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The Immune System and Its Contribution to the Radiotherapeutic Response of Glioblastoma

  • Benjamin CooperEmail author
  • Ralph Vatner
  • Encouse Golden
  • Joshua Silverman
  • Silvia Formenti
Chapter
  • 640 Downloads
Part of the Current Clinical Pathology book series (CCPATH)

Abstract

The immune system plays an important role in both counteracting and facilitating cancer development, as well as contributing to the effects of standard cancer treatments. As such, the immune system is most certainly involved in the response of glioblastoma to radiotherapy; however, it is difficult to elucidate the specific role of immunity due to limitations in animal models and the difficulty in obtaining tissue to study molecular correlates of progression and response. Yet there is abundant evidence that leukocytes and other immune mediators recognize and respond to glioma cells, and indirect evidence that they participate in the therapeutic response to radiation. After a brief introduction on the role of the innate and adaptive immune response to cancer, we review the effects of radiotherapy on the anti-tumor immune response, including inflammation, T-cell priming, and immune suppression. We first introduce the concept of radiation induced immunogenic cell death, its application to the unique immunological landscape of the CNS, and present available evidence that radiation induces an immune response against glioblastoma. We then discuss some of the barriers of the brain/tumor microenvironment that may interfere with effective anti-tumor immunity, and conclude with suggested approaches to better harness the immune response in the treatment of glioblastoma with radiotherapy.

Keywords

Radiation Radiotherapy Immunotherapy Abscopal Vaccine Microenvironment Glioblastoma Brain tumor Immune system Blood–brain barrier Adoptive cell transfer 

References

  1. 1.
    Srivastava P. Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol. 2002;2(3):185–94.PubMedCrossRefGoogle Scholar
  2. 2.
    Pasi F, Paolini A. Effects of single or combined treatments with radiation and chemotherapy on survival and danger signals expression in glioblastoma cell lines. BioMed Res Int. 2014;2014:453497.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13(9):1050–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. 2003;425(6957):516–21.PubMedCrossRefGoogle Scholar
  5. 5.
    Coley II WB. Contribution to the knowledge of sarcoma. Ann Surg. 1891;14(3):199–220.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    De Bonis P, Albanese A, Lofrese G, de Waure C, Mangiola A, Pettorini BL, et al. Postoperative infection may influence survival in patients with glioblastoma: simply a myth? Neurosurgery. 2011;69(4):864–8; discussion 8–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21(2):137–48.PubMedCrossRefGoogle Scholar
  8. 8.
    Serraino D, Piselli P, Busnach G, Burra P, Citterio F, Arbustini E, et al. Risk of cancer following immunosuppression in organ transplant recipients and in HIV-positive individuals in southern Europe. Eur J Cancer. 2007;43(14):2117–23.PubMedCrossRefGoogle Scholar
  9. 9.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.PubMedCrossRefGoogle Scholar
  10. 10.
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22.PubMedCrossRefGoogle Scholar
  11. 11.
    Burnet M. Cancer; a biological approach. I. The processes of control. Br Med J. 1957;1(5022):779–86.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Gabrilovich D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol. 2004;4(12):941–52.PubMedCrossRefGoogle Scholar
  13. 13.
    Seliger B, Massa C. The dark side of dendritic cells: development and exploitation of tolerogenic activity that favor tumor outgrowth and immune escape. Front Immunol. 2013;4:419.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Bouquet F, Pal A, Pilones KA, Demaria S, Hann B, Akhurst RJ, et al. TGFbeta1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res. 2011;17(21):6754–65.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Sotomayor EM, Borrello I, Rattis FM, Cuenca AG, Abrams J, Staveley-O’Carroll K, et al. Cross-presentation of tumor antigens by bone marrow-derived antigen-presenting cells is the dominant mechanism in the induction of T-cell tolerance during B-cell lymphoma progression. Blood. 2001;98(4):1070–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Cuenca A, Cheng F, Wang H, Brayer J, Horna P, Gu L, et al. Extra-lymphatic solid tumor growth is not immunologically ignored and results in early induction of antigen-specific T-cell anergy: dominant role of cross-tolerance to tumor antigens. Cancer Res. 2003;63(24):9007–15.PubMedGoogle Scholar
  17. 17.
