Journal of Neuro-Oncology

, Volume 123, Issue 3, pp 459–464 | Cite as

Combining immunotherapy with radiation for the treatment of glioblastoma

  • Kevin K. H. Chow
  • Wendy Hara
  • Michael Lim
  • Gordon Li
Editors' Invited Manuscript


Glioblastoma is a devastating cancer with universally poor outcomes in spite of current standard multimodal therapy. Immunotherapy is an attractive new treatment modality given its potential for exquisite specificity and its favorable side effect profile; however, clinical trials of immunotherapy in GBM have thus far shown modest benefit. Optimally combining radiation with immunotherapy may be the key to unlocking the potential of both therapies given the evidence that radiation can enhance anti-tumor immunity. Here we review this evidence and discuss considerations for combined therapy.


Glioblastoma Immunotherapy Radiation therapy Immunosuppression 


Conflict of interest

None of the authors have any conflicts of interest to disclose.


  1. 1.
    Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  2. 2.
    Xu LW, Chow KKH, Lim M, Li G (2014) Current vaccine trials in glioblastoma: a review. J Immunol Res 2014:796856PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Chow KH, Gottschalk S (2011) Cellular immunotherapy for high-grade glioma. Immunotherapy 3:423–434PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Heimberger AB, Sun W, Hussain SF et al (2008) Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: case study. Neuro Oncol 10:98–103PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Patel MA, Kim JE, Ruzevick J, Li G, Lim M (2014) The future of glioblastoma therapy: synergism of standard of care and immunotherapy. Cancers (Basel) 6:1953–1985CrossRefGoogle Scholar
  6. 6.
    Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, Fu Y-X, Auh SL (2011) The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res 71:2488–2496PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Reits EA, Hodge JW, Herberts CA et al (2006) Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 203:1259–1271PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Nicholas S, Mathios D, Ruzevick J, Jackson C, Yang I, Lim M (2013) Current trends in glioblastoma multiforme treatment: radiation therapy and immune checkpoint inhibitors. Brain Tumor Res Treat 1:2–8PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Waziri A (2010) Glioblastoma-derived mechanisms of systemic immunosuppression. Neurosurg Clin N Am 21:31–42PubMedCrossRefGoogle Scholar
  10. 10.
    Jackson C, Ruzevick J, Phallen J, Belcaid Z, Lim M (2011) Challenges in immunotherapy presented by the glioblastoma multiforme microenvironment. Clin Dev Immunol 2011:732413PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Liu G, Ying H, Zeng G, Wheeler C, Black K, John S (2004) HER-2, gp100, and MAGE-1 are expressed in human glioblastoma and recognized by cytotoxic T cells. Cancer Res 64:4980–4986PubMedCrossRefGoogle Scholar
  12. 12.
    Saikali S, Avril T, Collet B, Hamlat A, Bansard J-Y, Drenou B, Guegan Y, Quillien V (2007) Expression of nine tumour antigens in a series of human glioblastoma multiforme: interest of EGFRvIII, IL-13Ralpha2, gp100 and TRP-2 for immunotherapy. J Neurooncol 81:139–148PubMedCrossRefGoogle Scholar
  13. 13.
    Camara-Quintana JQ, Nitta RT, Li G (2012) Pathology: commonly monitored glioblastoma markers: EFGR, EGFRvIII, PTEN, and MGMT. Neurosurg Clin N Am 23:237–246PubMedCrossRefGoogle Scholar
  14. 14.
    Chow KKH, Naik S, Kakarla S et al (2013) T cells redirected to EphA2 for the immunotherapy of glioblastoma. Mol Ther 21:629–637PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Didenko VV, Ngo HN, Minchew C, Baskin DS (2002) Apoptosis of T lymphocytes invading glioblastomas multiforme: a possible tumor defense mechanism. J Neurosurg 96:580–584PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Ichinose M, Masuoka J, Shiraishi T, Mineta T, Tabuchi K (2001) Fas ligand expression and depletion of T-cell infiltration in astrocytic tumors. Brain Tumor Pathol 18:37–42PubMedCrossRefGoogle Scholar
