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Immunotherapy and radiation in glioblastoma

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Abstract

Radiation therapy plays a central role in the management of glioblastoma. Although primarily thought of as modality to provide local tumor control through DNA damage, the capacity of ionizing radiation to modulate tumor immune response has long been recognized. The recent emergence of clinically active immunotherapies offers exciting potential for harnessing the immune modulatory effects or radiation through combinatorial strategies designed to enhance clinical outcomes. In this Review, we provide background describing the unique immune environment within the central nervous system, how ionizing radiation may modulate the tumor immune response, preclinical and clinical data testing the combination of radiation and immune modulating agents, and highlight some of the current challenges in extending these findings clinically.

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References

  1. Klein G, Sjogren HO, Klein E, Hellstrom KE (1960) Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res 20:1561–1572

    CAS  PubMed  Google Scholar 

  2. Prehn RT, Main JM (1957) Immunity to methylcholanthrene-induced sarcomas. J Natl Cancer Inst 18:769–778

    CAS  PubMed  Google Scholar 

  3. Burnet M (1957) Cancer; a biological approach. I. The processes of control. Br Med J 1:779–786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Boon T, Kellermann O (1977) Rejection by syngeneic mice of cell variants obtained by mutagenesis of a malignant teratocarcinoma cell line. Proc Natl Acad Sci USA 74:272–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Uyttenhove C, Snick JV, Boon T (1980) Immunogenic variants obtained by mutagenesis of mouse mastocytoma P815. I. Rejection by syngeneic mice. J Exp Med 152:1175–1183

    Article  CAS  PubMed  Google Scholar 

  6. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ et al (2015) Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science 348:124–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK et al (2016) Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351:1463–1469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  9. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L et al (2015) Pembrolizumab versus Ipilimumab in advanced melanoma. N Engl J Med 372:2521–2532

    Article  CAS  PubMed  Google Scholar 

  10. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S et al (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197–203

    Article  CAS  PubMed  Google Scholar 

  11. Wainwright DA, Balyasnikova IV, Chang AL, Ahmed AU, Moon K-S, Auffinger B et al (2012) IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res 18:6110–6121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B et al (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281:1191–1193

    Article  CAS  PubMed  Google Scholar 

  13. Perry VH (1998) A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation. J Neuroimmunol 90:113–121

    Article  CAS  PubMed  Google Scholar 

  14. Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M et al (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212:991–999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Louveau A, Harris TH, Kipnis J (2015) Revisiting the mechanisms of CNS immune privilege. Trends Immunol 36:569–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cohen JV, Alomari AK, Vortmeyer AO, Jilaveanu LB, Goldberg SB, Mahajan A et al (2015) Melanoma brain metastasis pseudoprogression after pembrolizumab treatment. Cancer Immunol Res 4(3):1–4

    Google Scholar 

  17. Okada H, Weller M, Huang R, Finocchiaro G, Gilbert MR, Wick W et al (2015) Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol 16:e534–e542

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rempel SA, Dudas S, Ge S, Gutiérrez JA (2000) Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 6:102–111

    CAS  PubMed  Google Scholar 

  19. Ludwig A, Schulte A, Schnack C, Hundhausen C, Reiss K, Brodway N et al (2005) Enhanced expression and shedding of the transmembrane chemokine CXCL16 by reactive astrocytes and glioma cells. J Neurochem 93:1293–1303

    Article  CAS  PubMed  Google Scholar 

  20. Chow KKH, Naik S, Kakarla S, Brawley VS, Shaffer DR, Yi Z et al (2013) T cells redirected to EphA2 for the immunotherapy of glioblastoma. Mol Ther 21:629–637

    Article  CAS  PubMed  Google Scholar 

  21. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS et al (2010) Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 28:4722–4729

    Article  PubMed  PubMed Central  Google Scholar 

  22. Weller M, Butowski N, Tran D, Recht L, Lim M, Hirte H, et al (2016) ATIM-03. ACT IV: an international, double-Blind, Phase 3 trial of rindopepimut in newly diagnosed, EGFR vIII-expressing glioblastoma. Neuro Oncol 18:vi17–vi18

    Article  Google Scholar 

  23. Gromeier M, Lachmann S, Rosenfeld MR, Gutin PH, Wimmer E (2000) Intergeneric poliovirus recombinants for the treatment of malignant glioma. Proc Natl Acad Sci USA 97:6803–6808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sharabi AB, Lim M, DeWeese TL, Drake CG. (2015) Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol 16:e498–e509

    Article  PubMed  Google Scholar 

  25. Gameiro SR, Jammeh ML, Wattenberg MM, Tsang KY, Ferrone S, Hodge JW (2014) Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget 5:403–416