    Perrot I, Blanchard D, Freymond N, Isaac S, Guibert B, Pacheco Y, et al. Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage. J Immunol. 2007;178(5):2763–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Willimsky G, Blankenstein T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature. 2005;437(7055):141–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007;450(7171):903–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Zhong H, Gutkin DW, Han B, Ma Y, Keskinov AA, Shurin MR, et al. Origin and pharmacological modulation of tumor-associated regulatory dendritic cells. Int J Cancer. 2014;134(11):2633–45.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Gajewski TF, Meng Y, Blank C, Brown I, Kacha A, Kline J, et al. Immune resistance orchestrated by the tumor microenvironment. Immunol Rev. 2006;213:131–45.PubMedCrossRefGoogle Scholar
  23. 23.
    Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787–95.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Ostrand-Rosenberg S, Sinha P, Beury DW, Clements VK. Cross-talk between myeloid-derived suppressor cells (MDSC), macrophages, and dendritic cells enhances tumor-induced immune suppression. Semin Cancer Biol. 2012;22(4):275–81.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014–22.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 2004;64(16):5839–49.PubMedCrossRefGoogle Scholar
  27. 27.
    Rodriguez PC, Ochoa AC. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev. 2008;222:180–91.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12(4):253–68.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Medawar PB. Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol. 1948;29(1):58–69.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Xie L, Yang SH. Interaction of astrocytes and T cells in physiological and pathological conditions. Brain Res. 2015;1623:63–73.PubMedCrossRefGoogle Scholar
  31. 31.
    Arbab AS. Cytotoxic T-cells as imaging probes for detecting glioma. World J Clin Oncol. 2010;1(1):3–11.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Louveau A, et al. (2015). Structural and functional features of central nervous system lymphatic vessels. Nature 523(7560):337–341.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Goldmann J, Kwidzinski E, Brandt C, Mahlo J, Richter D, Bechmann I. T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J Leukoc Biol. 2006;80(4):797–801.PubMedCrossRefGoogle Scholar
  34. 34.
    Handel AE, Lincoln MR, Ramagopalan SV. Of mice and men: experimental autoimmune encephalitis and multiple sclerosis. Eur J Clin Invest. 2011;41(11):1254–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Pitroda SP, Zhou T, Sweis RF, Filippo M, Labay E, Beckett MA, et al. Tumor endothelial inflammation predicts clinical outcome in diverse human cancers. PLoS One. 2012;7(10), e46104.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Gousias K, Voulgaris S, Vartholomatos G, Voulgari P, Kyritsis AP, Markou M. Prognostic value of the preoperative immunological profile in patients with glioblastoma. Surg Neurol Int. 2014;5:89.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Choi BD, Gedeon PC, Sanchez-Perez L, Bigner DD, Sampson JH. Regulatory T cells are redirected to kill glioblastoma by an EGFRvIII-targeted bispecific antibody. Oncoimmunology. 2013;2(12), e26757.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Crane CA, Ahn BJ, Han SJ, Parsa AT. Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy. Neuro Oncol. 2012;14(5):584–95.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Yue Q, Zhang X, Ye HX, Wang Y, Du ZG, Yao Y, et al. The prognostic value of Foxp3+ tumor-infiltrating lymphocytes in patients with glioblastoma. J Neurooncol. 2014;116(2):251–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 2006;66(6):3294–302.PubMedCrossRefGoogle Scholar
  41. 41.
    Morford LA, Elliott LH, Carlson SL, Brooks WH, Roszman TL. T cell receptor-mediated signaling is defective in T cells obtained from patients with primary intracranial tumors. J Immunol. 1997;159(9):4415–25.PubMedGoogle Scholar
  42. 42.
    Zou JP, Morford LA, Chougnet C, Dix AR, Brooks AG, Torres N, et al. Human glioma-induced immunosuppression involves soluble factor(s) that alters monocyte cytokine profile and surface markers. J Immunol. 1999;162(8):4882–92.PubMedGoogle Scholar
  43. 43.
    Ogden AT, Horgan D, Waziri A, Anderson D, Louca J, McKhann GM, et al. Defective receptor expression and dendritic cell differentiation of monocytes in glioblastomas. Neurosurgery. 2006;59(4):902–9; discussion 9–10.PubMedCrossRefGoogle Scholar
  44. 44.
    Lampson LA, Hickey WF. Monoclonal antibody analysis of MHC expression in human brain biopsies: tissue ranging from “histologically normal” to that showing different levels of glial tumor involvement. J Immunol. 1986;136(11):4054–62.PubMedGoogle Scholar
  45. 45.
    Zagzag D, Salnikow K, Chiriboga L, Yee H, Lan L, Ali MA, et al. Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain. Lab Invest. 2005;85(3):328–41.PubMedCrossRefGoogle Scholar
  46. 46.
