Immunological effects of chemotherapy and radiotherapy against brain tumors

Expert Review of Anticancer Therapy

Volumn 16, Issue 10, 2016, Pages 1087-1094

  Weiss, Tobias ^a   Weller, Michael ^a   Roth, Patrick ^a  

^a UNIVERSITY HOSPITAL ZURICH   (Switzerland)

Author keywords

brain tumor; checkpoint inhibition; chemotherapy; glioblastoma; immunogenic cell death; Radiotherapy; vaccination

Indexed keywords

BEVACIZUMAB; CALRETICULIN; CARBOPLATIN; CARMUSTINE; CISPLATIN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DACARBAZINE; DNA; EPIDERMAL GROWTH FACTOR RECEPTOR; FOTEMUSTINE; HEAT SHOCK PROTEIN 70; HIGH MOBILITY GROUP B1 PROTEIN; INTERLEUKIN 2 RECEPTOR ALPHA; IPILIMUMAB; IRINOTECAN; LOMUSTINE; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 1; METHYLATED DNA PROTEIN CYSTEINE METHYLTRANSFERASE; MONOCYTE CHEMOTACTIC PROTEIN 1; MULTIDRUG RESISTANCE PROTEIN 1; OXALIPLATIN; PATHOGEN ASSOCIATED MOLECULAR PATTERN; PROCARBAZINE; PROGRAMMED DEATH 1 LIGAND 2; PROGRAMMED DEATH 1 RECEPTOR; TEMOZOLOMIDE; TRANSFORMING GROWTH FACTOR BETA; VASCULOTROPIN; VINCRISTINE; ANTINEOPLASTIC AGENT;

BRAIN TUMOR; CANCER CHEMOTHERAPY; CANCER GRADING; CANCER RADIOTHERAPY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; DENDRITIC CELL; DNA DAMAGE; DRUG EFFICACY; GLIOBLASTOMA; GLIOMA; HUMAN; IMMUNOLOGY; MACROPHAGE; MULTICENTER STUDY (TOPIC); NATURAL KILLER CELL; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; PROTEIN FUNCTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REGULATORY T LYMPHOCYTE; REVIEW; ADAPTIVE IMMUNITY; ANIMAL; BRAIN NEOPLASMS; IMMUNOTHERAPY; INNATE IMMUNITY; MULTIMODALITY CANCER THERAPY; PROCEDURES; TUMOR MICROENVIRONMENT;

ADAPTIVE IMMUNITY; ANIMALS; ANTINEOPLASTIC AGENTS; BRAIN NEOPLASMS; COMBINED MODALITY THERAPY; HUMANS; IMMUNITY, INNATE; IMMUNOTHERAPY; TUMOR MICROENVIRONMENT;

EID: 84988845049     PISSN: 14737140     EISSN: 17448328     Source Type: Journal    
DOI: 10.1080/14737140.2016.1229600     Document Type: Review

References (90)

