mammary Gland Biol Neoplasia 15(4):411–421. doi:10.1007/s10911-010-9194-9

    Article  PubMed Central  PubMed  Google Scholar 

  53. Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, Camphausen K, Luiten RM, de Ru AH, Neijssen J, Griekspoor A, Mesman E, Verreck FA, Spits H, Schlom J, van Veelen P, Neefjes JJ (2006) Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 203(5):1259–1271. doi:10.1084/jem.20052494

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  54. Kojima H, Shinohara N, Hanaoka S, Someya-Shirota Y, Takagaki Y, Ohno H, Saito T, Katayama T, Yagita H, Okumura K, et al. (1994) Two distinct pathways of specific killing revealed by perforin mutant cytotoxic T lymphocytes. Immunity 1(5):357–364

    Article  PubMed  CAS  Google Scholar 

  55. Slavin-Chiorini DC, Catalfamo M, Kudo-Saito C, Hodge JW, Schlom J, Sabzevari H (2004) Amplification of the lytic potential of effector/memory CD8+ cells by vector-based enhancement of ICAM-1 (CD54) in target cells: implications for intratumoral vaccine therapy. Cancer Gene Ther 11(10):665–680. doi:10.1038/sj.cgt.7700741

    Article  PubMed  CAS  Google Scholar 

  56. Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW (2004) External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res 64(12):4328–4337. doi:10.1158/0008-5472.can-04-0073

    Article  PubMed  CAS  Google Scholar 

  57. Yoshimura M, Itasaka S, Harada H, Hiraoka M (2013) Microenvironment and radiation therapy. BioMed Res Int 2013:685308. doi:10.1155/2013/685308

    Article  PubMed Central  PubMed  Google Scholar 

  58. Golden EB, Formenti SC (2014) Is tumor (R)ejection by the immune system the "5th R" of radiobiology? Oncoimmunology 3(1):e28133. doi:10.4161/onci.28133

    Article  PubMed Central  PubMed  Google Scholar 

  59. Thompson RF, Maity A (2014) Radiotherapy and the tumor microenvironment: mutual influence and clinical implications. Adv Exp Med Biol 772:147–165. doi:10.1007/978-1-4614-5915-6_7

    Article  PubMed  CAS  Google Scholar 

  60. Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM (2008) Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J Immunol 180(5):3132–3139

    Article  PubMed  CAS  Google Scholar 

  61. Matsumura S, Demaria S (2010) Up-regulation of the pro-inflammatory chemokine CXCL16 is a common response of tumor cells to ionizing radiation. Radiat Res 173(4):418–425. doi:10.1667/rr1860.1

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  62. Garnett CT, Palena C, Chakraborty M, Tsang KY, Schlom J, Hodge JW (2004) Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res 64(21):7985–7994. doi:10.1158/0008-5472.can-04-1525

    Article  PubMed  CAS  Google Scholar 

  63. Chakraborty M, Abrams SI, Camphausen K, Liu K, Scott T, Coleman CN, Hodge JW (2003) Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy. J Immunol 170(12):6338–6347

    Article  PubMed  CAS  Google Scholar 

  64. Gasser S, Orsulic S, Brown EJ, Raulet DH (2005) The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436(7054):1186–1190. doi:10.1038/nature03884

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  65. Ohba K, Omagari K, Nakamura T, Ikuno N, Saeki S, Matsuo I, Kinoshita H, Masuda J, Hazama H, Sakamoto I, Kohno S (1998) Abscopal regression of hepatocellular carcinoma after radiotherapy for bone metastasis. Gut 43(4):575–577

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  66. Nam SW, Han JY, Kim JI, Park SH, Cho SH, Han NI, Yang JM, Kim JK, Choi SW, Lee YS, Chung KW, Sun HS (2005) Spontaneous regression of a large hepatocellular carcinoma with skull metastasis. J Gastroenterol Hepatol 20(3):488–492. doi:10.1111/j.1440-1746.2005.03243.x

    Article  PubMed  Google Scholar 

  67. Mole RH (1953) Whole body irradiation; radiobiology or medicine? Br J Radiol 26(305):234–241. doi:10.1259/0007-1285-26-305-234

    Article  PubMed  CAS  Google Scholar 

  68. Ishiyama H, Teh BS, Ren H, Chiang S, Tann A, Blanco AI, Paulino AC, Amato R (2012) Spontaneous regression of thoracic metastases while progression of brain metastases after stereotactic radiosurgery and stereotactic body radiotherapy for metastatic renal cell carcinoma: abscopal effect prevented by the blood-brain barrier? Clin Genitourin Cancer 10(3):196–198. doi:10.1016/j.clgc.2012.01.004