    Wintterle S, Schreiner B, Mitsdoerffer M, Schneider D, Chen L, Meyermann R, et al. Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res. 2003;63(21):7462–7.PubMedGoogle Scholar
  47. 47.
    Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wohrer A, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol. 2015;17:1064–75.PubMedCrossRefGoogle Scholar
  48. 48.
    Badie B, Schartner J, Klaver J, Vorpahl J. In vitro modulation of microglia motility by glioma cells is mediated by hepatocyte growth factor/scatter factor. Neurosurgery. 1999;44(5):1077–82; discussion 82–3.PubMedCrossRefGoogle Scholar
  49. 49.
    Coniglio SJ, Eugenin E, Dobrenis K, Stanley ER, West BL, Symons MH, et al. Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol Med. 2012;18:519–27.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Held-Feindt J, Hattermann K, Muerkoster SS, Wedderkopp H, Knerlich-Lukoschus F, Ungefroren H, et al. CX3CR1 promotes recruitment of human glioma-infiltrating microglia/macrophages (GIMs). Exp Cell Res. 2010;316(9):1553–66.PubMedCrossRefGoogle Scholar
  51. 51.
    Okada M, Saio M, Kito Y, Ohe N, Yano H, Yoshimura S, et al. Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1. Int J Oncol. 2009;34(6):1621–7.PubMedGoogle Scholar
  52. 52.
    Eibinger G, Fauler G, Bernhart E, Frank S, Hammer A, Wintersperger A, et al. On the role of 25-hydroxycholesterol synthesis by glioblastoma cell lines. Implications for chemotactic monocyte recruitment. Exp Cell Res. 2013;319(12):1828–38.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Jacobs VL, Liu Y, De Leo JA. Propentofylline targets TROY, a novel microglial signaling pathway. PLoS One. 2012;7(5), e37955.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Markovic DS, Vinnakota K, Chirasani S, Synowitz M, Raguet H, Stock K, et al. Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc Natl Acad Sci U S A. 2009;106(30):12530–5.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Munz C, Naumann U, Grimmel C, Rammensee HG, Weller M. TGF-beta-independent induction of immunogenicity by decorin gene transfer in human malignant glioma cells. Eur J Immunol. 1999;29(3):1032–40.PubMedCrossRefGoogle Scholar
  56. 56.
    Siepl C, Bodmer S, Frei K, MacDonald HR, De Martin R, Hofer E, et al. The glioblastoma-derived T cell suppressor factor/transforming growth factor-beta 2 inhibits T cell growth without affecting the interaction of interleukin 2 with its receptor. Eur J Immunol. 1988;18(4):593–600.PubMedCrossRefGoogle Scholar
  57. 57.
    Bodmer S, Strommer K, Frei K, Siepl C, de Tribolet N, Heid I, et al. Immunosuppression and transforming growth factor-beta in glioblastoma. Preferential production of transforming growth factor-beta 2. J Immunol. 1989;143(10):3222–9.PubMedGoogle Scholar
  58. 58.
    Schneider J, Hofman FM, Apuzzo ML, Hinton DR. Cytokines and immunoregulatory molecules in malignant glial neoplasms. J Neurosurg. 1992;77(2):265–73.PubMedCrossRefGoogle Scholar
  59. 59.
    Lichtor T, Libermann TA. Coexpression of interleukin-1 beta and interleukin-6 in human brain tumors. Neurosurgery. 1994;34(4):669–72; discussion 72–3.PubMedCrossRefGoogle Scholar
  60. 60.
    Huettner C, Paulus W, Roggendorf W. Messenger RNA expression of the immunosuppressive cytokine IL-10 in human gliomas. Am J Pathol. 1995;146(2):317–22.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Fontana A, Kristensen F, Dubs R, Gemsa D, Weber E. Production of prostaglandin E and an interleukin-1 like factor by cultured astrocytes and C6 glioma cells. J Immunol. 1982;129(6):2413–9.PubMedGoogle Scholar
  62. 62.
    Gondo T, Nakashima J, Ohno Y, Choichiro O, Horiguchi Y, Namiki K, et al. Prognostic value of neutrophil-to-lymphocyte ratio and establishment of novel preoperative risk stratification model in bladder cancer patients treated with radical cystectomy. Urology. 2012;79(5):1085–91.PubMedCrossRefGoogle Scholar
  63. 63.
    Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol. 2005;91(3):181–4.PubMedCrossRefGoogle Scholar
  64. 64.