1. Q.T.Ostrom, H.Gittleman, J.Fulop, et al. CBTRUS statistical report:primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol. 2015;17(Suppl 4):iv1–iv62.
2. D.N.Louis, A.Perry, G.Reifenberger, et al. The World Health Organization classification of tumors of the central nervous system:a summary. Acta Neuropathol. 2016;131(6):803–820.
3. W.Stummer, U.Pichlmeier, T.Meinel, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma:a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392–401.
4. B.Suchorska, M.Weller, G.Tabatabai, et al. Complete resection of contrast-enhancing tumor volume is associated with improved survival in recurrent glioblastoma-results from the DIRECTOR trial. Neuro Oncol. 2016;18(4):549–556.
5. R.Stupp, W.P.Mason, M.J.van den Bent, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–996.
6. M.Weller, M.van den Bent, K.Hopkins, et al. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol. 2014;15(9):e395–e403.
7. M.Kocher, R.Soffietti, U.Abacioglu, et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases:results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29(2):134–141.
8. M.Reck, S.Popat, N.Reinmuth, et al. Metastatic non-small-cell lung cancer (NSCLC):ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii27–iii39.
9. R.Addeo, S.Zappavigna, A.Luce, et al. Chemotherapy in the management of brain metastases:the emerging role of fotemustine for patients with melanoma and NSCLC. Expert Opin Drug Saf. 2013;12(5):729–740.
10. S.S.Agarwala, J.M.Kirkwood, M.Gore, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma:a phase II study. J Clin Oncol. 2004;22(11):2101–2107.
11. H.Kluger, S.B.Goldberg, M.Sznol, et al. Safety and activity of pembrolizumab in melanoma patients with untreated brain metastases. J Clin Oncol. 2015;33(suppl):abstr 9009.
12. K.Margolin, M.S.Ernstoff, O.Hamid, et al. Ipilimumab in patients with melanoma and brain metastases:an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459–465.• This phase 2 clinical trial demonstrates the safety and activity of immune checkpoint inhibition in brain metastases from melanoma.
13. T.Weiss, M.Weller, P.Roth Immunotherapy for glioblastoma:concepts and challenges. Curr Opin Neurol. 2015;28(6):639–646.
14. M.Weller, W.Wick, K.Aldape, et al. Glioma. Nat Rev Dis Primers. 2015;1:15017.
15. F.Macbeth, J.Newton-Bishop, S.O’Connell, et al. Guideline development G. Melanoma:summary of NICE guidance. BMJ. 2015;351:h3708.
16. M.Van den Bent, S.Erridge, M.Vogelbaum, et al. Results of the interim analysis of the EORTC randomized phase III CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q co-deletion:an Intergroup trial. J Clin Oncol. 2016;34(suppl):abstr LBA2000.
17. J.C.Buckner, E.G.Shaw, S.L.Pugh, et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med. 2016;374(14):1344–1355.
18. G.Cairncross, M.Wang, E.Shaw, et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma:long-term results of RTOG 9402. J Clin Oncol. 2013;31(3):337–343.
19. M.J.van den Bent, A.A.Brandes, M.J.Taphoorn, et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma:long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31(3):344–350.
20. S.Ostermann, C.Csajka, T.Buclin, et al. Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res. 2004;10(11):3728–3736.
21. M.J.Paul, Y.Summers, A.H.Calvert, et al. Effect of temozolomide on central nervous system relapse in patients with advanced melanoma. Melanoma Res. 2002;12(2):175–178.
22. M.R.Middleton, J.J.Grob, N.Aaronson, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. 2000;18(1):158–166.
23. A.V.Knizhnik, W.P.Roos, T.Nikolova, et al. Survival and death strategies in glioma cells:autophagy, senescence and apoptosis triggered by a single type of temozolomide-induced DNA damage. PLoS One. 2013;8(1):e55665.
24. J.F.Curtin, N.Liu, M.Candolfi, et al. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med. 2009;6(1):e10.
25. T.G.Kim, C.H.Kim, J.S.Park, et al. Immunological factors relating to the antitumor effect of temozolomide chemoimmunotherapy in a murine glioma model. Clin Vaccine Immunol. 2010;17(1):143–153.
26. A.D.Garg, L.Galluzzi, L.Apetoh, et al. Molecular and translational classifications of DAMPs in immunogenic cell death. Front Immunol. 2015;6:588.
27. G.Kroemer, L.Galluzzi, O.Kepp, et al. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.
28. M.Candolfi, K.Yagiz, M.Wibowo, et al. Temozolomide does not impair gene therapy-mediated antitumor immunity in syngeneic brain tumor models. Clin Cancer Res. 2014;20(6):1555–1565.
29. H.Ardon, S.Van Gool, I.S.Lopes, 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):261–272.
30. C.E.Fadul, J.L.Fisher, T.H.Hampton, 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):382–389.
31. J.H.Sampson, K.D.Aldape, G.E.Archer, 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):324–333.• This phase II multicenter trial demonstrates that the combination of chemotherapy with a peptide-based vaccination in glioblastoma is safe and that TMZ may boost humoral and cellular vaccine-induced immune responses.
