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Journal of Neuro-Oncology

Erschienen in:

06.04.2020 | Topic Review

A review of glioblastoma immunotherapy

verfasst von: Ravi Medikonda, Gavin Dunn, Maryam Rahman, Peter Fecci, Michael Lim

Erschienen in: Journal of Neuro-Oncology | Ausgabe 1/2021

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Abstract

Introduction

Glioblastoma is a very aggressive cancer with dismal prognosis despite standard of care including surgical resection, radiation therapy, and chemotherapy. There is interest in applying immunotherapy to glioblastoma as this modality has demonstrated remarkable improvements in the management of several solid tumors including melanoma, renal cell carcinoma, and non-small cell lung cancer. This review aims to provide an overview of the current state of glioblastoma immunotherapy.

Methods

Literature search was performed on PubMed between 1961 and 2020.

Results

Initial clinical trials of checkpoint inhibitors and vaccine therapy for glioblastoma have largely been disappointing for both primary and recurrent glioblastoma. This failure has been attributed to glioblastoma’s highly immunosuppressive environment and multiple mechanisms of therapy resistance including high tumor heterogeneity, low mutational burden, systemic immunosuppression, and local immune dysfunction.

Conclusions

Current clinical trials are exploring combination therapy and novel treatment strategies beyond immune checkpoint therapies and vaccine therapy such as CAR T cells. There is also an effort to establish synergy between immunotherapy and current standard of care. Furthermore, recent advances in personalized neoantigen vaccines suggest a shift towards personalized, patient-specific GBM treatment.

Burnet M (1957) Cancer: a biological approach: III. Viruses associated with neoplastic conditions: IV. practical applications. Br Med J 1(5023):841–847. https://doi.org/10.1136/bmj.1.5023.841CrossRefPubMedPubMedCentral

Burnet FM (1970) The concept of immunological surveillance. Prog Exp Tumor Res 13:1–27CrossRefPubMed

Thomas L (1961) Cellular and humoral aspects of the hypersensitive states. Acta Medica Scandinavica 170(1):128–128. https://doi.org/10.1111/j.0954-6820.1961.tb00220.xCrossRef

Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21(2):137–148. https://doi.org/10.1016/j.immuni.2004.07.017CrossRefPubMed

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

Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science 359(6382):1350–1355. https://doi.org/10.1126/science.aar4060CrossRefPubMedPubMedCentral

Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264. https://doi.org/10.1038/nrc3239CrossRefPubMedPubMedCentral

Paz-Ares L, Horn L, Borghaei H, Spigel DR, Steins M, Ready N, Chow LQM, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaeufl M, Rodriguez O, Burgio MA, Fayette J, Gettinger SN, Harbison C, Dorange C, Finckenstein FG, Brahmer JR (2015) Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). J Clin Oncol 33((18_suppl)):LBA109–LBA109. https://doi.org/10.1200/jco.2015.33.18_suppl.lba109CrossRef

Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. New Engl J Med 373(19):1803–1813. https://doi.org/10.1056/NEJMoa1510665CrossRefPubMed

10.

Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm M-O, Bracarda S, Arranz JÁ, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18(3):312–322. https://doi.org/10.1016/S1470-2045(17)30065-7CrossRefPubMed

11.

El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim T-Y, Choo S-P, Trojan J, Welling TH, Meyer T, Kang Y-K, Yeo W, Chopra A, Anderson J, dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I (2017) Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. The Lancet 389(10088):2492–2502. https://doi.org/10.1016/S0140-6736(17)31046-2CrossRef

12.

Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob J-J, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16(4):375–384. https://doi.org/10.1016/S1470-2045(15)70076-8CrossRefPubMed

13.

Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, Hermes B, Cay Senler F, Csoszi T, Fulop A, Rodriguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM (2018) Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. New Engl J Med 379(21):2040–2051. https://doi.org/10.1056/NEJMoa1810865CrossRefPubMed

14.

Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, Hodi FS, Schachter J, Pavlick AC, Lewis KD, Cranmer LD, Blank CU, O'Day SJ, Ascierto PA, Salama AKS, Margolin KA, Loquai C, Eigentler TK, Gangadhar TC, Carlino MS, Agarwala SS, Moschos SJ, Sosman JA, Goldinger SM, Shapira-Frommer R, Gonzalez R, Kirkwood JM, Wolchok JD, Eggermont A, Li XN, Zhou W, Zernhelt AM, Lis J, Ebbinghaus S, Kang SP, Daud A (2015) Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 16(8):908–918. https://doi.org/10.1016/S1470-2045(15)00083-2CrossRefPubMedPubMedCentral

15.

Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges J-P, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang Y-J, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH (2018) Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trialpembrolizumab in advanced gastric and gastroesophageal junction cancerpembrolizumab in advanced gastric and gastroesophageal junction cancer. JAMA Oncol 4 (5): e180013-e180013. doi:10.1001/jamaoncol.2018.0013

16.

McDermott D, Haanen J, Chen TT, Lorigan P, O'Day S (2013) Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol: Off J Eur Soc Med Oncol 24(10):2694–2698. https://doi.org/10.1093/annonc/mdt291CrossRef

17.

Weber J, Thompson JA, Hamid O, Minor D, Amin A, Ron I, Ridolfi R, Assi H, Maraveyas A, Berman D, Siegel J, O'Day SJ (2009) A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res: Off J Am Assoc Cancer Res 15(17):5591–5598. https://doi.org/10.1158/1078-0432.ccr-09-1024CrossRef

18.

Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. New Engl J Med 363(8):711–723. https://doi.org/10.1056/NEJMoa1003466CrossRefPubMed

19.