    Keizman D, Gottfried M, Ish-Shalom M, Maimon N, Peer A, Neumann A, et al. Pretreatment neutrophil-to-lymphocyte ratio in metastatic castration-resistant prostate cancer patients treated with ketoconazole: association with outcome and predictive nomogram. Oncologist. 2012;17(12):1508–14.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Bambury RM, Teo MY, Power DG, Yusuf A, Murray S, Battley JE, et al. The association of pre-treatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme. J Neurooncol. 2013;114(1):149–54.PubMedCrossRefGoogle Scholar
  66. 66.
    Badie B, Schartner J. Role of microglia in glioma biology. Microsc Res Tech. 2001;54(2):106–13.PubMedCrossRefGoogle Scholar
  67. 67.
    Watters JJ, Schartner JM, Badie B. Microglia function in brain tumors. J Neurosci Res. 2005;81(3):447–55.PubMedCrossRefGoogle Scholar
  68. 68.
    Wesolowska A, Kwiatkowska A, Slomnicki L, Dembinski M, Master A, Sliwa M, et al. Microglia-derived TGF-beta as an important regulator of glioblastoma invasion—an inhibition of TGF-beta-dependent effects by shRNA against human TGF-beta type II receptor. Oncogene. 2008;27(7):918–30.PubMedCrossRefGoogle Scholar
  69. 69.
    Ye XZ, Xu SL, Xin YH, Yu SC, Ping YF, Chen L, et al. Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-beta1 signaling pathway. J Immunol. 2012;189(1):444–53.PubMedCrossRefGoogle Scholar
  70. 70.
    Hu F, Ku MC, Markovic D, ADzaye OD, Lehnardt S, Synowitz M, et al. Glioma-associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline. Int J Cancer. 2014;135(11):2569–78.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Rajaraman P, Brenner AV, Butler MA, Wang SS, Pfeiffer RM, Ruder AM, et al. Common variation in genes related to innate immunity and risk of adult glioma. Cancer Epidemiol Biomarkers Prev. 2009;18(5):1651–8.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Basu A, Krady JK, Levison SW. Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res. 2004;78(2):151–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Golden EB, Formenti SC. Is tumor (R)ejection by the immune system the “5th R” of radiobiology? Oncoimmunology. 2014;3(1), e28133.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013;105(4):256–65.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Golden EB, Formenti SC. Radiation therapy and immunotherapy: growing pains. Int J Radiat Oncol Biol Phys. 2015;91(2):252–4.PubMedCrossRefGoogle Scholar
  76. 76.
    Shohan J. Some theoretical considerations on the present status of roentgen therapy. Boston Med Surg J. 1916;175(10):321–7.CrossRefGoogle Scholar
  77. 77.
    Sellins KS, Cohen JJ. Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes. J Immunol. 1987;139(10):3199–206.PubMedGoogle Scholar
  78. 78.
    Weeke E. The development of lymphopenia in uremic patients undergoing extracorporeal irradiation of the blood with portable beta units. Radiat Res. 1973;56(3):554–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Yovino S, Kleinberg L, Grossman SA, Narayanan M, Ford E. The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells. Cancer Invest. 2013;31(2):140–4.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Brock CS, Newlands ES, Wedge SR, Bower M, Evans H, Colquhoun I, et al. Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res. 1998;58(19):4363–7.PubMedGoogle Scholar
  81. 81.
    Alvino E, Pepponi R, Pagani E, Lacal PM, Nunziata C, Bonmassar E, et al. O(6)-benzylguanine enhances the in vitro immunotoxic activity of temozolomide on natural or antigen-dependent immunity. J Pharmacol Exp Ther. 1999;291(3):1292–300.PubMedGoogle Scholar
  82. 82.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.PubMedCrossRefGoogle Scholar
  83. 83.
    Cifone MG, Migliorati G, Parroni R, Marchetti C, Millimaggi D, Santoni A, et al. Dexamethasone-induced thymocyte apoptosis: apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases. Blood. 1999;93(7):2282–96.PubMedGoogle Scholar
  84. 84.
    Cohen O, Ish-Shalom E, Kfir-Erenfeld S, Herr I, Yefenof E. Nitric oxide and glucocorticoids synergize in inducing apoptosis of CD4(+)8(+) thymocytes: implications for ‘Death by Neglect’ and T-cell function. Int Immunol. 2012;24(12):783–91.PubMedCrossRefGoogle Scholar
  85. 85.