32. C.J.Wheeler, A.Das, G.Liu, et al. Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination. Clin Cancer Res. 2004;10(16):5316–5326.
33. M.Preusser, M.Lim, D.A.Hafler, et al. Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol. 2015;11(9):504–514.
34. E.Bouffet, V.Larouche, B.B.Campbell, et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol. 2016;34(19):2206–2211.•• This study demonstrates that in pediatric brain tumor patients, tumors which harbor a high mutation load may respond best to immune checkpoint inhibition.
35. J.Felsberg, N.Thon, S.Eigenbrod, et al. Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. Int J Cancer. 2011;129(3):659–670.
36. C.Happold, P.Roth, W.Wick, et al. Distinct molecular mechanisms of acquired resistance to temozolomide in glioblastoma cells. J Neurochem. 2012;122(2):444–455.
37. M.Bauer, M.Goldstein, D.Heylmann, et al. Human monocytes undergo excessive apoptosis following temozolomide activating the ATM/ATR pathway while dendritic cells and macrophages are resistant. PLoS One. 2012;7(6):e39956.
38. J.C.Rodrigues, G.C.Gonzalez, L.Zhang, et al. Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol. 2010;12(4):351–365.
39. C.Banissi, F.Ghiringhelli, L.Chen, et al. Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol Immunother. 2009;58(10):1627–1634.
40. L.Ridolfi, M.Petrini, A.M.Granato, et al. Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients. J Transl Med. 2013;11:135.
41. C.E.Fadul, J.L.Fisher, J.Gui, et al. Immune modulation effects of concomitant temozolomide and radiation therapy on peripheral blood mononuclear cells in patients with glioblastoma multiforme. Neuro Oncol. 2011;13(4):393–400.
42. S.Ellsworth, A.Balmanoukian, F.Kos, et al. Sustained CD4 T cell-driven lymphopenia without a compensatory IL-7/IL-15 response among high-grade glioma patients treated with radiation and temozolomide. Oncoimmunology. 2014;3(1):e27357.
43. J.S.Mendez, A.Govindan, J.Leong, et al. Association between treatment-related lymphopenia and overall survival in elderly patients with newly diagnosed glioblastoma. J Neurooncol. 2016;127(2):329–335.
44. P.Maier, I.Spier, S.Laufs, et al. Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O(6)-methylguanine-DNA methyltransferase(P140K). Gene Ther. 2010;17(3):389–399.
45. D.A.Mitchell, X.Cui, R.J.Schmittling, et al. Monoclonal antibody blockade of IL-2 receptor alpha during lymphopenia selectively depletes regulatory T cells in mice and humans. Blood. 2011;118(11):3003–3012.
46. J.H.Sampson, R.J.Schmittling, G.E.Archer, et al. A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma. PLoS One. 2012;7(2):e31046.
47. A.J.Litterman, A.Z.Dudek, D.A.Largaespada. Alkylating chemotherapy may exert a uniquely deleterious effect upon neo-antigen-targeting anticancer vaccination. Oncoimmunology. 2013;2(10):e26294.
48. M.Hebeisen, M.Allard, P.O.Gannon, et al. Identifying individual T cell receptors of optimal avidity for tumor antigens. Front Immunol. 2015;6:582.
49. A.J.Litterman, D.M.Zellmer, K.L.Grinnen, et al. Profound impairment of adaptive immune responses by alkylating chemotherapy. J Immunol. 2013;190(12):6259–6268.
50. A.M.Di Giacomo, P.A.Ascierto, L.Pilla, et al. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1):an open-label, single-arm phase 2 trial. Lancet Oncol. 2012;13(9):879–886.
51. A.M.Di Giacomo, P.A.Ascierto, P.Queirolo, et al. Three-year follow-up of advanced melanoma patients who received ipilimumab plus fotemustine in the Italian network for tumor biotherapy (NIBIT)-M1 phase II study. Ann Oncol. 2015;26(4):798–803.
52. M.Westphal, D.C.Hilt, E.Bortey, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003;5(2):79–88.
53. A.Tesniere, F.Schlemmer, V.Boige, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. 2010;29(4):482–491.
54. W.J.Lesterhuis, C.J.Punt, S.V.Hato, et al. Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J Clin Invest. 2011;121(8):3100–3108.
55. N.Schafer, J.Tichy, S.Thanendrarajan, et al. Ifosfamide, carboplatin and etoposide in recurrent malignant glioma. Oncology. 2011;80(5–6):330–332.
56. M.Tonder, M.Weller, G.Eisele, et al. Carboplatin and etoposide in heavily pretreated patients with progressive high-grade glioma. Chemotherapy. 2014;60(5–6):375–378.
57. J.Kanterman, M.Sade-Feldman, M.Biton, et al. Adverse immunoregulatory effects of 5FU and CPT11 chemotherapy on myeloid-derived suppressor cells and colorectal cancer outcomes. Cancer Res. 2014;74(21):6022–6035.
58. M.N.Tsao, D.Rades, A.Wirth, et al. Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es):an American Society for radiation oncology evidence-based guideline. Pract Radiat Oncol. 2012;2(3):210–225.
59. P.Km, J.M.O’Sullivan. Radiation-induced bystander signalling in cancer therapy. Nat Rev Cancer. 2009;9(5):351–360.
60. Y.Rubner, C.Muth, A.Strnad, 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.