    Article  PubMed  Google Scholar 

  26. Rovere-Querini P, Capobianco A, Scaffidi P, Valentinis B, Catalanotti F, Giazzon M et al (2004) HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep 5:825–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sharabi AB, Nirschl CJ, Kochel CM, Nirschl TR, Francica BJ, Velarde E, et al (2015) Stereotactic radiation therapy augments antigen-specific PD-1–mediated antitumor immune responses via cross-presentation of tumor antigen. Cancer Immunol Res 3:345–355

    Article  CAS  PubMed  Google Scholar 

  28. Bernstein MB, Garnett CT, Zhang H, Velcich A, Wattenberg MM, Gameiro SR et al (2014) Radiation-induced modulation of costimulatory and coinhibitory T-cell signaling molecules on human prostate carcinoma cells promotes productive antitumor immune interactions. Cancer Biother Radiopharm 29:153–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hauser SH, Calorini L, Wazer DE, Gattoni-Celli S (1993) Radiation-enhanced expression of major histocompatibility complex class I antigen H-2Db in B16 melanoma cells. Cancer Res 53:1952–1955

    CAS  PubMed  Google Scholar 

  30. Garnett CT, Palena C, Chakarborty M, Tsang K-Y, Schlom J, Hodge JW (2004) Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res 64:7985–7994

    Article  CAS  PubMed  Google Scholar 

  31. Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK et al (2006) Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 203:1259–1271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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 170:6338–6347

    Article  CAS  PubMed  Google Scholar 

  33. Slone HB, Peters LJ, Milas L (1979) Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma. J Natl Cancer Inst 63:1229–1235

    Google Scholar 

  34. Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y et al (2009) Therapeutic effects of ablative radiation on local tumor require CD8 + T cells: changing strategies for cancer treatment. Blood 114:589–595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR et al (2011) The efficacy of radiotherapy relies upon induction of type I interferon–dependent innate and adaptive immunity. Cancer Res 71:2488–2496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Friedman EJ (2002) Immune modulation by ionizing radiation and its implications for cancer immunotherapy. Curr Pharm Des 8:1765–1780

    Article  CAS  PubMed  Google Scholar 

  37. Drake C (2011) Radiation induced immune modulation. In: DeWeese TL, Laiho M (eds) Molecular determinants of radiation response. Springer, New York, pp 251–263

    Chapter  Google Scholar 

  38. Formenti SC, Demaria S (2013) Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst 105:256–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J et al (2013) Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol* Biol* Phys 86:343–349

    Article  CAS  Google Scholar 

  40. Demaria S, Pilones KA, Vanpouille-Box C, Golden EB, Formenti SC (2014) The optimal partnership of radiation and immunotherapy: from preclinical studies to clinical translation. Radiat Res 182:170–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Belcaid Z, Phallen JA, Zeng J, See AP, Mathios D, Gottschalk C et al (2014) Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model. PLoS ONE 9:e101764

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kim JE, Patel MA, Mangraviti A, Kim ES, Theodros D, Velarde E et al (2017) Combination therapy with anti-PD-1, anti-TIM-3, and focal radiation results in regression of murine gliomas. Clin Cancer Res 23:124–136

    Article  CAS  PubMed  Google Scholar 

  43. Patel MA, Kim JE, Theodros D, Tam A, Velarde E, Kochel CM et al (2016) Agonist anti-GITR monoclonal antibody and stereotactic radiation induce immune-mediated survival advantage in murine intracranial glioma. J Immunother Cancer 4:28

    Article  PubMed  PubMed Central  Google Scholar 

  44. Nelson MH, Bowers JS, Bailey SR, Diven MA, Fugle CW, Kaiser AD et al (2016) Toll-like receptor agonist therapy can profoundly augment the antitumor activity of adoptively transferred CD8 + T cells without host preconditioning. J Immunother Cancer 4:6

    Article  PubMed  PubMed Central  Google Scholar 

  45. Wen P, Reardon D, Phuphanich S, Aiken R, Landolfi J, Curry W et al (2015) IMCT-20 association of survival and progression-free survival with immune response in HLA-A2 + newly-diagnosed GBM patients in randomized double-blind placebo-controlled phase 2 trial of dendritic cell (dc) immunotherapy with ICT-107. Neuro Oncol 17:v112

    Article  PubMed Central  Google Scholar 

  46. Schuster J, Lai RK, Recht LD, Reardon DA, Paleologos NA, Groves MD et al (2015) A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol 17:854–861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Reardon DA, Schuster JM, Tran DD, Fink KL, Nabors LB, Li G et al (2015) ReACT: overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. Neurosurgery 62:198–199

    Article  Google Scholar 

  48. Ahmed N, Brawley V, Hegde M, Bielamowicz K, Wakefield A, Ghazi A et al (2015) Autologous HER2 CMV bispecific CAR T cells are safe and demonstrate clinical benefit for glioblastoma in a Phase I trial. J Immunother Cancer 3:O11