    Herold MJ, McPherson KG, Reichardt HM. Glucocorticoids in T cell apoptosis and function. Cell Mol Life Sci. 2006;63(1):60–72.PubMedCrossRefGoogle Scholar
  86. 86.
    Schiff D. Pneumocystis pneumonia in brain tumor patients: risk factors and clinical features. J Neurooncol. 1996;27(3):235–40.PubMedCrossRefGoogle Scholar
  87. 87.
    Rubner Y, Muth C, Strnad A, Derer A, Sieber R, Buslei R, et al. Fractionated radiotherapy is the main stimulus for the induction of cell death and of Hsp70 release of p53 mutated glioblastoma cell lines. Radiat Oncol. 2014;9(1):89.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Shi Y, Rock KL. Cell death releases endogenous adjuvants that selectively enhance immune surveillance of particulate antigens. Eur J Immunol. 2002;32(1):155–62.PubMedCrossRefGoogle Scholar
  89. 89.
    Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin Radiat Oncol. 2015;25(1):11–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology. 2014;3, e28518.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Golden EB, Pellicciotta I, Demaria S, Barcellos-Hoff MH, Formenti SC. The convergence of radiation and immunogenic cell death signaling pathways. Fronti Oncol. 2012;2:88.Google Scholar
  92. 92.
    Paolini A, Pasi F, Facoetti A, Mazzini G, Corbella F, Di Liberto R, et al. Cell death forms and HSP70 expression in U87 cells after ionizing radiation and/or chemotherapy. Anticancer Res. 2011;31(11):3727–31.PubMedGoogle Scholar
  93. 93.
    Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114(3):589–95.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Lugade AA, Moran JP, Gerber SA, Rose RC, Frelinger JG, Lord EM. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol. 2005;174(12):7516–23.PubMedCrossRefGoogle Scholar
  95. 95.
    Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys. 2012;83(4):1306–10.PubMedCrossRefGoogle Scholar
  96. 96.
    Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15(17):5379–88.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Vom Berg J, Vrohlings M, Haller S, Haimovici A, Kulig P, Sledzinska A, et al. Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection. J Exp Med. 2013;210(13):2803–11.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86(2):343–9.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Newcomb EW, Lukyanov Y, Kawashima N, Alonso-Basanta M, Wang SC, Liu M, et al. Radiotherapy enhances antitumor effect of anti-CD137 therapy in a mouse Glioma model. Radiat Res. 2010;173(4):426–32.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Belcaid Z, Phallen JA, Zeng J, See AP, Mathios D, Gottschalk C, et al. 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. 2014;9(7), e101764.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Heisel SM, Ketter R, Keller A, Klein V, Pallasch CP, Lenhof HP, et al. Increased seroreactivity to glioma-expressed antigen 2 in brain tumor patients under radiation. PLoS One. 2008;3(5), e2164.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Pallasch CP, Struss AK, Munnia A, Konig J, Steudel WI, Fischer U, et al. Autoantibodies against GLEA2 and PHF3 in glioblastoma: tumor-associated autoantibodies correlated with prolonged survival. Int J Cancer. 2005;117(3):456–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Weidle UH, Georges G, Tiefenthaler G. TCR-MHC/peptide interaction: prospects for new anti-tumoral agents. Cancer Genomics Proteomics. 2014;11(6):267–77.PubMedGoogle Scholar
  104. 104.
    Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203(5):1259–71.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Newcomb EW, Demaria S, Lukyanov Y, Shao Y, Schnee T, Kawashima N, et al. The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas. Clin Cancer Res. 2006;12(15):4730–7.PubMedCrossRefGoogle Scholar
  106. 106.
    Ip NY. The neurotrophins and neuropoietic cytokines: two families of growth factors acting on neural and hematopoietic cells. Ann N Y Acad Sci. 1998;840:97–106.PubMedCrossRefGoogle Scholar
  107. 107.
    Lee WH, Sonntag WE, Mitschelen M, Yan H, Lee YW. Irradiation induces regionally specific alterations in pro-inflammatory environments in rat brain. Int J Radiat Biol. 2010;86(2):132–44.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Ross HJ, Canada AL, Antoniono RJ, Redpath JL. High and low dose rate irradiation have opposing effects on cytokine gene expression in human glioblastoma cell lines. Eur J Cancer. 1997;33(1):144–52.PubMedCrossRefGoogle Scholar
  109. 109.
    Chiang CS, McBride WH. Radiation enhances tumor necrosis factor alpha production by murine brain cells. Brain Res. 1991;566(1-2):265–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Gaber MW, Sabek OM, Fukatsu K, Wilcox HG, Kiani MF, Merchant TE. Differences in ICAM-1 and TNF-alpha expression between large single fraction and fractionated irradiation in mouse brain. Int J Radiat Biol. 2003;79(5):359–66.PubMedCrossRefGoogle Scholar
  111. 111.
    Vanpouille-Box C, Lacoeuille F, Belloche C, Lepareur N, Lemaire L, LeJeune JJ, et al. Tumor eradication in rat glioma and bypass of immunosuppressive barriers using internal radiation with (188)Re-lipid nanocapsules. Biomaterials. 2011;32(28):|6781–90.PubMedCrossRefGoogle Scholar
  112. 112.
    Zagzag D, Zhong H, Scalzitti JM, Laughner E, Simons JW, Semenza GL. Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. Cancer. 2000;88(11):2606–18.PubMedCrossRefGoogle Scholar
  113. 113.
    Sharma V, Dixit D, Koul N, Mehta VS, Sen E. Ras regulates interleukin-1beta-induced HIF-1alpha transcriptional activity in glioblastoma. J Mol Med. 2011;89(2):123–36.PubMedCrossRefGoogle Scholar
  114. 114.
    Barcellos-Hoff MH. Radiation-induced transforming growth factor beta and subsequent extracellular matrix reorganization in murine mammary gland. Cancer Res. 1993;53(17):3880–6.PubMedGoogle Scholar
  115. 115.
    Ehrhart EJ, Segarini P, Tsang ML, Carroll AG, Barcellos-Hoff MH. Latent transforming growth factor beta1 activation in situ: quantitative and functional evidence after low-dose gamma-irradiation. FASEB J. 1997;11(12):991–1002.PubMedGoogle Scholar
  116. 116.
    Wang J, Zheng H, Sung CC, Richter KK, Hauer-Jensen M. Cellular sources of transforming growth factor-beta isoforms in early and chronic radiation enteropathy. Am J Pathol. 1998;153(5):1531–40.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Satoh E, Naganuma H, Sasaki A, Nagasaka M, Ogata H, Nukui H. Effect of irradiation on transforming growth factor-beta secretion by malignant glioma cells. J Neurooncol. 1997;33(3):195–200.PubMedCrossRefGoogle Scholar
  118. 118.
    Kirshner J, Jobling MF, Pajares MJ, Ravani SA, Glick AB, Lavin MJ, et al. Inhibition of transforming growth factor-beta1 signaling attenuates ataxia telangiectasia mutated activity in response to genotoxic stress. Cancer Res. 2006;66(22):10861–9.PubMedCrossRefGoogle Scholar
  119. 119.
    Hardee ME, Marciscano AE, Medina-Ramirez CM, Zagzag D, Narayana A, Lonning SM, et al. Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-beta. Cancer Res. 2012;72(16):4119–29.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Desmarais G, Fortin D, Bujold R, Wagner R, Mathieu D, Paquette B. Infiltration of glioma cells in brain parenchyma stimulated by radiation in the F98/Fischer rat model. Int J Radiat Biol. 2012;88(8):565–74.PubMedCrossRefGoogle Scholar
  121. 121.
    Rubin LL, Staddon JM. The cell biology of the blood-brain barrier. Annu Rev Neurosci. 1999;22:11–28.PubMedCrossRefGoogle Scholar
  122. 122.
    Riccardi R, Riccardi A, Lasorella A, Servidei T, Mastrangelo S. Cranial irradiation and permeability of blood-brain barrier to cytosine arabinoside in children with acute leukemia. Clin Cancer Res. 1998;4(1):69–73.PubMedGoogle Scholar
  123. 123.
    Qin DX, Zheng R, Tang J, Li JX, Hu YH. Influence of radiation on the blood-brain barrier and optimum time of chemotherapy. Int J Radiat Oncol Biol Phys. 1990;19(6):1507–10.PubMedCrossRefGoogle Scholar
  124. 124.
    Badie B, Schartner JM. Flow cytometric characterization of tumor-associated macrophages in experimental gliomas. Neurosurgery. 2000;46(4):957–61. discussion 61-2.PubMedGoogle Scholar
  125. 125.
    Vatner RE, Formenti SC. Myeloid-derived cells in tumors: effects of radiation. Semin Radiat Oncol. 2015;25(1):18–27.PubMedCrossRefGoogle Scholar
  126. 126.