61. E.W.Newcomb, S.Demaria, Y.Lukyanov, 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):4730–4737.
62. C.M.Jackson, C.M.Kochel, C.J.Nirschl, et al. Systemic tolerance mediated by melanoma brain tumors is reversible by radiotherapy and vaccination. Clin Cancer Res. 2016;22(5):1161–1172.
63. C.E.Brown, R.P.Vishwanath, B.Aguilar, et al. Tumor-derived chemokine MCP-1/CCL2 is sufficient for mediating tumor tropism of adoptively transferred T cells. J Immunol. 2007;179(5):3332–3341.
64. J.M.Morganti, T.D.Jopson, S.Liu, et al. Cranial irradiation alters the brain’s microenvironment and permits CCR2+ macrophage infiltration. PLoS One. 2014;9(4):e93650.
65. J.Zhang, S.Sarkar, R.Cua, et al. A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis. Carcinogenesis. 2012;33(2):312–319.
66. A.L.Chang, J.Miska, D.A.Wainwright, et al. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res. 2016. [Epub ahead of print].
67. X.Zhu, M.Fujita, L.A.Snyder, et al. Systemic delivery of neutralizing antibody targeting CCL2 for glioma therapy. J Neurooncol. 2011;104(1):83–92.
68. E.A.Chiocca, L.K.Aguilar, S.D.Bell, et al. Phase IB study of gene-mediated cytotoxic immunotherapy adjuvant to up-front surgery and intensive timing radiation for malignant glioma. J Clin Oncol. 2011;29(27):3611–3619.
69. L.A.Wheeler, A.G.Manzanera, S.D.Bell, et al. Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma. Neuro Oncol. 2016;18(8):1137–1145.
70. C.Twyman-Saint Victor, A.J.Rech, A.Maity, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373–377.• This study assessed the induction of PD-L1 after irradiation in melanoma mouse models and patients with metastatic melanoma. Blockade of PD-1 restored the anti-tumor immune responses and improved survival, which provides a rational for a combination of radiation therapy and immune checkpoint inhibition.
71. L.Shi, L.Chen, C.Wu, et al. PD-1 blockade boosts radiofrequency ablation-elicited adaptive immune responses against tumor. Clin Cancer Res. 2016;22(5):1173–1184.
72. Z.Belcaid, J.A.Phallen, J.Zeng, 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.
73. J.Zeng, A.P.See, J.Phallen, 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):343–349.
74. H.C.Dancea, M.M.Shareef, M.M.Ahmed. Role of radiation-induced TGF-beta signaling in cancer therapy. Mol Cell Pharmacol. 2009;1(1):44–56.
75. E.L.Kachikwu, K.S.Iwamoto, Y.P.Liao, et al. Radiation enhances regulatory T cell representation. Int J Radiat Oncol Biol Phys. 2011;81(4):1128–1135.
76. S.A.Grossman, X.Ye, G.Lesser, et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res. 2011;17(16):5473–5480.
77. S.Yovino, L.Kleinberg, S.A.Grossman, et al. 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):140–144.
78. J.L.Campian, X.Ye, D.E.Gladstone, et al. Pre-radiation lymphocyte harvesting and post-radiation reinfusion in patients with newly diagnosed high grade gliomas. J Neurooncol. 2015;124(2):307–316.
79. P.Roth, C.Happold, M.Weller. Corticosteroid use in neuro-oncology:an update. Neuro-Oncology Practice. 2015;2(1):6–12.
80. M.J.Olnes, Y.Kotliarov, A.Biancotto, et al. Effects of systemically administered hydrocortisone on the human immunome. Sci Rep. 2016;6:23002.
81. K.L.Pitter, I.Tamagno, K.Alikhanyan, et al. Corticosteroids compromise survival in glioblastoma. Brain. 2016;139(Pt 5):1458–1471.• This study identified steroid administration as an independent predictor of poor outcome in glioblastoma patients.
82. E.T.Wong, E.Lok, S.Gautam, et al. Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma. Br J Cancer. 2015;113(2):232–241.
83. D.Gabrilovich, T.Ishida, T.Oyama, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998;92(11):4150–4166.
84. A.C.Ziogas, N.G.Gavalas, M.Tsiatas, et al. VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor type 2. Int J Cancer. 2012;130(4):857–864.
85. J.Buchroithner, J.Pichler, C.Marosi, et al. Vascular endothelia growth factor targeted therapy may improve the effect of dendritic cell-based cancer immune therapy. Int J Clin Pharmacol Ther. 2014;52(1):76–77.
86. D.A.Reardon, J.Schuster, D.Tran, et al. ReACT:overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. J Clin Oncol. 2015;33(suppl):abstr 2009.• This study demonstrates clinical activity of a peptide-based vaccination in combination with anti-VEGF treatment in patients with recurrent glioblastoma.
87. R.Y.Huang, M.R.Neagu, D.A.Reardon, et al. Pitfalls in the neuroimaging of glioblastoma in the era of antiangiogenic and immuno/targeted therapy - detecting illusive disease, defining response. Front Neurol. 2015;6:33.
88. D.Brandsma. M.J.van den Bent. Pseudoprogression and pseudoresponse in the treatment of gliomas. Curr Opin Neurol. 2009;22(6):633–638.
89. H.Okada, M.Weller, R.Huang, et al. Immunotherapy response assessment in neuro-oncology:a report of the RANO working group. Lancet Oncol. 2015;16(15):e534–e542.
90. B.Becher, A.Schlitzer, J.Chen, et al. High-dimensional analysis of the murine myeloid cell system. Nat Immunol. 2014;15(12):1181–1189.