  17. 17.
    Saas P, Walker PR, Hahne M et al (1997) Fas ligand expression by astrocytoma in vivo : Maintaining immune privilege in the brain? J Clin Invest 99:1173–1178PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Wintterle S, Schreiner B, Mitsdoerffer M, Schneider D, Chen L, Meyermann R, Weller M, Wiendl H (2003) Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res 63:7462–7467PubMedGoogle Scholar
  19. 19.
    Parsa AT, Waldron JS, Panner A et al (2007) Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13:84–88PubMedCrossRefGoogle Scholar
  20. 20.
    Dunn GP, Dunn IF, Curry WT (2007) Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human glioma. Cancer Immun 7:12PubMedCentralPubMedGoogle Scholar
  21. 21.
    Fontana A, Hengartner H, de Tribolet N, Weber E (1984) Glioblastoma cells release interleukin 1 and factors inhibiting interleukin 2-mediated effects. J Immunol 132:1837–1844PubMedGoogle Scholar
  22. 22.
    Bodmer S, Strommer K, Frei K, Siepl C, de Tribolet N, Heid I, Fontana A (1989) Immunosuppression and transforming growth factor-beta in glioblastoma. Preferential production of transforming growth factor-beta 2. J Immunol 143:3222–3229PubMedGoogle Scholar
  23. 23.
    Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, Herndon JE, Bigner DD, Dranoff G, Sampson JH (2006) Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 66:3294–3302PubMedCrossRefGoogle Scholar
  24. 24.
    El Andaloussi A, Lesniak MS (2006) An increase in CD4+ CD25+ FOXP3+ regulatory T cells in tumor-infiltrating lymphocytes of human glioblastoma multiforme. Neuro Oncol 8:234–243PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Crane CA, Han SJ, Barry JJ, Ahn BJ, Lanier LL, Parsa AT (2010) TGF-b downregulates the activating receptor NKG2D on NK cells and CD8 + T cells in glioma patients. Neuro Oncol 12:7–13PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Walker M, Green S, Byar D et al (1980) Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303:1323–1329PubMedCrossRefGoogle Scholar
  27. 27.
    Walker M, Alexander E Jr, Hunt W et al (1978) Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial. J Neurosurg 49:333–343PubMedCrossRefGoogle Scholar
  28. 28.
    Coffey R, Lunsford D, Taylor F (1988) Survival after stereotactic biopsy of malignant gliomas. Neurosurgery 22:465–473PubMedCrossRefGoogle Scholar
  29. 29.
    Chang C, Horton J, Schoenfeld D, Salazer O, Perez-Tamayo R, Kramer S, Weinstein A, Nelson J, Tsukada Y (1983) Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas: a joint radiation therapy oncology group and eastern cooperative oncology group study. Cancer 52:997–1007PubMedCrossRefGoogle Scholar
  30. 30.
    Wallner K, Galicich J, Krol G, Arbit E, Malkin M (1989) Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16:1405–1409PubMedCrossRefGoogle Scholar
  31. 31.
    Choucair A, Levin V, Gutin P, Davis R, Silver P, Edwards M, Wilson C (1986) Development of multiple lesions during radiation therapy and chemotherapy in patients with gliomas. J Neurosurg 65:654–658PubMedCrossRefGoogle Scholar
  32. 32.
    Narayana A, Yamada J, Berry S, Shah P, Hunt M, Gutin PH, Leibel SA (2006) Intensity-modulated radiotherapy in high-grade gliomas: clinical and dosimetric results. Int J Radiat Oncol Biol Phys 64:892–897PubMedCrossRefGoogle Scholar
  33. 33.
    Chan J, Lee S, Fraass B, Normolle D, Greenberg H, Junck L, Gebarski S, Sandler H (2002) Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. J Clin Oncol 20:1635–1642PubMedCrossRefGoogle Scholar
  34. 34.
    Souhami L, Seiferheld W, Brachman D et al (2004) Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 60:853–860PubMedCrossRefGoogle Scholar
  35. 35.
    Klein B, Loven D, Lurie H, Rakowsky E, Nyska A, Levin I, Klein T (1994) The effect of irradiation on expression of HLA class I antigens in human brain tumors in culture. J Neurosurg 80:1074–1077PubMedCrossRefGoogle Scholar