    Julow J, Szeifert GT, Balint K, Nyary I, Nemes Z. The role of microglia/macrophage system in the tissue response to I-125 interstitial brachytherapy of cerebral gliomas. Neurol Res. 2007;29(3):233–8.PubMedCrossRefGoogle Scholar
  127. 127.
    Mongiardi MP. Angiogenesis and hypoxia in glioblastoma: a focus on cancer stem cells. CNS Neurol Disord Drug Targets. 2012;11(7):878–83.PubMedCrossRefGoogle Scholar
  128. 128.
    Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst. 1990;82(1):4–6.PubMedCrossRefGoogle Scholar
  129. 129.
    Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376(6535):62–6.PubMedCrossRefGoogle Scholar
  130. 130.
    Kerber M, Reiss Y, Wickersheim A, Jugold M, Kiessling F, Heil M, et al. Flt-1 signaling in macrophages promotes glioma growth in vivo. Cancer Res. 2008;68(18):7342–51.PubMedCrossRefGoogle Scholar
  131. 131.
    Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest. 2010;120(3):694–705.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Ahn GO, Brown JM. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell. 2008;13(3):193–205.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Jin DK, Shido K, Kopp HG, Petit I, Shmelkov SV, Young LM, et al. Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes. Nat Med. 2006;12(5):557–67.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Formenti SC, Demaria S. Radiation therapy to convert the tumor into an in situ vaccine. Int J Radiat Oncol Biol Phys. 2012;84(4):879–80.PubMedCrossRefGoogle Scholar
  135. 135.
    Demaria S, Formenti SC. Radiotherapy effects on anti-tumor immunity: implications for cancer treatment. Front Oncol. 2013;3:128.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Talmadge JE, Adams J, Phillips H, Collins M, Lenz B, Schneider M, et al. Immunomodulatory effects in mice of polyinosinic-polycytidylic acid complexed with poly-L-lysine and carboxymethylcellulose. Cancer Res. 1985;45(3):1058–65.PubMedGoogle Scholar
  137. 137.
    Levy HB, Lvovsky E, Riley F, Harrington D, Anderson A, Moe J, et al. Immune modulating effects of poly ICLC. Ann N Y Acad Sci. 1980;350:33–41.PubMedCrossRefGoogle Scholar
  138. 138.
    Hubbell HR, Liu RS, Maxwell BL. Independent sensitivity of human tumor cell lines to interferon and double-stranded RNA. Cancer Res. 1984;44(8):3252–7.PubMedGoogle Scholar
  139. 139.
    Dick RS, Hubbell HR. Sensitivities of human glioma cell lines to interferons and double-stranded RNAs individually and in synergistic combinations. J Neurooncol. 1987;5(4):331–8.PubMedCrossRefGoogle Scholar
  140. 140.
    Strayer DR, Weisband J, Carter WA, Black P, Nidzgorski F, Cook AW. Growth of astrocytomas in the human tumor clonogenic assay and sensitivity to mismatched dsRNA and interferons. Am J Clin Oncol. 1987;10(4):281–4.PubMedCrossRefGoogle Scholar
  141. 141.
    Butowski N, Chang SM, Junck L, DeAngelis LM, Abrey L, Fink K, et al. A phase II clinical trial of poly-ICLC with radiation for adult patients with newly diagnosed supratentorial glioblastoma: a North American Brain Tumor Consortium (NABTC01-05). J Neurooncol. 2009;91(2):175–82.PubMedCrossRefGoogle Scholar
  142. 142.
    Maus MV, Fraietta JA, Levine BL, Kalos M, Zhao Y, June CH. Adoptive immunotherapy for cancer or viruses. Annu Rev Immunol. 2014;32:189–225.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Plautz GE, Barnett GH, Miller DW, Cohen BH, Prayson RA, Krauss JC, et al. Systemic T cell adoptive immunotherapy of malignant gliomas. J Neurosurg. 1998;89(1):42–51.PubMedCrossRefGoogle Scholar
  144. 144.
    Plautz GE, Miller DW, Barnett GH, Stevens GH, Maffett S, Kim J, et al. T cell adoptive immunotherapy of newly diagnosed gliomas. Clin Cancer Res. 2000;6(6):2209–18.PubMedGoogle Scholar
  145. 145.
    Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan TE, et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol. 2011;29(3):330–6.PubMedCrossRefGoogle Scholar
  146. 146.
    Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H, Nuno MA, et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother. 2013;62(1):125–35.PubMedCrossRefGoogle Scholar
  147. 147.