Haslam A, Prasad V (2019) Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open 2(5):e192535–e192535. https://doi.org/10.1001/jamanetworkopen.2019.2535CrossRefPubMedPubMedCentral

20.

Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2015) Nivolumab in previously untreated melanoma without BRAF mutation. New Engl J Med 372(4):320–330. https://doi.org/10.1056/NEJMoa1412082CrossRefPubMed

21.

Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. New Engl J Med 373(17):1627–1639. https://doi.org/10.1056/NEJMoa1507643CrossRefPubMed

22.

Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372(26):2521–2532. https://doi.org/10.1056/NEJMoa1503093CrossRefPubMed

23.

Magee DE, Hird AE, Klaassen Z, Sridhar SS, Nam RK, Wallis CJD, Kulkarni GS (2020) Adverse event profile for immunotherapy agents compared with chemotherapy in solid organ tumors: a systematic review and meta-analysis of randomized clinical trials. Ann Oncol: Off J Eur Soc Med Oncol 31(1):50–60. https://doi.org/10.1016/j.annonc.2019.10.008CrossRef

24.

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New Engl J Med 352(10):987–996. https://doi.org/10.1056/NEJMoa043330CrossRefPubMed

25.

Di Carlo DT, Cagnazzo F, Benedetto N, Morganti R, Perrini P (2019) Multiple high-grade gliomas: epidemiology, management, and outcome: a systematic review and meta-analysis. Neurosurg Rev 42(2):263–275. https://doi.org/10.1007/s10143-017-0928-7CrossRefPubMed

26.

Cohen MH, Shen YL, Keegan P, Pazdur R (2009) FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 14(11):1131–1138. https://doi.org/10.1634/theoncologist.2009-0121CrossRefPubMed

27.

Sampson JH, Vlahovic G, Sahebjam S, Omuro AMP, Baehring JM, Hafler DA, Voloschin AD, Paliwal P, Grosso J, Coric V, Cloughesy TF, Lim M, Reardon DA (2015) Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CHECKMATE-143. J Clin Oncol 33((15_suppl)):3010–3010. https://doi.org/10.1200/jco.2015.33.15_suppl.3010CrossRef

28.

Omuro A, Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T, Voloschin A, Ramkissoon SH, Ligon KL, Latek R, Zwirtes R, Strauss L, Paliwal P, Harbison CT, Reardon DA, Sampson JH (2018) Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol 20(5):674–686. https://doi.org/10.1093/neuonc/nox208CrossRefPubMed

29.

Lim M, Omuro A, Vlahovic G, Reardon DA, Sahebjam S, Cloughesy T, Baehring J, Butowski N, Potter V, Zwirtes R, Paliwal P, Carleton M, Sampson J, Brandes AA (2017) 325ONivolumab (nivo) in combination with radiotherapy (RT) ± temozolomide (TMZ): updated safety results from CheckMate 143 in pts with methylated or unmethylated newly diagnosed glioblastoma (GBM). Ann Oncol 28 (suppl_5). doi:10.1093/annonc/mdx366

30.

, 2020. B-MSB-MSMhnbcp-rc-nb-m-s-a-p--c--s-dAJ Bristol-Myers squibb announces phase 3 CheckMate -498 study did not meet primary endpoint of overall survival with opdivo (nivolumab) plus radiation in patients with newly diagnosed MGMT-unmethylated glioblastoma multiforme

31.

Squibb B-M Bristol-Myers squibb provides update on phase 3 opdivo (nivolumab) CheckMate -548 trial in patients with newly diagnosed MGMT-methylated glioblastoma multiforme. Bristol-Myers Squibb

32.

Weller M, Kaulich K, Hentschel B, Felsberg J, Gramatzki D, Pietsch T, Simon M, Westphal M, Schackert G, Tonn JC, von Deimling A, Davis T, Weiss WA, Loeffler M, Reifenberger G (2014) Assessment and prognostic significance of the epidermal growth factor receptor vIII mutation in glioblastoma patients treated with concurrent and adjuvant temozolomide radiochemotherapy. Int J Cancer 134(10):2437–2447. https://doi.org/10.1002/ijc.28576CrossRefPubMed

33.

Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE 2nd, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD (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: Off J Am Soc Clin Oncol 28(31):4722–4729. https://doi.org/10.1200/jco.2010.28.6963CrossRef

34.

Schuster J, Lai RK, Recht LD, Reardon DA, Paleologos NA, Groves MD, Mrugala MM, Jensen R, Baehring JM, Sloan A, Archer GE, Bigner DD, Cruickshank S, Green JA, Keler T, Davis TA, Heimberger AB, Sampson JH (2015) A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol 17(6):854–861. https://doi.org/10.1093/neuonc/nou348CrossRefPubMedPubMedCentral

35.

Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, Friedman HS, Gilbert MR, Herndon JE, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling R, Shi W, Vredenburgh JJ, Bigner DD, Heimberger AB (2011) Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol 13(3):324–333. https://doi.org/10.1093/neuonc/noq157CrossRefPubMed

36.

Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, Ashby L, Mechtler L, Goldlust SA, Iwamoto F, Drappatz J, O'Rourke DM, Wong M, Hamilton MG, Finocchiaro G, Perry J, Wick W, Green J, He Y, Turner CD, Yellin MJ, Keler T, Davis TA, Stupp R, Sampson JH (2017) Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol 18(10):1373–1385. https://doi.org/10.1016/s1470-2045(17)30517-xCrossRefPubMed

37.

Reardon DA, Schuster J, Tran DD, Fink KL, Nabors LB, Li G, Bota DA, Lukas RV, Desjardins A, Ashby LS, Duic JP, Mrugala MM, Werner A, Hawthorne T, He Y, Green JA, Yellin MJ, Turner CD, Davis TA, Sampson JH, Group TRS (2015) ReACT: overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. J Clin Oncol 33((15_suppl)):2009–2009. https://doi.org/10.1200/jco.2015.33.15_suppl.2009CrossRef

38.

Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H, Nuno MA, Richardson JE, Fan X, Ji J, Chu RM, Bender JG, Hawkins ES, Patil CG, Black KL, Yu JS (2013) Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother: CII 62(1):125–135. https://doi.org/10.1007/s00262-012-1319-0CrossRefPubMed

39.

Wen PY, Reardon DA, Phuphanich S, Aiken R, Landolfi JC, Curry WT, Zhu J-J, 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 (2014) A randomized, double-blind, placebo-controlled phase 2 trial of dendritic cell (DC) vaccination with ICT-107 in newly diagnosed glioblastoma (GBM) patients. J Clin Oncol 32((15_suppl)):2005–2005. https://doi.org/10.1200/jco.2014.32.15_suppl.2005CrossRef

40.

Liau LM, Ashkan K, Tran DD, Campian JL, Trusheim JE, Cobbs CS, Heth JA, Salacz M, Taylor S, D'Andre SD, Iwamoto FM, Dropcho EJ, Moshel YA, Walter KA, Pillainayagam CP, Aiken R, Chaudhary R, Goldlust SA, Bota DA, Duic P, Grewal J, Elinzano H, Toms SA, Lillehei KO, Mikkelsen T, Walbert T, Abram SR, Brenner AJ, Brem S, Ewend MG, Khagi S, Portnow J, Kim LJ, Loudon WG, Thompson RC, Avigan DE, Fink KL, Geoffroy FJ, Lindhorst S, Lutzky J, Sloan AE, Schackert G, Krex D, Meisel H-J, Wu J, Davis RP, Duma C, Etame AB, Mathieu D, Kesari S, Piccioni D, Westphal M, Baskin DS, New PZ, Lacroix M, May S-A, Pluard TJ, Tse V, Green RM, Villano JL, Pearlman M, Petrecca K, Schulder M, Taylor LP, Maida AE, Prins RM, Cloughesy TF, Mulholland P, Bosch ML (2018) First results on survival from a large phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med 16(1):142–142. https://doi.org/10.1186/s12967-018-1507-6CrossRefPubMedPubMedCentral

41.

Razavi S-M, Lee KE, Jin BE, Aujla PS, Gholamin S, Li G (2016) Immune evasion strategies of glioblastoma. Front Surg 3 (11). doi:10.3389/fsurg.2016.00011

42.

Lim M, Xia Y, Bettegowda C, Weller M (2018) Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol 15(7):422–442. https://doi.org/10.1038/s41571-018-0003-5CrossRefPubMed

43.

Jackson CM, Choi J, Lim M (2019) Mechanisms of immunotherapy resistance: lessons from glioblastoma. Nat Immunol 20(9):1100–1109. https://doi.org/10.1038/s41590-019-0433-yCrossRefPubMed

44.

Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, Cahill DP, Nahed BV, Curry WT, Martuza RL, Louis DN, Rozenblatt-Rosen O, Suva ML, Regev A, Bernstein BE (2014) Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344(6190):1396–1401. https://doi.org/10.1126/science.1254257CrossRefPubMedPubMedCentral

45.

Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O'Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110. https://doi.org/10.1016/j.ccr.2009.12.020CrossRefPubMedPubMedCentral

46.

Sidaway P (2017) CNS cancer: Glioblastoma subtypes revisited. Nat Rev Clin Oncol 14(10):587. https://doi.org/10.1038/nrclinonc.2017.122CrossRefPubMed

47.

Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, deCarvalho AC, Lyu S, Li P, Li Y, Barthel F, Cho HJ, Lin Y-H, Satani N, Martinez-Ledesma E, Zheng S, Chang E, Sauvé C-EG, Olar A, Lan ZD, Finocchiaro G, Phillips JJ, Berger MS, Gabrusiewicz KR, Wang G, Eskilsson E, Hu J, Mikkelsen T, DePinho RA, Muller F, Heimberger AB, Sulman EP, Nam D-H, Verhaak RGW (2017) Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell 32(1):42–56.e46. https://doi.org/10.1016/j.ccell.2017.06.003CrossRefPubMedPubMedCentral

48.

Teo W-Y, Sekar K, Seshachalam P, Shen J, Chow W-Y, Lau CC, Yang H, Park J, Kang S-G, Li X, Nam D-H, Hui KM (2019) Relevance of a TCGA-derived glioblastoma subtype gene-classifier among patient populations. Sci Rep 9(1):7442. https://doi.org/10.1038/s41598-019-43173-yCrossRefPubMedPubMedCentral

49.

Sottoriva A, Spiteri I, Piccirillo SG, Touloumis A, Collins VP, Marioni JC, Curtis C, Watts C, Tavare S (2013) Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci USA 110(10):4009–4014. https://doi.org/10.1073/pnas.1219747110CrossRefPubMedPubMedCentral

50.

Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, Cahill DP, Nahed BV, Curry WT, Martuza RL, Louis DN, Rozenblatt-Rosen O, Suvà ML, Regev A, Bernstein BE (2014) Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344(6190):1396–1401. https://doi.org/10.1126/science.1254257CrossRefPubMedPubMedCentral

51.

Mahlokozera T, Vellimana AK, Li T, Mao DD, Zohny ZS, Kim DH, Tran DD, Marcus DS, Fouke SJ, Campian JL, Dunn GP, Miller CA, Kim AH (2017) Biological and therapeutic implications of multisector sequencing in newly diagnosed glioblastoma. Neuro-Oncol 20(4):472–483. https://doi.org/10.1093/neuonc/nox232CrossRefPubMedCentral

52.