    Article  PubMed Central  Google Scholar 

  49. Nduom EK, Wei J, Yaghi NK, Huang N, Kong L-Y, Gabrusiewicz K et al (2016) PD-L1 expression and prognostic impact in glioblastoma. Neuro Oncol 18:195–205

    Article  PubMed  Google Scholar 

  50. Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wöhrer A et al (2015) Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol 17:1064–1075

    Article  PubMed  Google Scholar 

  51. Reardon DA, Sampson JH, Sahebjam S, Lim M, Baehring JM, Vlahovic G et al (2016) Safety and activity of nivolumab (nivo) monotherapy and nivo in combination with ipilimumab (ipi) in recurrent glioblastoma (GBM): updated results from checkmate-143. J Clin Oncol 34

  52. Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, Formenti SC (2005) Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 11:728–734

    CAS  PubMed  Google Scholar 

  53. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, Fu Y-X (2014) Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124:687–695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. (2013) An abscopal response to radiation and ipilimumab in a patient with metastatic non–small cell lung cancer. Cancer Immunol Res 1:365–372

    Article  PubMed  PubMed Central  Google Scholar 

  55. Papadopoulos, K, M Crittenden, ML Johnson, AC Lockhart, KN Moore, GS Falchook, S Formenti et al (2016) A first-in-human study of REGN2810, a monoclonal, fully human antibody to programmed death-1 (PD-1), in combination with immunomodulators including hypofractionated radiotherapy (hfrt). ASCO Meet Abstr 34:3024

    Google Scholar 

  56. Sahebjam S, Johnstone PA, Forsyth PA, Arrington J, Vrionis FD, Etame AB et al (2016) Safety and antitumor activity of hypofractionated stereotactic irradiation (HFSRT) with pembrolizumab (Pembro) and bevacizumab (Bev) in patients (pts) with recurrent high grade gliomas: Preliminary results from phase I study. ASCO Meet Abstr 34:2041

    Google Scholar 

  57. Grossman SA, Ye X, Lesser G, Sloan A, Carraway H, Desideri S, Piantadosi S (2011) Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res 17:5473–5480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Campian JL, Ye X, Gladstone DE, Ambady P, Nirschl TR, Borrello I et al (2015) Pre-radiation lymphocyte harvesting and post-radiation reinfusion in patients with newly diagnosed high grade gliomas. J Neurooncol 124:307–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Huang J, DeWees TA, Badiyan SN, Speirs CK, Mullen DF, Fergus S et al (2015) Clinical and dosimetric predictors of acute severe lymphopenia during radiation therapy and concurrent temozolomide for high-grade glioma. Int J Radiat Oncol Biol Phys 92:1000–1007

    Article  CAS  Google Scholar 

  60. Yovino S, Grossman SA (2012) Severity, etiology and possible consequences of treatment-related lymphopenia in patients with newly diagnosed high-grade gliomas. CNS Oncol 1:149–154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Razzaghdoust A, Mozdarani H, Mofid B, Aghamiri SMR, Heidari AH (2014) Reduction in radiation-induced lymphocytopenia by famotidine in patients undergoing radiotherapy for prostate cancer. Prostate 74:41–47

    Article  CAS  PubMed  Google Scholar 

  62. Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH et al (2011) Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol 13:324–333

    Article  CAS  PubMed  Google Scholar 

  63. Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M et al (2012) Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 13:707–715

    Article  CAS  PubMed  Google Scholar 

  64. Baumert BG, Hegi ME, van den Bent MJ, von Deimling A, Gorlia T, Hoang-Xuan K et al (2016) Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033–26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol 17:1521–1532

    Article  CAS  PubMed  Google Scholar 

  65. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ (2008) Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9:453–461

    Article  PubMed  Google Scholar 

  66. Shultz LD, Goodwin N, Ishikawa F, Hosur V, Lyons BL, Greiner DL (2014) Human cancer growth and therapy in immunodeficient mouse models. Cold Spring Harb Protoc 7:694–708

    Google Scholar 

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Authors and Affiliations

  1. Neuro Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    Solmaz Sahebjam

  2. Radiation Medicine & Applied Sciences, University of California at San Diego, San Diego, CA, USA

    Andrew Sharabi

  3. Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Michael Lim

  4. Radiation Oncology, Oakland University William Beaumont School of Medicine, Royak Oak, MI, USA

    Pravin Kesarwani & Prakash Chinnaiyan

  5. Radiation Oncology Research (105-RI), Suite 507, Beaumont Health System, 3811 West Thirteen Mile Road, Royal Oak, MI, 48073, USA

    Prakash Chinnaiyan

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Correspondence to Prakash Chinnaiyan.

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Sahebjam, S., Sharabi, A., Lim, M. et al. Immunotherapy and radiation in glioblastoma. J Neurooncol 134, 531–539 (2017). https://doi.org/10.1007/s11060-017-2413-0

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