    Wen PY, Reardon DA, Phuphanich S, Aiken R, Landolfi JC, Curry WT, Zhu JJ, Glantz MJ, Peereboom DM, Markert J, LaRocca RV, O’Rourke D, Fink KL, Kim LJ, Gruber ML, Lesser GJ, Pan E, Kesari S, Hawkins ES, Yu J. A randomized, double-blind, placebocontrolled phase 2 trial of dendritic cell (DC) vaccination with ICT-107 in newly diagnosed glioblastoma (GBM) patients. J Clin Oncol. 2014;32:5s.CrossRefGoogle Scholar
  148. 148.
    Frederick L, Wang XY, Eley G, James CD. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res. 2000;60(5):1383–7.PubMedGoogle Scholar
  149. 149.
    Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon 2nd JE, Lally-Goss D, et al. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther. 2009;8(10):2773–9.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, et al. 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. 2010;28(31):4722–9.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2011;13(3):324–33.PubMedCrossRefGoogle Scholar
  152. 152.
    Yu JS, Wheeler CJ, Zeltzer PM, Ying H, Finger DN, Lee PK, et al. Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res. 2001;61(3):842–7.PubMedGoogle Scholar
  153. 153.
    Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res. 2004;64(14):4973–9.PubMedCrossRefGoogle Scholar
  154. 154.
    Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, Giovannone AJ, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005;11(15):5515–25.PubMedCrossRefGoogle Scholar
  155. 155.
    Yamanaka R, Homma J, Yajima N, Tsuchiya N, Sano M, Kobayashi T, et al. Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin Cancer Res. 2005;11(11):4160–7.PubMedCrossRefGoogle Scholar
  156. 156.
    De Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, Goffin J, et al. Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res. 2008;14(10):3098–104.PubMedCrossRefGoogle Scholar
  157. 157.
    Wheeler CJ, Black KL, Liu G, Mazer M, Zhang XX, Pepkowitz S, et al. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res. 2008;68(14):5955–64.PubMedCrossRefGoogle Scholar
  158. 158.
    Ardon H, Van Gool S, Lopes IS, Maes W, Sciot R, Wilms G, et al. Integration of autologous dendritic cell-based immunotherapy in the primary treatment for patients with newly diagnosed glioblastoma multiforme: a pilot study. J Neurooncol. 2010;99(2):261–72.PubMedCrossRefGoogle Scholar
  159. 159.
    Fadul CE, Fisher JL, Hampton TH, Lallana EC, Li Z, Gui J, et al. Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy. J Immunother. 2011;34(4):382–9.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, Yong WH, et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res. 2011;17(6):1603–15.PubMedCrossRefGoogle Scholar
  161. 161.
    Ardon H, Van Gool SW, Verschuere T, Maes W, Fieuws S, Sciot R, et al. Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial. Cancer Immunol Immunother. 2012;61(11):2033–44.PubMedCrossRefGoogle Scholar
  162. 162.
    Prins RM, Wang X, Soto H, Young E, Lisiero DN, Fong B, et al. Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients. J Immunother. 2013;36(2):152–7.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Cho DY, Yang WK, Lee HC, Hsu DM, Lin HL, Lin SZ, et al. Adjuvant immunotherapy with whole-cell lysate dendritic cells vaccine for glioblastoma multiforme: a phase II clinical trial. World Neurosurg. 2012;77(5–6):736–44.PubMedCrossRefGoogle Scholar
  164. 164.
    Binder RJ, Han DK, Srivastava PK. CD91: a receptor for heat shock protein gp96. Nat Immunol. 2000;1(2):151–5.PubMedCrossRefGoogle Scholar
  165. 165.
    Crane CA, Han SJ, Ahn B, Oehlke J, Kivett V, Fedoroff A, et al. Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein. Clin Cancer Res. 2013;19(1):205–14.PubMedCrossRefGoogle Scholar
  166. 166.
    Bloch O, Crane CA, Fuks Y, Kaur R, Aghi MK, Berger MS, et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol. 2014;16(2):274–9.PubMedCrossRefGoogle Scholar
  167. 167.
    Vik-Mo EO, Nyakas M, Mikkelsen BV, Moe MC, Due-Tonnesen P, Suso EM, et al. Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma. Cancer Immunol Immunother. 2013;62(9):1499–509.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Benjamin Cooper
    • 1
    Email author
  • Ralph Vatner
    • 1
  • Encouse Golden
    • 1
  • Joshua Silverman
    • 1
  • Silvia Formenti
    • 1
  1. 1.Radiation OncologyNYU Langone Medical CenterNew YorkUSA

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