Hodges TR, Ott M, Xiu J, Gatalica Z, Swensen J, Zhou S, Huse JT, de Groot J, Li S, Overwijk WW, Spetzler D, Heimberger AB (2017) Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro Oncol 19(8):1047–1057. https://doi.org/10.1093/neuonc/nox026CrossRefPubMedPubMedCentral

53.

Gubin MM, Artyomov MN, Mardis ER, Schreiber RD (2015) Tumor neoantigens: building a framework for personalized cancer immunotherapy. J Clin Invest 125(9):3413–3421. https://doi.org/10.1172/jci80008CrossRefPubMedPubMedCentral

54.

Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, Stephens PJ, Daniels GA, Kurzrock R (2017) Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther 16(11):2598–2608. https://doi.org/10.1158/1535-7163.MCT-17-0386CrossRefPubMedPubMedCentral

55.

Johanns TM, Miller CA, Dorward IG, Tsien C, Chang E, Perry A, Uppaluri R, Ferguson C, Schmidt RE, Dahiya S, Ansstas G, Mardis ER, Dunn GP (2016) Immunogenomics of Hypermutated Glioblastoma: A patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov 6(11):1230–1236. https://doi.org/10.1158/2159-8290.cd-16-0575CrossRefPubMedPubMedCentral

56.

Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, Durno C, Krueger J, Cabric V, Ramaswamy V, Zhukova N, Mason G, Farah R, Afzal S, Yalon M, Rechavi G, Magimairajan V, Walsh MF, Constantini S, Dvir R, Elhasid R, Reddy A, Osborn M, Sullivan M, Hansford J, Dodgshun A, Klauber-Demore N, Peterson L, Patel S, Lindhorst S, Atkinson J, Cohen Z, Laframboise R, Dirks P, Taylor M, Malkin D, Albrecht S, Dudley RWR, Jabado N, Hawkins CE, Shlien A, Tabori U (2016) Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol 34(19):2206–2211. https://doi.org/10.1200/JCO.2016.66.6552CrossRefPubMed

57.

Indraccolo S, Lombardi G, Fassan M, Pasqualini L, Giunco S, Marcato R, Gasparini A, Candiotto C, Nalio S, Fiduccia P, Fanelli GN, Pambuku A, Della Puppa A, D'Avella D, Bonaldi L, Gardiman MP, Bertorelle R, De Rossi A, Zagonel V (2019) Genetic, epigenetic, and immunologic profiling of MMR-deficient relapsed glioblastoma. Clin Cancer Res 25(6):1828–1837. https://doi.org/10.1158/1078-0432.ccr-18-1892CrossRefPubMed

58.

Roszman T, Elliott L, Brooks W (1991) Modulation of T-cell function by gliomas. Immunol Today 12(10):370–374. https://doi.org/10.1016/0167-5699(91)90068-5CrossRefPubMed

59.

Bloch O, Crane CA, Kaur R, Safaee M, Rutkowski MJ, Parsa AT (2013) Gliomas promote immunosuppression through induction of B7–H1 expression in tumor-associated macrophages. Clin Cancer Res: Official J Am Assoc Cancer Res 19(12):3165–3175. https://doi.org/10.1158/1078-0432.ccr-12-3314CrossRef

60.

Chae M, Peterson TE, Balgeman A, Chen S, Zhang L, Renner DN, Johnson AJ, Parney IF (2015) Increasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model. Neuro Oncol 17(7):978–991. https://doi.org/10.1093/neuonc/nou343CrossRefPubMed

61.

Elliott LH, Brooks WH, Roszman TL (1987) Activation of immunoregulatory lymphocytes obtained from patients with malignant gliomas. J Neurosurg 67(2):231–236. https://doi.org/10.3171/jns.1987.67.2.0231CrossRefPubMed

62.

Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, Herndon JE 2nd, 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. Can Res 66(6):3294–3302. https://doi.org/10.1158/0008-5472.can-05-3773CrossRef

63.

Dunn GP, Fecci PE, Curry WT (2012) Cancer immunoediting in malignant glioma. Neurosurgery 71 (2):201–222; discussion 222-203. doi:10.1227/NEU.0b013e31824f840d

64.

Hutter G, Theruvath J, Graef CM, Zhang M, Schoen MK, Manz EM, Bennett ML, Olson A, Azad TD, Sinha R, Chan C, Assad Kahn S, Gholamin S, Wilson C, Grant G, He J, Weissman IL, Mitra SS, Cheshier SH (2019) Microglia are effector cells of CD47-SIRPalpha antiphagocytic axis disruption against glioblastoma. Proc Natl Acad Sci USA 116(3):997–1006. https://doi.org/10.1073/pnas.1721434116CrossRefPubMedPubMedCentral

65.

Klein RS, Izikson L, Means T, Gibson HD, Lin E, Sobel RA, Weiner HL, Luster AD (2004) IFN-Inducible protein 10/CXC chemokine ligand 10-independent induction of experimental autoimmune encephalomyelitis. J Immunol 172(1):550–559. https://doi.org/10.4049/jimmunol.172.1.550CrossRefPubMed

66.

Chongsathidkiet P, Jackson C, Koyama S, Loebel F, Cui X, Farber SH, Woroniecka K, Elsamadicy AA, Dechant CA, Kemeny HR, Sanchez-Perez L, Cheema TA, Souders NC, Herndon JE, Coumans JV, Everitt JI, Nahed BV, Sampson JH, Gunn MD, Martuza RL, Dranoff G, Curry WT, Fecci PE (2018) Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med 24(9):1459–1468. https://doi.org/10.1038/s41591-018-0135-2CrossRefPubMedPubMedCentral

67.

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: Off J Am Assoc Cancer Res 17(16):5473–5480. https://doi.org/10.1158/1078-0432.ccr-11-0774CrossRef

68.

Wild AT, Herman JM, Dholakia AS, Moningi S, Lu Y, Rosati LM, Hacker-Prietz A, Assadi RK, Saeed AM, Pawlik TM, Jaffee EM, Laheru DA, Tran PT, Weiss MJ, Wolfgang CL, Ford E, Grossman SA, Ye X, Ellsworth SG (2016) Lymphocyte-sparing effect of stereotactic body radiation therapy in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 94(3):571–579. https://doi.org/10.1016/j.ijrobp.2015.11.026CrossRefPubMed

69.

Liao G, Zhao Z, Yang H, Li X (2019) Efficacy and safety of hypofractionated radiotherapy for the treatment of newly diagnosed glioblastoma multiforme: a systematic review and meta-analysis. Front Oncol 9 (1017). doi:10.3389/fonc.2019.01017

70.

Mathios D, Kim JE, Mangraviti A, Phallen J, Park CK, Jackson CM, Garzon-Muvdi T, Kim E, Theodros D, Polanczyk M, Martin AM, Suk I, Ye X, Tyler B, Bettegowda C, Brem H, Pardoll DM, Lim M (2016) Anti-PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. Sci Transl Med 8 (370):370ra180. doi:10.1126/scitranslmed.aag2942

71.

Giles AJ, Hutchinson M-KND, Sonnemann HM, Jung J, Fecci PE, Ratnam NM, Zhang W, Song H, Bailey R, Davis D, Reid CM, Park DM, Gilbert MR (2018) Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer 6(1):51. https://doi.org/10.1186/s40425-018-0371-5CrossRefPubMedPubMedCentral

72.

Maxwell R, Luksik AS, Garzon-Muvdi T, Hung AL, Kim ES, Wu A, Xia Y, Belcaid Z, Gorelick N, Choi J, Theodros D, Jackson CM, Mathios D, Ye X, Tran PT, Redmond KJ, Brem H, Pardoll DM, Kleinberg LR, Lim M (2018) Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system. Oncoimmunology 7(12):e1500108. https://doi.org/10.1080/2162402x.2018.1500108CrossRefPubMedPubMedCentral

73.

Sugihara AQ, Rolle CE, Lesniak MS (2009) Regulatory T cells actively infiltrate metastatic brain tumors. Int J Oncol 34(6):1533–1540. https://doi.org/10.3892/ijo_00000282CrossRefPubMed

74.

Kennedy BC, Maier LM, D'Amico R, Mandigo CE, Fontana EJ, Waziri A, Assanah MC, Canoll P, Anderson RCE, Anderson DE, Bruce JN (2009) Dynamics of central and peripheral immunomodulation in a murine glioma model. BMC Immunol 10(1):11. https://doi.org/10.1186/1471-2172-10-11CrossRefPubMedPubMedCentral

75.

Ueda R, Fujita M, Zhu X, Sasaki K, Kastenhuber ER, Kohanbash G, McDonald HA, Harper J, Lonning S, Okada H (2009) Systemic inhibition of transforming growth factor-beta in glioma-bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines. Clin Cancer Res: Off J Am Assoc Cancer Res 15(21):6551–6559. https://doi.org/10.1158/1078-0432.ccr-09-1067CrossRef

76.

Kaminska B, Kocyk M, Kijewska M (2013) TGF beta signaling and its role in glioma pathogenesis. Adv Exp Med Biol 986:171–187. https://doi.org/10.1007/978-94-007-4719-7_9CrossRefPubMed

77.

Wainwright DA, Balyasnikova IV, Chang AL, Ahmed AU, Moon K-S, Auffinger B, Tobias AL, Han Y, Lesniak MS (2012) IDO Expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res 18(22):6110–6121. https://doi.org/10.1158/1078-0432.ccr-12-2130CrossRefPubMedPubMedCentral

78.

Heimberger AB, Abou-Ghazal M, Reina-Ortiz C, Yang DS, Sun W, Qiao W, Hiraoka N, Fuller GN (2008) Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas. Clin Cancer Res: Off J Am Assoc Cancer Res 14(16):5166–5172. https://doi.org/10.1158/1078-0432.ccr-08-0320CrossRef

79.

Lohr J, Ratliff T, Huppertz A, Ge Y, Dictus C, Ahmadi R, Grau S, Hiraoka N, Eckstein V, Ecker RC, Korff T, von Deimling A, Unterberg A, Beckhove P, Herold-Mende C (2011) Effector T-cell infiltration positively impacts survival of glioblastoma patients and is impaired by tumor-derived TGF-beta. Clin Cancer Res: Off J Am Assoc Cancer Res 17(13):4296–4308. https://doi.org/10.1158/1078-0432.ccr-10-2557CrossRef

80.

Chen Z, Hambardzumyan D (2018) Immune microenvironment in glioblastoma subtypes. Front Immunol 9:1004. https://doi.org/10.3389/fimmu.2018.01004CrossRefPubMedPubMedCentral

81.

Takenaka MC, Gabriely G, Rothhammer V, Mascanfroni ID, Wheeler MA, Chao CC, Gutierrez-Vazquez C, Kenison J, Tjon EC, Barroso A, Vandeventer T, de Lima KA, Rothweiler S, Mayo L, Ghannam S, Zandee S, Healy L, Sherr D, Farez MF, Prat A, Antel J, Reardon DA, Zhang H, Robson SC, Getz G, Weiner HL, Quintana FJ (2019) Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat Neurosci 22(5):729–740. https://doi.org/10.1038/s41593-019-0370-yCrossRefPubMedPubMedCentral

82.

Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14(7):399–416. https://doi.org/10.1038/nrclinonc.2016.217CrossRefPubMedPubMedCentral

83.

Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, Ahmed R (1998) Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 188(12):2205–2213. https://doi.org/10.1084/jem.188.12.2205CrossRefPubMedPubMedCentral

84.

Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R (2003) Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol 77(8):4911–4927. https://doi.org/10.1128/jvi.77.8.4911-4927.2003CrossRefPubMedPubMedCentral

85.

Woroniecka K, Chongsathidkiet P, Rhodin K, Kemeny H, Dechant C, Farber SH, Elsamadicy AA, Cui X, Koyama S, Jackson C, Hansen LJ, Johanns TM, Sanchez-Perez L, Chandramohan V, Yu YA, Bigner DD, Giles A, Healy P, Dranoff G, Weinhold KJ, Dunn GP, Fecci PE (2018) T-cell exhaustion signatures vary with tumor type and are severe in glioblastoma. Clin Cancer Res: Off J Am Assoc Cancer Res 24(17):4175–4186. https://doi.org/10.1158/1078-0432.ccr-17-1846CrossRef

86.

Chahlavi A, Rayman P, Richmond AL, Biswas K, Zhang R, Vogelbaum M, Tannenbaum C, Barnett G, Finke JH (2005) Glioblastomas induce T-lymphocyte death by two distinct pathways involving gangliosides and CD70. Can Res 65(12):5428–5438. https://doi.org/10.1158/0008-5472.can-04-4395CrossRef

87.

Wainwright DA, Chang AL, Dey M, Balyasnikova IV, Kim CK, Tobias A, Cheng Y, Kim JW, Qiao J, Zhang L, Han Y, Lesniak MS (2014) Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res: Off J Am Assoc Cancer Res 20(20):5290–5301. https://doi.org/10.1158/1078-0432.ccr-14-0514CrossRef

88.

Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, Wang AC, Ellingson BM, Rytlewski JA, Sanders CM, Kawaguchi ES, Du L, Li G, Yong WH, Gaffey SC, Cohen AL, Mellinghoff IK, Lee EQ, Reardon DA, O'Brien BJ, Butowski NA, Nghiemphu PL, Clarke JL, Arrillaga-Romany IC, Colman H, Kaley TJ, de Groot JF, Liau LM, Wen PY, Prins RM (2019) Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med 25(3):477–486. https://doi.org/10.1038/s41591-018-0337-7CrossRefPubMedPubMedCentral

89.

Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, López-Janeiro A, Porciuncula A, Idoate MA, Inogés S, de Andrea C, López-Diaz de Cerio A, Tejada S, Berraondo P, Villarroel-Espindola F, Choi J, Gúrpide A, Giraldez M, Goicoechea I, Gallego Perez-Larraya J, Sanmamed MF, Perez-Gracia JL, Melero I (2019) Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat Med 25(3):470–476. https://doi.org/10.1038/s41591-018-0339-5CrossRefPubMed

90.

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

91.

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

92.

Germano G, Lamba S, Rospo G, Barault L, Magri A, Maione F, Russo M, Crisafulli G, Bartolini A, Lerda G, Siravegna G, Mussolin B, Frapolli R, Montone M, Morano F, de Braud F, Amirouchene-Angelozzi N, Marsoni S, D'Incalci M, Orlandi A, Giraudo E, Sartore-Bianchi A, Siena S, Pietrantonio F, Di Nicolantonio F, Bardelli A (2017) Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 552(7683):116–120. https://doi.org/10.1038/nature24673CrossRefPubMed

93.

Pouessel D, Mervoyer A, Larrieu-Ciron D, Cabarrou B, Attal J, Robert M, Frenel J-S, Olivier P, Poublanc M, Mounier M, Moyal E (2018) Hypofractionnated stereotactic radiotherapy and anti-PDL1 durvalumab combination in recurrent glioblastoma: results of the phase I part of the phase I/II STERIMGLI trial. J Clin Oncol 36((15_suppl)):2046–2046. https://doi.org/10.1200/JCO.2018.36.15_suppl.2046CrossRef

94.

Martikainen M, Essand M (2019) Virus-based immunotherapy of glioblastoma Cancers (Basel) 11:11

95.

Westphal M, Yla-Herttuala S, Martin J, Warnke P, Menei P, Eckland D, Kinley J, Kay R, Ram Z (2013) Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial. Lancet Oncol 14(9):823–833. https://doi.org/10.1016/s1470-2045(13)70274-2CrossRefPubMed

96.

Cloughesy TF, Landolfi J, Vogelbaum MA, Ostertag D, Elder JB, Bloomfield S, Carter B, Chen CC, Kalkanis SN, Kesari S, Lai A, Lee IY, Liau LM, Mikkelsen T, Nghiemphu P, Piccioni D, Accomando W, Diago OR, Hogan DJ, Gammon D, Kasahara N, Kheoh T, Jolly DJ, Gruber HE, Das A, Walbert T (2018) Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. Neuro Oncol 20(10):1383–1392. https://doi.org/10.1093/neuonc/noy075CrossRefPubMedPubMedCentral

97.

Cloughesy TF, Landolfi J, Hogan DJ, Bloomfield S, Carter B, Chen CC, Elder JB, Kalkanis SN, Kesari S, Lai A, Lee IY, Liau LM, Mikkelsen T, Nghiemphu PL, Piccioni D, Walbert T, Chu A, Das A, Diago OR, Gammon D, Gruber HE, Hanna M, Jolly DJ, Kasahara N, McCarthy D, Mitchell L, Ostertag D, Robbins JM, Rodriguez-Aguirre M, Vogelbaum MA (2016) Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma. Sci Transl Med 8(341):341–375. https://doi.org/10.1126/scitranslmed.aad9784CrossRef

98.

Cockle JV, Rajani K, Zaidi S, Kottke T, Thompson J, Diaz RM, Shim K, Peterson T, Parney IF, Short S, Selby P, Ilett E, Melcher A, Vile R (2016) Combination viroimmunotherapy with checkpoint inhibition to treat glioma, based on location-specific tumor profiling. Neuro Oncol 18(4):518–527. https://doi.org/10.1093/neuonc/nov173CrossRefPubMed

99.

Jiang H, Rivera-Molina Y, Gomez-Manzano C, Clise-Dwyer K, Bover L, Vence LM, Yuan Y, Lang FF, Toniatti C, Hossain MB, Fueyo J (2017) Oncolytic adenovirus and tumor-targeting immune modulatory therapy improve autologous cancer vaccination. Can Res 77(14):3894–3907. https://doi.org/10.1158/0008-5472.can-17-0468CrossRef

100.

Chen CY, Hutzen B, Wedekind MF, Cripe TP (2018) Oncolytic virus and PD-1/PD-L1 blockade combination therapy. Oncol Virother 7:65–77. https://doi.org/10.2147/ov.s145532CrossRef

101.

Maus MV, Grupp SA, Porter DL, June CH (2014) Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123(17):2625–2635. https://doi.org/10.1182/blood-2013-11-492231CrossRefPubMedPubMedCentral

102.

Finney HM, Akbar AN, Lawson AD (2004) Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol 172(1):104–113. https://doi.org/10.4049/jimmunol.172.1.104CrossRefPubMed

103.

Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J, Kurien A, Priceman SJ, Wang X, Harshbarger TL, D'Apuzzo M, Ressler JA, Jensen MC, Barish ME, Chen M, Portnow J, Forman SJ, Badie B (2016) Regression of glioblastoma after chimeric antigen receptor T-cell therapy. New Engl J Med 375(26):2561–2569. https://doi.org/10.1056/NEJMoa1610497CrossRefPubMed

104.

O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, Martinez-Lage M, Brem S, Maloney E, Shen A, Isaacs R, Mohan S, Plesa G, Lacey SF, Navenot JM, Zheng Z, Levine BL, Okada H, June CH, Brogdon JL, Maus MV (2017) A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 9(399):984. https://doi.org/10.1126/scitranslmed.aaa0984CrossRef

105.

Ahmed N, Brawley V, Hegde M, Bielamowicz K, Kalra M, Landi D, Robertson C, Gray TL, Diouf O, Wakefield A, Ghazi A, Gerken C, Yi Z, Ashoori A, Wu M-F, Liu H, Rooney C, Dotti G, Gee A, Su J, Kew Y, Baskin D, Zhang YJ, New P, Grilley B, Stojakovic M, Hicks J, Powell SZ, Brenner MK, Heslop HE, Grossman R, Wels WS, Gottschalk S (2017) HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncol 3(8):1094–1101. https://doi.org/10.1001/jamaoncol.2017.0184CrossRefPubMedPubMedCentral

106.

Fecci PE, Sampson JH (2019) The current state of immunotherapy for gliomas: an eye toward the future. J Neurosurg 131(3):657–666. https://doi.org/10.3171/2019.5.jns181762CrossRefPubMed

107.

Bielamowicz K, Fousek K, Byrd TT, Samaha H, Mukherjee M, Aware N, Wu M-F, Orange JS, Sumazin P, Man T-K, Joseph SK, Hegde M, Ahmed N (2017) Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro-Oncology 20(4):506–518. https://doi.org/10.1093/neuonc/nox182CrossRefPubMedCentral

108.

Ding AS, Routkevitch D, Jackson C, Lim M (2019) Targeting myeloid cells in combination treatments for glioma and other tumors. Front Immunol 10:1715. https://doi.org/10.3389/fimmu.2019.01715CrossRefPubMedPubMedCentral

109.

Coniglio SJ, Eugenin E, Dobrenis K, Stanley ER, West BL, Symons MH, Segall JE (2012) Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol Med (Cambridge, Mass) 18:519–527. https://doi.org/10.2119/molmed.2011.00217CrossRef

110.

Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, Olson OC, Quick ML, Huse JT, Teijeiro V, Setty M, Leslie CS, Oei Y, Pedraza A, Zhang J, Brennan CW, Sutton JC, Holland EC, Daniel D, Joyce JA (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19(10):1264–1272. https://doi.org/10.1038/nm.3337CrossRefPubMedPubMedCentral

111.

Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, Zhang W, Luoma A, Giobbie-Hurder A, Peter L, Chen C, Olive O, Carter TA, Li S, Lieb DJ, Eisenhaure T, Gjini E, Stevens J, Lane WJ, Javeri I, Nellaiappan K, Salazar AM, Daley H, Seaman M, Buchbinder EI, Yoon CH, Harden M, Lennon N, Gabriel S, Rodig SJ, Barouch DH, Aster JC, Getz G, Wucherpfennig K, Neuberg D, Ritz J, Lander ES, Fritsch EF, Hacohen N, Wu CJ (2017) An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547(7662):217–221. https://doi.org/10.1038/nature22991CrossRefPubMedPubMedCentral

112.

Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal J, Petti AA, Ly A, Lie WR, Hildebrand WH, Mardis ER, Linette GP (2015) Cancer immunotherapy: a dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348(6236):803–808. https://doi.org/10.1126/science.aaa3828CrossRefPubMedPubMedCentral

113.

Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Lower M, Bukur V, Tadmor AD, Luxemburger U, Schrors B, Omokoko T, Vormehr M, Albrecht C, Paruzynski A, Kuhn AN, Buck J, Heesch S, Schreeb KH, Muller F, Ortseifer I, Vogler I, Godehardt E, Attig S, Rae R, Breitkreuz A, Tolliver C, Suchan M, Martic G, Hohberger A, Sorn P, Diekmann J, Ciesla J, Waksmann O, Bruck AK, Witt M, Zillgen M, Rothermel A, Kasemann B, Langer D, Bolte S, Diken M, Kreiter S, Nemecek R, Gebhardt C, Grabbe S, Holler C, Utikal J, Huber C, Loquai C, Tureci O (2017) Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547(7662):222–226. https://doi.org/10.1038/nature23003CrossRefPubMed

114.

Johanns TM, Miller CA, Liu CJ, Perrin RJ, Bender D, Kobayashi DK, Campian JL, Chicoine MR, Dacey RG, Huang J, Fritsch EF, Gillanders WE, Artyomov MN, Mardis ER, Schreiber RD, Dunn GP (2019) Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma. OncoImmunology 8(4):e1561106. https://doi.org/10.1080/2162402X.2018.1561106CrossRefPubMedPubMedCentral

115.

Hilf N, Kuttruff-Coqui S, Frenzel K, Bukur V, Stevanovic S, Gouttefangeas C, Platten M, Tabatabai G, Dutoit V, van der Burg SH, Thor Straten P, Martinez-Ricarte F, Ponsati B, Okada H, Lassen U, Admon A, Ottensmeier CH, Ulges A, Kreiter S, von Deimling A, Skardelly M, Migliorini D, Kroep JR, Idorn M, Rodon J, Piro J, Poulsen HS, Shraibman B, McCann K, Mendrzyk R, Lower M, Stieglbauer M, Britten CM, Capper D, Welters MJP, Sahuquillo J, Kiesel K, Derhovanessian E, Rusch E, Bunse L, Song C, Heesch S, Wagner C, Kemmer-Bruck A, Ludwig J, Castle JC, Schoor O, Tadmor AD, Green E, Fritsche J, Meyer M, Pawlowski N, Dorner S, Hoffgaard F, Rossler B, Maurer D, Weinschenk T, Reinhardt C, Huber C, Rammensee HG, Singh-Jasuja H, Sahin U, Dietrich PY, Wick W (2019) Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565(7738):240–245. https://doi.org/10.1038/s41586-018-0810-yCrossRefPubMed

116.

Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, Oliveira G, Giobbie-Hurder A, Felt K, Gjini E, Shukla SA, Hu Z, Li L, Le PM, Allesoe RL, Richman AR, Kowalczyk MS, Abdelrahman S, Geduldig JE, Charbonneau S, Pelton K, Iorgulescu JB, Elagina L, Zhang W, Olive O, McCluskey C, Olsen LR, Stevens J, Lane WJ, Salazar AM, Daley H, Wen PY, Chiocca EA, Harden M, Lennon NJ, Gabriel S, Getz G, Lander ES, Regev A, Ritz J, Neuberg D, Rodig SJ, Ligon KL, Suva ML, Wucherpfennig KW, Hacohen N, Fritsch EF, Livak KJ, Ott PA, Wu CJ, Reardon DA (2019) Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565(7738):234–239. https://doi.org/10.1038/s41586-018-0792-9CrossRefPubMed

117.

Johanns TM, Bowman-Kirigin JA, Liu C, Dunn GP (2017) Targeting neoantigens in glioblastoma: an overview of cancer immunogenomics and translational implications. Neurosurgery 64 (CN_suppl_1):165–176. https://doi.org/10.1093/neuros/nyx321CrossRefPubMedPubMedCentral

Titel: A review of glioblastoma immunotherapy
verfasst von: Ravi Medikonda
Gavin Dunn
Maryam Rahman
Peter Fecci
Michael Lim
Publikationsdatum: 06.04.2020
Verlag: Springer US
Erschienen in: Journal of Neuro-Oncology / Ausgabe 1/2021
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-020-03448-1

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Sozialer Aufstieg verringert Demenzgefahr

24.05.2024 Demenz Nachrichten

Ein hohes soziales Niveau ist mit die beste Versicherung gegen eine Demenz. Noch geringer ist das Demenzrisiko für Menschen, die sozial aufsteigen: Sie gewinnen fast zwei demenzfreie Lebensjahre. Umgekehrt steigt die Demenzgefahr beim sozialen Abstieg.

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

17.05.2024 Direkte orale Antikoagulanzien Nachrichten

Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.

Was nützt die Kraniektomie bei schwerer tiefer Hirnblutung?

17.05.2024 Hirnblutung Nachrichten

Eine Studie zum Nutzen der druckentlastenden Kraniektomie nach schwerer tiefer supratentorieller Hirnblutung deutet einen Nutzen der Operation an. Für überlebende Patienten ist das dennoch nur eine bedingt gute Nachricht.

Thrombektomie auch bei großen Infarkten von Vorteil

16.05.2024 Ischämischer Schlaganfall Nachrichten

Auch ein sehr ausgedehnter ischämischer Schlaganfall scheint an sich kein Grund zu sein, von einer mechanischen Thrombektomie abzusehen. Dafür spricht die LASTE-Studie, an der Patienten und Patientinnen mit einem ASPECTS von maximal 5 beteiligt waren.

Update Neurologie

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Weitere Artikel der Ausgabe 1/2021

Brain stem gliomas and current landscape

Nanoparticles as immunomodulators and translational agents in brain tumors

Immune suppression in gliomas

Blood–brain barrier opening with low intensity pulsed ultrasound for immune modulation and immune therapeutic delivery to CNS tumors

Journal of Neuro Oncology: immunotherapy for brain tumors