    Article  PubMed  Google Scholar 

  69. Rees GJ, Ross CM (1983) Abscopal regression following radiotherapy for adenocarcinoma. Br J Radiol 56(661):63–66. doi:10.1259/0007-1285-56-661-63

    Article  PubMed  CAS  Google Scholar 

  70. Boissonnas A, Fetler L, Zeelenberg IS, Hugues S, Amigorena S (2007) In vivo imaging of cytotoxic T cell infiltration and elimination of a solid tumor. J Exp Med 204(2):345–356. doi:10.1084/jem.20061890

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  71. Breart B, Lemaitre F, Celli S, Bousso P (2008) Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice. J Clin Invest 118(4):1390–1397. doi:10.1172/jci34388

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  72. Drake CG (2012) Combination immunotherapy approaches. Ann Oncol 23(Suppl 8):viii41–viii46. doi:10.1093/annonc/mds262

    Article  PubMed  Google Scholar 

  73. Kamrava M, Bernstein MB, Camphausen K, Hodge JW (2009) Combining radiation, immunotherapy, and antiangiogenesis agents in the management of cancer: the three musketeers or just another quixotic combination? Mol BioSyst 5(11):1262–1270. doi:10.1039/b911313b

    Article  PubMed  CAS  Google Scholar 

  74. Kwilas AR, Donahue RN, Bernstein MB, Hodge JW (2012) In the field: exploiting the untapped potential of immunogenic modulation by radiation in combination with immunotherapy for the treatment of cancer. Front Oncol 2:104. doi:10.3389/fonc.2012.00104

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  75. Sharma A, Bode B, Studer G, Moch H, Okoniewski M, Knuth A, von Boehmer L, van den Broek M (2013) Radiotherapy of human sarcoma promotes an intratumoral immune effector signature. Clin Cancer Res 19(17):4843–4853. doi:10.1158/1078-0432.ccr-13-0352

    Article  PubMed  CAS  Google Scholar 

  76. Eastham JA, Chen SH, Sehgal I, Yang G, Timme TL, Hall SJ, Woo SL, Thompson TC (1996) 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(4):515–523. doi:10.1089/hum.1996.7.4-515

    Article  PubMed  CAS  Google Scholar 

  77. Hall SJ, Mutchnik SE, Chen SH, Woo SL, Thompson TC (1997) 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(2):183–187

    Article  PubMed  CAS  Google Scholar 

  78. Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3(2):133–146. doi:10.1038/nri1001

    Article  PubMed  CAS  Google Scholar 

  79. Vatner RE, Cooper BT, Vanpouille-Box C, Demaria S, Formenti SC (2014) Combinations of immunotherapy and radiation in cancer therapy. Front Oncol 4:325. doi:10.3389/fonc.2014.00325

    Article  PubMed Central  PubMed  Google Scholar 

  80. Chambers CA, Kuhns MS, Egen JG, Allison JP (2001) CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 19:565–594. doi:10.1146/annurev.immunol.19.1.565

    Article  PubMed  CAS  Google Scholar 

  81. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. doi:10.1056/NEJMoa1200690

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  82. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369(2):134–144. doi:10.1056/NEJMoa1305133

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  83. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465. doi:10.1056/NEJMoa1200694

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  84. Hurwitz AA, Foster BA, Kwon ED, Truong T, Choi EM, Greenberg NM, Burg MB, Allison JP (2000) Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res 60(9):2444–2448

    PubMed  CAS  Google Scholar 

  85. 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. doi:10.1056/NEJMoa1001294

    Article  PubMed  CAS  Google Scholar 

  86. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, Scher HI, Chin K, Gagnier P, McHenry MB, Beer TM (2013) Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol 24(7):1813–1821. doi:10.1093/annonc/mdt107

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  87. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengelov L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR (2014) Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 15(7):700–712. doi:10.1016/s1470-2045(14)70189-5

    Article  PubMed Central  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

    Ying Huang

  2. Department of General Surgery, Guangdong General Hospital, Guangzhou, China

    Wei Chen

  3. Department of Radiation Oncology, Houston Methodist Hospital, 6565 Fannin, DB1-077, Houston, TX, 77030, USA

    Ying Huang, Wei Chen, Bin S. Teh & E. Brian Butler

Authors
  1. Ying Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bin S. Teh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Brian Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Brian Butler.

Ethics declarations

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Funding

This review article was not funded.

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Ying Huang and Wei Chen contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, Y., Chen, W., Teh, B.S. et al. Combining radiotherapy and immunotherapy for prostate cancer: two decades of research from preclinical to clinical trials. J Radiat Oncol 4, 365–375 (2015). https://doi.org/10.1007/s13566-015-0240-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13566-015-0240-5

Keywords

Search

Navigation