  36. 36.
    Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM (2008) Radiation-Induced IFN-production within the tumor microenvironment influences antitumor immunity. J Immunol 180:3132–3139PubMedCrossRefGoogle Scholar
  37. 37.
    Garnett CT, Palena C, Chakarborty M, Tsang K, Schlom J, Hodge JW (2004) Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res 64:7985–7994PubMedCrossRefGoogle Scholar
  38. 38.
    Kim J-Y, Son Y-O, Park S-W, Bae J-H, Chung JS, Kim HH, Chung B-S, Kim S-H, Kang C-D (2006) Increase of NKG2D ligands and sensitivity to NK cell-mediated cytotoxicity of tumor cells by heat shock and ionizing radiation. Exp Mol Med 38:474–484PubMedCrossRefGoogle Scholar
  39. 39.
    Chakraborty M, Abrams S, Norman Coleman C, Camphausen K, Schlom J, Hodge J (2004) External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res 64:4328–4337PubMedCrossRefGoogle Scholar
  40. 40.
    Lee Y, Auh SL, Wang Y et al (2009) Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114:589–595PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Postow MA, Callahan MK, Barker CA et al (2012) Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366:925–931PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Robin HI, AuBuchon J, Varanasi VR, Weinstein AB (1981) The abscopal effect: demonstration in lymphomatous involvement of kidneys. Med Pediatr Oncol 9:473–476PubMedCrossRefGoogle Scholar
  43. 43.
    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 45:493–497PubMedCrossRefGoogle Scholar
  44. 44.
    Formenti SC, Demaria S (2012) Radiation therapy to convert the tumor into an in situ vaccine. Int J Radiat Oncol Biol Phys 84:879–880PubMedCrossRefGoogle Scholar
  45. 45.
    Formenti SC, Demaria S (2013) Combining radiotherapy and cancer immunotherapy: a paradigm shift. JNCI J Natl Cancer Inst 105:256–265PubMedCrossRefGoogle Scholar
  46. 46.
    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 182:170–181PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Newcomb EW, Demaria S, Lukyanov Y et al (2006) The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas. Clin Cancer Res 12:4730–4737PubMedCrossRefGoogle Scholar
  48. 48.
    Zeng J, See AP, Phallen 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 86:343–349PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Belcaid Z, Phallen JA, Zeng J 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:e101764PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Newcomb EW, Lukyanov Y, Kawashima N, Alonso-Basanta M, Wang S-C, Liu M, Jure-Kunkel M, Zagzag D, Demaria S, Formenti SC (2010) Radiotherapy enhances antitumor effect of anti-CD137 therapy in a mouse Glioma model. Radiat Res 173:426–432PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    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 17:5473–5480PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Yang S, Rafla S, Youssef E, Selim H, Salloum N, Chuang J (1988) Changes in T-cell subsets after radiation therapy. Radiology 168:537–540PubMedCrossRefGoogle Scholar
  53. 53.
    Crane CA, Ahn BJ, Han SJ, Parsa AT (2012) Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy. Neuro Oncol 14:584–595PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S (2009) Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15:5379–5388PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Bouquet F, Pal A, Pilones KA et al (2011) TGFβ1 inhibition increases the radiosensitivity of breast cancer cells in vitro and promotes tumor control by radiation in vivo. Clin Cancer Res 17:6754–6765PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Kevin K. H. Chow
    • 1
  • Wendy Hara
    • 2
  • Michael Lim
    • 3
  • Gordon Li
    • 1
  1. 1.Department of NeurosurgeryStanford University Medical CenterStanfordUSA
  2. 2.Department of Radiation Oncology-Radiation TherapyStanford University Medical CenterStanfordUSA
  3. 3.Department of NeurosurgeryJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations