Translational landscape of glioblastoma immunotherapy for physicians: guiding clinical practice with basic scientific evidence

1.

Cote DJ, Ostrom QT, Gittleman H, Duncan KR, Crevecoeur TS, Kruchko C, et al. Glioma incidence and survival variations by county-level socioeconomic measures. Cancer. 2019;125(19):3390–400. https://doi.org/10.1002/cncr.32328.CrossRefPubMed

2.

Marenco-Hillembrand L, Wijesekera O, Suarez-Meade P, Mampre D, Jackson C, Peterson J, et al. Trends in glioblastoma: outcomes over time and type of intervention: a systematic evidence based analysis. J Neurooncol. 2020;147(2):297–307. https://doi.org/10.1007/s11060-020-03451-6.CrossRefPubMed

3.

Delgado-López PD, Corrales-García EM. Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol. 2016;18(11):1062–71. https://doi.org/10.1007/s12094-016-1497-x.CrossRefPubMed

4.

Reifenberger G, Weber RG, Riehmer V, Kaulich K, Willscher E, Wirth H, et al. Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling. Int J Cancer. 2014;135(8):1822–31. https://doi.org/10.1002/ijc.28836.CrossRefPubMed

5.

Kristensen BW, Priesterbach-Ackley LP, Petersen JK, Wesseling P. Molecular pathology of tumors of the central nervous system. Ann Oncol. 2019;30(8):1265–78. https://doi.org/10.1093/annonc/mdz164.CrossRefPubMedPubMedCentral

6.

Louis DN, Perry A, Reifenberger G, Von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20. https://doi.org/10.1007/s00401-016-1545-1.CrossRefPubMed

7.

Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the united states in 2012–2016. Neuro Oncol. 2019;21(Supplement_5):v1–100. https://doi.org/10.1093/neuonc/noz150.CrossRefPubMedPubMedCentral

8.

Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 2021;23(8):1231–51. https://doi.org/10.1093/neuonc/noab106.CrossRefPubMed

9.

Brat DJ, Aldape K, Colman H, Holland EC, Louis DN, Jenkins RB, et al. cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV.” Acta Neuropathol. 2018;136(5):805–10. https://doi.org/10.1007/s00401-018-1913-0.CrossRefPubMedPubMedCentral

10.

Sharma A, Graber JJ. Overview of prognostic factors in adult gliomas. Ann Palliat Med. 2021;10(1):863–74.CrossRef

11.

Scott JN, Rewcastle NB, Brasher PM, Fulton D, MacKinnon JA, Hamilton M, et al. Which glioblastoma multiforme patient will become a long-term survivor. A population-based study. Ann Neurol. 1999;46(2):183–8.CrossRef

12.

Chaudhry NS, Shah AH, Ferraro N, Snelling BM, Bregy A, Madhavan K, et al. Predictors of long-term survival in patients with glioblastoma multiforme: advancements from the last quarter century. Cancer Invest. 2013;31(5):287–308. https://doi.org/10.3109/07357907.2013.789899.CrossRefPubMed

13.

Stupp R, Mason WP, Van Den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96. https://doi.org/10.1056/nejmoa043330.CrossRefPubMed

14.

De Leeuw CN, Vogelbaum MA. Supratotal resection in glioma: a systematic review. Neuro Oncol. 2019;21(2):179–88. https://doi.org/10.1093/neuonc/noy166.CrossRefPubMed

15.

Brown TJ, Brennan MC, Li M, Church EW, Brandmeir NJ, Rakszawski KL, et al. Association of the extent of resection with survival in glioblastoma. JAMA Oncol. 2016;2(11):1460. https://doi.org/10.1001/jamaoncol.2016.1373.CrossRefPubMedPubMedCentral

16.

Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708. https://doi.org/10.1056/nejmoa1308573.CrossRefPubMedPubMedCentral

17.

Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma. JAMA Oncol. 2020;6(7):1003. https://doi.org/10.1001/jamaoncol.2020.1024.CrossRefPubMed

18.

Stupp R, Taillibert S, Kanner A, Read W, Steinberg DM, Lhermitte B, et al. Effect of tumor-treating fields plus maintenance Temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma. JAMA. 2017;318(23):2306. https://doi.org/10.1001/jama.2017.18718.CrossRefPubMedPubMedCentral

19.

Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma. JAMA. 2015;314(23):2535. https://doi.org/10.1001/jama.2015.16669.CrossRefPubMed

20.

Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–22. https://doi.org/10.1056/nejmoa1308345.CrossRefPubMed

21.

Narayana A, Gruber D, Kunnakkat S, Golfinos JG, Parker E, Raza S, et al. A clinical trial of bevacizumab, temozolomide, and radiation for newly diagnosed glioblastoma. J Neurosurg. 2012;116(2):341–5. https://doi.org/10.3171/2011.9.jns11656.CrossRefPubMed

22.

Vredenburgh JJ, Desjardins A, Reardon DA, Peters KB, Herndon JE, Marcello J, et al. The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma. Clin Cancer Res. 2011;17(12):4119–24. https://doi.org/10.1158/1078-0432.ccr-11-0120.CrossRefPubMedPubMedCentral

23.

Touat M, Li YY, Boynton AN, Spurr LF, Iorgulescu JB, Bohrson CL, et al. Mechanisms and therapeutic implications of hypermutation in gliomas. Nature. 2020;580(7804):517–23. https://doi.org/10.1038/s41586-020-2209-9.CrossRefPubMedPubMedCentral

24.

Hodges TR, Ott M, Xiu J, Gatalica Z, Swensen J, Zhou S, et al. Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro Oncol. 2017;19(8):1047–57. https://doi.org/10.1093/neuonc/nox026.CrossRefPubMedPubMedCentral

25.

Turajlic S, Litchfield K, Xu H, Rosenthal R, Mcgranahan N, Reading JL, et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 2017;18(8):1009–21. https://doi.org/10.1016/s1470-2045(17)30516-8.CrossRefPubMed

26.

Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, et al. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell. 2017;32(1):42-56.e6. https://doi.org/10.1016/j.ccell.2017.06.003.CrossRefPubMedPubMedCentral

27.

Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110. https://doi.org/10.1016/j.ccr.2009.12.020.CrossRefPubMedPubMedCentral

28.

Martinez-Lage M, Lynch TM, Bi Y, Cocito C, Way GP, Pal S, et al. Immune landscapes associated with different glioblastoma molecular subtypes. Acta Neuropathol Commun. 2019;7(1):1–12. https://doi.org/10.1186/s40478-019-0803-6.CrossRef

29.

Doucette T, Rao G, Rao A, Shen L, Aldape K, Wei J, et al. Immune heterogeneity of glioblastoma subtypes: extrapolation from the cancer genome atlas. Cancer Immunol Res. 2013;1(2):112–22. https://doi.org/10.1158/2326-6066.cir-13-0028.CrossRefPubMed

30.

Schmitt MJ, Company C, Dramaretska Y, Barozzi I, Göhrig A, Kertalli S, et al. Phenotypic mapping of pathologic cross-talk between glioblastoma and innate immune cells by synthetic genetic tracing. Cancer Discov. 2021;11(3):754–77. https://doi.org/10.1158/2159-8290.cd-20-0219.CrossRefPubMed

31.

Kaffes I, Szulzewsky F, Chen Z, Herting CJ, Gabanic B, Velázquez Vega JE, et al. Human mesenchymal glioblastomas are characterized by an increased immune cell presence compared to proneural and classical tumors. OncoImmunology. 2019;8(11):e1655360. https://doi.org/10.1080/2162402x.2019.1655360.CrossRefPubMedPubMedCentral

32.

Bhat PLK, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, et al. Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell. 2013;24(3):331–46.CrossRef

33.

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.PubMedPubMedCentral

34.

Ringstad G, Valnes LM, Dale AM, Pripp AH, Vatnehol SAS, Emblem KE, et al. Brain wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight. 2018;3(13):e121537.CrossRef

35.

Papadopoulos Z, Herz J, Kipnis J. Meningeal lymphatics: from anatomy to central nervous system immune surveillance. J Immunol. 2020;204(2):286–93. https://doi.org/10.4049/jimmunol.1900838.CrossRefPubMed

36.

Cugurra A, Mamuladze T, Rustenhoven J, Dykstra T, Beroshvili G, Greenberg ZJ, et al. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma. Science. 2021;373:eabf7844. https://doi.org/10.1126/science.abf7844.CrossRefPubMedPubMedCentral

37.

Tamura R, Yoshida K, Toda M. Current understanding of lymphatic vessels in the central nervous system. Neurosurg Rev. 2020;43(4):1055–64. https://doi.org/10.1007/s10143-019-01133-0.CrossRefPubMed

38.

Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–41. https://doi.org/10.1038/nature14432.CrossRefPubMedPubMedCentral

39.

Sas AR, Carbajal KS, Jerome AD, Menon R, Yoon C, Kalinski AL, et al. A new neutrophil subset promotes CNS neuron survival and axon regeneration. Nat Immunol. 2020;21(12):1496–505. https://doi.org/10.1038/s41590-020-00813-0.CrossRefPubMedPubMedCentral

40.

Mundt S, Mrdjen D, Utz SG, Greter M, Schreiner B, Becher B. Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation. Sci Immunol. 2019;4(31):eaau8380. https://doi.org/10.1126/sciimmunol.aau8380.CrossRefPubMed

41.

Yee PP, Wei Y, Kim S-Y, Lu T, Chih SY, Lawson C, et al. Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression. Nat Commun. 2020;11(1):1–22. https://doi.org/10.1038/s41467-020-19193-y.CrossRef

42.

Lin YJ, Wei KC, Chen PY, Lim M, Hwang TL. Roles of neutrophils in glioma and brain metastases. Front Immunol. 2021;12:701383. https://doi.org/10.3389/fimmu.2021.701383.CrossRefPubMedPubMedCentral

43.

van de Walle T, Vaccaro A, Ramachandran M, Pietilä I, Essand M, Dimberg A. Tertiary lymphoid structures in the central nervous system: implications for glioblastoma. Front Immunol. 2021;12:724739. https://doi.org/10.3389/fimmu.2021.724739.CrossRefPubMedPubMedCentral

44.

Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu KJ, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153(1):139–52. https://doi.org/10.1016/j.cell.2013.02.021.CrossRefPubMedPubMedCentral

45.

Sarkaria JN, Hu LS, Parney IF, Pafundi DH, Brinkmann DH, Laack NN, et al. Is the blood–brain barrier really disrupted in all glioblastomas. a critical assessment of existing clinical data. Neuro Oncol. 2018;20(2):184–91. https://doi.org/10.1093/neuonc/nox175.CrossRefPubMed

46.

Zhou W, Chen C, Shi Y, Wu Q, Gimple RC, Fang X, et al. Targeting glioma stem cell-derived pericytes disrupts the blood-tumor barrier and improves chemotherapeutic efficacy. Cell Stem Cell. 2017;21(5):591-603.e4. https://doi.org/10.1016/j.stem.2017.10.002.CrossRefPubMedPubMedCentral

47.

Beccaria K, Canney M, Bouchoux G, Desseaux C, Grill J, Heimberger AB, et al. Ultrasound-induced blood-brain barrier disruption for the treatment of gliomas and other primary CNS tumors. Cancer Lett. 2020;479:13–22. https://doi.org/10.1016/j.canlet.2020.02.013.CrossRefPubMed

48.

Gregory JV, Kadiyala P, Doherty R, Cadena M, Habeel S, Ruoslahti E, et al. Systemic brain tumor delivery of synthetic protein nanoparticles for glioblastoma therapy. Nat Commun. 2020. https://doi.org/10.1038/s41467-020-19225-7.CrossRefPubMedPubMedCentral

49.

De Boeck A, Ahn BY, D’Mello C, Lun X, Menon SV, Alshehri MM, et al. Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression. Nat Commun. 2020;11(1):1–24. https://doi.org/10.1038/s41467-020-18569-4.CrossRef

50.

Frei K, Gramatzki D, Tritschler I, Schroeder JJ, Espinoza L, Rushing EJ, et al. Transforming growth factor-β pathway activity in glioblastoma. Oncotarget. 2015;6(8):5963–77.CrossRef

51.

Joseph JV, Balasubramaniyan V, Walenkamp A, Kruyt FAE. TGF-β as a therapeutic target in high grade gliomas—promises and challenges. Biochem Pharmacol. 2013;85(4):478–85. https://doi.org/10.1016/j.bcp.2012.11.005.CrossRefPubMed

52.

Metelli A, Salem M, Wallace CH, Wu BX, Li A, Li X, et al. Immunoregulatory functions and the therapeutic implications of GARP-TGF-β in inflammation and cancer. J Hematol Oncol. 2018;11(1):1–11. https://doi.org/10.1186/s13045-018-0570-z.CrossRef

53.

Golestaneh N, Mishra B. TGF-β, neuronal stem cells and glioblastoma. Oncogene. 2005;24(37):5722–30. https://doi.org/10.1038/sj.onc.1208925.CrossRefPubMed

54.

Eichhorn PJA, Rodón L, Gonzàlez-Juncà A, Dirac A, Gili M, Martínez-Sáez E, et al. USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma. Nat Med. 2012;18(3):429–35. https://doi.org/10.1038/nm.2619.CrossRefPubMed

55.

Batlle E, Massagué J. Transforming growth factor-β signaling in immunity and cancer. Immunity. 2019;50(4):924–40. https://doi.org/10.1016/j.immuni.2019.03.024.CrossRefPubMedPubMedCentral

56.

Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113(6):685–700. https://doi.org/10.1016/s0092-8674(03)00432-x.CrossRefPubMed

57.

Zhang C, Zhang X, Xu R, Huang B, Chen A-J, Li C, et al. TGF-β2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion. J Exp Clin Cancer Res. 2017. https://doi.org/10.1186/s13046-017-0628-8.CrossRefPubMedPubMedCentral

58.

Burghardt I, Schroeder JJ, Weiss T, Gramatzki D, Weller M. A tumor-promoting role for soluble TβRIII in glioblastoma. Mol Cell Biochem. 2021;476(8):2963–73. https://doi.org/10.1007/s11010-021-04128-y.CrossRefPubMedPubMedCentral

59.

Krishnan S, Szabo E, Burghardt I, Frei K, Tabatabai G, Weller M. Modulation of cerebral endothelial cell function by TGF-β in glioblastoma: VEGF-dependent angiogenesis versus endothelial mesenchymal transition. Oncotarget. 2015;6(26):22480–95.CrossRef

60.

Travis MA, Sheppard D. TGF-β activation and function in immunity. Annu Rev Immunol. 2014;32(1):51–82. https://doi.org/10.1146/annurev-immunol-032713-120257.CrossRefPubMed

61.

Metelli A, Wu BX, Riesenberg B, Guglietta S, Huck JD, Mills C, et al. Thrombin contributes to cancer immune evasion via proteolysis of platelet-bound GARP to activate LTGF-β. Sci Transl Med. 2020;12(525):eaay4860. https://doi.org/10.1126/scitranslmed.aay4860.CrossRefPubMedPubMedCentral

62.

Metelli A, Wu BX, Fugle CW, Rachidi S, Sun S, Zhang Y, et al. Surface expression of TGFβ docking receptor GARP promotes oncogenesis and immune tolerance in breast cancer. Can Res. 2016;76(24):7106–17. https://doi.org/10.1158/0008-5472.can-16-1456.CrossRef

63.

Dedobbeleer O, Stockis J, Van Der Woning B, Coulie PG, Lucas S. Cutting edge: active TGF-β1 released from GARP/TGF-β1 complexes on the surface of stimulated human B lymphocytes increases class-switch recombination and production of IgA. J Immunol. 2017;199(2):391–6. https://doi.org/10.4049/jimmunol.1601882.CrossRefPubMedPubMedCentral

64.

Cuende J, Liénart S, Dedobbeleer O, Van Der Woning B, De Boeck G, Stockis J, et al. Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. Sci Transl Med. 2015;7(284):284ra56-ra56. https://doi.org/10.1126/scitranslmed.aaa1983.CrossRefPubMed

65.

Rachidi S, Metelli A, Riesenberg B, Wu BX, Nelson MH, Wallace C, et al. Platelets subvert T cell immunity against cancer via GARP-TGFβ axis. Sci Immunol. 2017;2(11):eaai7911. https://doi.org/10.1126/sciimmunol.aai7911.CrossRefPubMedPubMedCentral

66.

Wang R, Zhu J, Dong X, Shi M, Lu C, Springer TA. GARP regulates the bioavailability and activation of TGFβ. Mol Biol Cell. 2012;23(6):1129–39. https://doi.org/10.1091/mbc.e11-12-1018.CrossRefPubMedPubMedCentral

67.

Salem M, Wallace C, Velegraki M, Li A, Ansa-Addo E, Metelli A, et al. GARP dampens cancer immunity by sustaining function and accumulation of regulatory T cells in the colon. Can Res. 2019;79(6):1178–90. https://doi.org/10.1158/0008-5472.can-18-2623.CrossRef

68.

Zhang X, Guo M, Yang J, Zheng Y, Xiao Y, Liu W, et al. Increased expression of GARP in papillary thyroid carcinoma. Endocr Pathol. 2019;30(1):1–7. https://doi.org/10.1007/s12022-018-9557-0.CrossRefPubMed

69.

Zimmer N, Kim E, Sprang J, Leukel P, Khafaji F, Ringel F, et al. GARP as an immune regulatory molecule in the tumor microenvironment of glioblastoma multiforme. Int J Mol Sci. 2019;20(15):3676.CrossRef

70.

Zimmer N, Krebs FK, Zimmer S, Mitzel-Rink H, Kumm EJ, Jurk K, et al. Platelet-derived GARP induces peripheral regulatory T Cells—potential impact on T cell suppression in patients with melanoma-associated thrombocytosis. Cancers. 2020;12(12):3653. https://doi.org/10.3390/cancers12123653.CrossRefPubMedCentral

71.

Riesenberg BP, Ansa-Addo EA, Gutierrez J, Timmers CD, Liu B, Li Z. Cutting edge: targeting thrombocytes to rewire anticancer immunity in the tumor microenvironment and potentiate efficacy of PD-1 blockade. J Immunol. 2019;203(5):1105–10. https://doi.org/10.4049/jimmunol.1900594.CrossRefPubMed

72.

Brockmann MA, Giese A, Mueller K, Kaba FJ, Lohr F, Weiss C, et al. Preoperative thrombocytosis predicts poor survival in patients with glioblastoma. Neuro Oncol. 2007;9(3):335–42. https://doi.org/10.1215/15228517-2007-013.CrossRefPubMedPubMedCentral

73.

Nolte I, Przibylla H, Bostel T, Groden C, Brockmann MA. Tumor-platelet interactions: glioblastoma growth is accompanied by increasing platelet counts. Clin Neurol Neurosurg. 2008;110(4):339–42. https://doi.org/10.1016/j.clineuro.2007.12.008.CrossRefPubMed

74.

Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824–35. https://doi.org/10.1056/nejmoa1709030.CrossRefPubMed

75.

Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim S-W, Carcereny Costa E, et al. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381(21):2020–31. https://doi.org/10.1056/nejmoa1910231.CrossRefPubMed

76.

Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257–65. https://doi.org/10.1016/s1470-2045(15)70054-9.CrossRefPubMedPubMedCentral

77.

Amaria RN, Reddy SM, Tawbi HA, Davies MA, Ross MI, Glitza IC, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med. 2018;24(11):1649–54. https://doi.org/10.1038/s41591-018-0197-1.CrossRefPubMedPubMedCentral

78.

Massarelli E, William W, Johnson F, Kies M, Ferrarotto R, Guo M, et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16–related cancer. JAMA Oncol. 2019;5(1):67. https://doi.org/10.1001/jamaoncol.2018.4051.CrossRefPubMed

79.

André T, Shiu K-K, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207–18. https://doi.org/10.1056/nejmoa2017699.CrossRefPubMed

80.

Sun C, Mezzadra R, Schumacher TN. Regulation and function of the PD-L1 checkpoint. Immunity. 2018;48(3):434–52. https://doi.org/10.1016/j.immuni.2018.03.014.CrossRefPubMedPubMedCentral

81.

Wang X, Guo G, Guan H, Yu Y, Lu J, Yu J. Challenges and potential of PD-1/PD-L1 checkpoint blockade immunotherapy for glioblastoma. J Exp Clin Cancer Res. 2019;38(1):1–13. https://doi.org/10.1186/s13046-019-1085-3.CrossRef

82.

Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med. 2016;375(18):1767–78. https://doi.org/10.1056/nejmra1514296.CrossRefPubMedPubMedCentral

83.

Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, et al. T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition. Science. 2017;355(6332):1428–33. https://doi.org/10.1126/science.aaf1292.CrossRefPubMedPubMedCentral

84.

Nduom EK, Wei J, Yaghi NK, Huang N, Kong LY, Gabrusiewicz K, et al. PD-L1 expression and prognostic impact in glioblastoma. Neuro Oncol. 2016;18(2):195–205. https://doi.org/10.1093/neuonc/nov172.CrossRefPubMed

85.

Berghoff AS, Lassmann H, Preusser M, Höftberger R. Characterization of the inflammatory response to solid cancer metastases in the human brain. Clin Exp Metas. 2013;30(1):69–81. https://doi.org/10.1007/s10585-012-9510-4.CrossRef

86.

Jang B-S, Kim IA. A radiosensitivity gene signature and PD-L1 status predict clinical outcome of patients with glioblastoma multiforme in the cancer genome atlas dataset. Cancer Res Treat. 2020;52(2):530–42. https://doi.org/10.4143/crt.2019.440.CrossRefPubMed

87.

Rao G, Latha K, Ott M, Sabbagh A, Marisetty A, Ling X, et al. Anti–PD-1 induces M1 polarization in the glioma microenvironment and exerts therapeutic efficacy in the absence of CD8 cytotoxic T cells. Clin Cancer Res. 2020;26(17):4699–712. https://doi.org/10.1158/1078-0432.ccr-19-4110.CrossRefPubMedPubMedCentral

88.

Lee AH, Sun L, Mochizuki AY, Reynoso JG, Orpilla J, Chow F, et al. Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma. Nat Commun. 2021;12(1):1–16. https://doi.org/10.1038/s41467-021-26940-2.CrossRef

89.

Squibb BM. Bristol Myers Squibb announces update on phase 3 CheckMate -548 trial evaluating patients with newly diagnosed MGMT-methylated glioblastoma multiforme. Online: Bristol Myers Squibb. 2020.

90.

Heynckes S, Gaebelein A, Haaker G, Grauvogel J, Franco P, Mader I, et al. Expression differences of programmed death ligand 1 in de-novo and recurrent glioblastoma multiforme. Oncotarget. 2017;8(43):74170–7.CrossRef

91.

Heynckes S, Daka K, Franco P, Gaebelein A, Frenking JH, Doria-Medina R, et al. Crosslink between temozolomide and PD-L1 immune-checkpoint inhibition in glioblastoma multiforme. BMC Cancer. 2019;19(1):1–7. https://doi.org/10.1186/s12885-019-5308-y.CrossRef

92.

Iorgulescu JB, Gokhale PC, Speranza MC, Eschle BK, Poitras MJ, Wilkens MK, et al. Concurrent dexamethasone limits the clinical benefit of immune checkpoint blockade in glioblastoma. Clin Cancer Res. 2021;27(1):276–87. https://doi.org/10.1158/1078-0432.ccr-20-2291.CrossRefPubMed

93.

Giles AJ, Hutchinson MKND, Sonnemann HM, Jung J, Fecci PE, Ratnam NM, et al. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer. 2018;6(1):1–13. https://doi.org/10.1186/s40425-018-0371-5.CrossRef

94.

Wolchok JD, Saenger Y. The mechanism of anti-CTLA-4 activity and the negative regulation of T-cell activation. Oncologist. 2008;13(S4):2–9. https://doi.org/10.1634/theoncologist.13-s4-2.CrossRefPubMed

95.

Brown NF, Ng SM, Brooks C, Coutts T, Holmes J, Roberts C, et al. A phase II open label, randomised study of ipilimumab with temozolomide versus temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: the Ipi-Glio trial protocol. BMC Cancer. 2020;20(1):1–5. https://doi.org/10.1186/s12885-020-6624-y.CrossRef

96.

Larkin J, Chiarion-Sileni V, Gonzalez R, Grob J-J, Rutkowski P, Lao CD, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535–46. https://doi.org/10.1056/nejmoa1910836.CrossRefPubMed

97.

Motzer RJ, Tannir NM, Mcdermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–90. https://doi.org/10.1056/nejmoa1712126.CrossRefPubMedPubMedCentral

98.

Omuro A, Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T, et al. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol. 2018;20(5):674–86. https://doi.org/10.1093/neuonc/nox208.CrossRefPubMed

99.

Postow MA, Sidlow R, Hellmann MD. Immune-Related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–68. https://doi.org/10.1056/nejmra1703481.CrossRefPubMed

100.

Santini FC, Rizvi H, Plodkowski AJ, Ni A, Lacouture ME, Gambarin-Gelwan M, et al. Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC. Cancer Immunol Res. 2018;6(9):1093–9. https://doi.org/10.1158/2326-6066.cir-17-0755.CrossRefPubMedPubMedCentral

101.

Thompson JA, Schneider BJ, Brahmer J, Andrews S, Armand P, Bhatia S, et al. NCCN guidelines insights: management of immunotherapy-related toxicities, version 1.2020. J Compr Cancer Netw. 2020;18(3):230–41. https://doi.org/10.6004/jnccn.2020.0012.CrossRef

102.

Weathers PS-S, Kamiya-Matsuoka C, Harrison RA, Liu DD, Dervin S, Yun C, et al. Phase I/II study to evaluate the safety and clinical efficacy of atezolizumab (atezo; aPDL1) in combination with temozolomide (TMZ) and radiation in patients with newly diagnosed glioblastoma (GBM). J Clin Oncol. 2020;38(15_suppl):2511. https://doi.org/10.1200/JCO.2020.38.15_suppl.2511.CrossRef

103.

Brioschi S, Wang W-L, Peng V, Wang M, Shchukina I, Greenberg ZJ, et al. Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders. Science. 2021;373:9277. https://doi.org/10.1126/science.abf9277.CrossRef

104.

Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 2016;19(1):20–7. https://doi.org/10.1038/nn.4185.CrossRefPubMedPubMedCentral

105.

Chen Z, Feng X, Herting CJ, Garcia VA, Nie K, Pong WW, et al. Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Can Res. 2017;77(9):2266–78. https://doi.org/10.1158/0008-5472.can-16-2310.CrossRef

106.

Gutmann DH, Kettenmann H. Microglia/brain macrophages as central drivers of brain tumor pathobiology. Neuron. 2019;104(3):442–9. https://doi.org/10.1016/j.neuron.2019.08.028.CrossRefPubMedPubMedCentral

107.

Liu H, Sun Y, Zhang Q, Jin W, Gordon RE, Zhang Y, et al. Pro-inflammatory and proliferative microglia drive progression of glioblastoma. Cell Rep. 2021;36(11):109718. https://doi.org/10.1016/j.celrep.2021.109718.CrossRefPubMed

108.

Komohara Y, Ohnishi K, Kuratsu J, Takeya M. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol. 2008;216(1):15–24. https://doi.org/10.1002/path.2370.CrossRefPubMed

109.

Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–86. https://doi.org/10.1016/j.it.2004.09.015.CrossRefPubMed

110.

Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549–55. https://doi.org/10.1016/s1471-4906(02)02302-5.CrossRefPubMed

111.

Umemura N, Saio M, Suwa T, Kitoh Y, Bai J, Nonaka K, et al. Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics. J Leukoc Biol. 2008;83(5):1136–44. https://doi.org/10.1189/jlb.0907611.CrossRefPubMed

112.

Hara T, Chanoch-Myers R, Mathewson ND, Myskiw C, Atta L, Bussema L, et al. Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma. Cancer Cell. 2021;39(6):779-92.e11. https://doi.org/10.1016/j.ccell.2021.05.002.CrossRefPubMed

113.

Raychaudhuri B, Rayman P, Ireland J, Ko J, Rini B, Borden EC, et al. Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro Oncol. 2011;13(6):591–9. https://doi.org/10.1093/neuonc/nor042.CrossRefPubMedPubMedCentral

114.

Won W-J, Deshane JS, Leavenworth JW, Oliva CR, Griguer CE. Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma. Cell Stress. 2019;3(2):47–65.CrossRef

115.

Dubinski D, Wölfer J, Hasselblatt M, Schneider-Hohendorf T, Bogdahn U, Stummer W, et al. CD4+T effector memory cell dysfunction is associated with the accumulation of granulocytic myeloid-derived suppressor cells in glioblastoma patients. Neuro Oncol. 2016;18(6):807–18. https://doi.org/10.1093/neuonc/nov280.CrossRefPubMed

116.

Rodríguez PC, Ochoa AC. Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev. 2008;222(1):180–91. https://doi.org/10.1111/j.1600-065x.2008.00608.x.CrossRefPubMedPubMedCentral

117.

Otvos B, Silver DJ, Mulkearns-Hubert EE, Alvarado AG, Turaga SM, Sorensen MD, et al. Cancer stem cell-secreted macrophage migration inhibitory factor stimulates myeloid derived suppressor cell function and facilitates glioblastoma immune evasion. Stem Cells. 2016;34(8):2026–39. https://doi.org/10.1002/stem.2393.CrossRefPubMedPubMedCentral

118.

Lee-Chang C, Rashidi A, Miska J, Zhang P, Pituch KC, Hou D, et al. Myeloid-derived suppressive cells promote B cell–mediated immunosuppression via transfer of PD-L1 in glioblastoma. Cancer Immunol Res. 2019;7(12):1928–43. https://doi.org/10.1158/2326-6066.cir-19-0240.CrossRefPubMedPubMedCentral

119.

Peereboom DM, Alban TJ, Grabowski MM, Alvarado AG, Otvos B, Bayik D, et al. Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cells. JCI Insight. 2019;4(22):e130748. https://doi.org/10.1172/jci.insight.130748.CrossRefPubMedCentral

120.

Joffre OP, Segura E, Savina A, Amigorena S. Cross-presentation by dendritic cells. Nat Rev Immunol. 2012;12(8):557–69. https://doi.org/10.1038/nri3254.CrossRefPubMed

121.

De Leo A, Ugolini A, Veglia F. Myeloid Cells in Glioblastoma Microenvironment. Cells. 2020;10(1):18. https://doi.org/10.3390/cells10010018.CrossRefPubMedCentral

122.

Tran Janco JM, Lamichhane P, Karyampudi L, Knutson KL. Tumor-infiltrating dendritic cells in cancer pathogenesis. J Immunol. 2015;194(7):2985–91. https://doi.org/10.4049/jimmunol.1403134.CrossRefPubMed

123.

Harimoto H, Shimizu M, Nakagawa Y, Nakatsuka K, Wakabayashi A, Sakamoto C, et al. Inactivation of tumor-specific CD8+ CTLs by tumor-infiltrating tolerogenic dendritic cells. Immunol Cell Biol. 2013;91(9):545–55. https://doi.org/10.1038/icb.2013.38.CrossRefPubMedPubMedCentral

124.

Yan J, Zhao Q, Gabrusiewicz K, Kong L-Y, Xia X, Wang J, et al. FGL2 promotes tumor progression in the CNS by suppressing CD103+ dendritic cell differentiation. Nat Commun. 2019;10(1):1–15. https://doi.org/10.1038/s41467-018-08271-x.CrossRef

125.

Wang J, Liu P, Xin S, Wang Z, Li J. Nrf2 suppresses the function of dendritic cells to facilitate the immune escape of glioma cells. Exp Cell Res. 2017;360(2):66–73. https://doi.org/10.1016/j.yexcr.2017.07.031.CrossRefPubMed

126.

Tyrinova T, Leplina O, Mishinov S, Tikhonova M, Dolgova E, Proskurina A, et al. Defective regulation of membrane TNFα expression in dendritic cells of glioblastoma patients leads to the impairment of cytotoxic activity against autologous tumor cells. Int J Mol Sci. 2020;21(8):2898. https://doi.org/10.3390/ijms21082898.CrossRefPubMedCentral

127.

Mitchell DA, Batich KA, Gunn MD, Huang M-N, Sanchez-Perez L, Nair SK, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature. 2015;519(7543):366–9. https://doi.org/10.1038/nature14320.CrossRefPubMedPubMedCentral

128.

Srivastava S, Jackson C, Kim T, Choi J, Lim M. A characterization of dendritic cells and their role in immunotherapy in glioblastoma: from preclinical studies to clinical trials. Cancers. 2019;11(4):537. https://doi.org/10.3390/cancers11040537.CrossRefPubMedCentral

129.

Lucas KG, Bao L, Bruggeman R, Dunham K, Specht C. The detection of CMV pp65 and IE1 in glioblastoma multiforme. J Neurooncol. 2011;103(2):231–8. https://doi.org/10.1007/s11060-010-0383-6.CrossRefPubMed

130.

Reap EA, Suryadevara CM, Batich KA, Sanchez-Perez L, Archer GE, Schmittling RJ, et al. Dendritic cells enhance polyfunctionality of adoptively transferred T cells that target cytomegalovirus in glioblastoma. Cancer Res. 2018;78(1):256–64. https://doi.org/10.1158/0008-5472.can-17-0469.CrossRefPubMed

131.

Nair SK, De Leon G, Boczkowski D, Schmittling R, Xie W, Staats J, et al. Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells. Clin Cancer Res. 2014;20(10):2684–94. https://doi.org/10.1158/1078-0432.ccr-13-3268.CrossRefPubMedPubMedCentral

132.

Batich KA, Reap EA, Archer GE, Sanchez-Perez L, Nair SK, Schmittling RJ, et al. Long-term survival in glioblastoma with cytomegalovirus pp65-targeted vaccination. Clin Cancer Res. 2017;23(8):1898–909. https://doi.org/10.1158/1078-0432.ccr-16-2057.CrossRefPubMedPubMedCentral

133.

Batich KA, Mitchell DA, Healy P, Herndon JE, Sampson JH. Once, twice, three times a finding: reproducibility of dendritic cell vaccine trials targeting cytomegalovirus in glioblastoma. Clin Cancer Res. 2020;26(20):5297–303. https://doi.org/10.1158/1078-0432.ccr-20-1082.CrossRefPubMed

134.

Akasaki Y, Kikuchi T, Homma S, Koido S, Ohkusa T, Tasaki T, et al. Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma. Cancer Immunol Immunother. 2016;65(12):1499–509. https://doi.org/10.1007/s00262-016-1905-7.CrossRefPubMed

135.

Wen PY, Reardon DA, Armstrong TS, Phuphanich S, Aiken RD, Landolfi JC, et al. A randomized double-blind placebo-controlled phase II trial of dendritic cell vaccine ICT-107 in newly diagnosed patients with glioblastoma. Clin Cancer Res. 2019;25(19):5799–807. https://doi.org/10.1158/1078-0432.ccr-19-0261.CrossRefPubMedPubMedCentral

136.

Phuphanich S, Wheeler CJ, Rudnick JD, Mazer M, Wang H, Nuño 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. https://doi.org/10.1007/s00262-012-1319-0.CrossRefPubMed

137.

Zhang JG, Eguchi J, Kruse CA, Gomez GG, Fakhrai H, Schroter S, et al. Antigenic profiling of glioma cells to generate allogeneic vaccines or dendritic cell-based therapeutics. Clin Cancer Res. 2007;13(2):566–75. https://doi.org/10.1158/1078-0432.ccr-06-1576.CrossRefPubMedPubMedCentral

138.

Buchroithner J, Erhart F, Pichler J, Widhalm G, Preusser M, Stockhammer G, et al. Audencel immunotherapy based on dendritic cells has no effect on overall and progression-free survival in newly diagnosed glioblastoma: a phase II randomized trial. Cancers. 2018;10(10):372. https://doi.org/10.3390/cancers10100372.CrossRefPubMedCentral

139.

Liau LM, Ashkan K, Tran DD, Campian JL, Trusheim JE, Cobbs CS, et al. First results on survival from a large phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med. 2018;16(1):1–9. https://doi.org/10.1186/s12967-018-1507-6.CrossRef

140.

Reardon DA, Desjardins A, Vredenburgh JJ, O’Rourke DM, Tran DD, Fink KL, et al. Rindopepimut with bevacizumab for patients with relapsed EGFRvIII-expressing glioblastoma (ReACT): results of a double-blind randomized phase II trial. Clin Cancer Res. 2020;26(7):1586–94. https://doi.org/10.1158/1078-0432.ccr-18-1140.CrossRefPubMed

141.

Elsamadicy AA, Chongsathidkiet P, Desai R, Woroniecka K, Farber SH, Fecci PE, et al. Prospect of rindopepimut in the treatment of glioblastoma. Expert Opin Biol Ther. 2017;17(4):507–13. https://doi.org/10.1080/14712598.2017.1299705.CrossRefPubMedPubMedCentral

142.

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. https://doi.org/10.1200/jco.2010.28.6963.CrossRefPubMedPubMedCentral

143.

Schuster J, Lai RK, Recht LD, Reardon DA, Paleologos NA, Groves MD, et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol. 2015;17(6):854–61. https://doi.org/10.1093/neuonc/nou348.CrossRefPubMedPubMedCentral

144.

Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18(10):1373–85. https://doi.org/10.1016/s1470-2045(17)30517-x.CrossRefPubMed

145.

Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, et al. Glioblastoma eradication following immune checkpoint blockade in an orthotopic immunocompetent model. Cancer Immunol Res. 2016;4(2):124–35. https://doi.org/10.1158/2326-6066.cir-15-0151.CrossRefPubMed

146.

Elamin YY, Rafee S, Toomey S, Hennessy BT. Immune effects of bevacizumab: killing two birds with one stone. Cancer Microenviron. 2015;8(1):15–21. https://doi.org/10.1007/s12307-014-0160-8.CrossRefPubMed

147.

Ji N, Zhang Y, Liu Y, Xie J, Wang Y, Hao S, et al. Heat shock protein peptide complex-96 vaccination for newly diagnosed glioblastoma: a phase I, single-arm trial. JCI Insight. 2018;3(10):e99145. https://doi.org/10.1172/jci.insight.99145.CrossRefPubMedCentral

148.

Wu BX, Hong F, Zhang Y, Ansa-Addo E, Li Z. GRP94/gp96 in cancer: biology, structure, immunology, and drug development. Adv Cancer Res. 2016;129:165–90. https://doi.org/10.1016/bs.acr.2015.09.001.CrossRefPubMed

149.

Srivastava P. Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol. 2002;2(3):185–94. https://doi.org/10.1038/nri749.CrossRefPubMed

150.

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. https://doi.org/10.1093/neuonc/not203.CrossRefPubMed

151.

Kodysh J, Rubinsteyn A, Blazquez A, Mandeli J, Bhardwaj N, Hormigo A. CTIM-17. phase I study of the safety and immunogenicity of personalized neoantigen vaccines and tumor treating fields in patients with newly diagnosed glioblastoma. Neuro Oncol. 2020;22(Supplement_2):ii36. https://doi.org/10.1093/neuonc/noaa215.151.CrossRefPubMedCentral

152.

Bota DA, Chung J, Dandekar M, Carrillo JA, Kong X-T, Fu BD, et al. Phase II study of ERC1671 plus bevacizumab versus bevacizumab plus placebo in recurrent glioblastoma: interim results and correlations with CD4+ T-lymphocyte counts. CNS Oncol. 2018;7(3):CNS22. https://doi.org/10.2217/cns-2018-0009.CrossRefPubMedPubMedCentral

153.

Hilf N, Kuttruff-Coqui S, Frenzel K, Bukur V, Stevanović S, Gouttefangeas C, et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature. 2019;565(7738):240–5. https://doi.org/10.1038/s41586-018-0810-y.CrossRefPubMed

154.

Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature. 2019;565(7738):234–9. https://doi.org/10.1038/s41586-018-0792-9.CrossRefPubMed

155.

Woroniecka K, Chongsathidkiet P, Rhodin K, Kemeny H, Dechant C, Farber SH, et al. T-cell exhaustion signatures vary with tumor type and are severe in glioblastoma. Clin Cancer Res. 2018;24(17):4175–86. https://doi.org/10.1158/1078-0432.ccr-17-1846.CrossRefPubMedPubMedCentral

156.

Chongsathidkiet P, Jackson C, Koyama S, Loebel F, Cui X, Farber SH, et al. Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors. Nat Med. 2018;24(9):1459–68. https://doi.org/10.1038/s41591-018-0135-2.CrossRefPubMedPubMedCentral

157.

Strand S, Hofmann WJ, Hug H, Müller M, Otto G, Strand D, et al. Lymphocyte apoptosis induced by CD95 (APO–1/Fas) ligand–expressing tumor cells—a mechanism of immune evasion? Nat Med. 1996;2(12):1361–6. https://doi.org/10.1038/nm1296-1361.CrossRefPubMed

158.

Walker DG, Chuah T, Rist MJ, Pender MP. T-cell apoptosis in human glioblastoma multiforme: implications for immunotherapy. J Neuroimmunol. 2006;175(1–2):59–68. https://doi.org/10.1016/j.jneuroim.2006.03.006.CrossRefPubMed

159.

Yang I, Tihan T, Han SJ, Wrensch MR, Wiencke J, Sughrue ME, et al. CD8+ T-cell infiltrate in newly diagnosed glioblastoma is associated with long-term survival. J Clin Neurosci. 2010;17(11):1381–5. https://doi.org/10.1016/j.jocn.2010.03.031.CrossRefPubMedPubMedCentral

160.

Pellegatta S, Eoli M, Cuccarini V, Anghileri E, Pollo B, Pessina S, et al. Survival gain in glioblastoma patients treated with dendritic cell immunotherapy is associated with increased NK but not CD8+ T cell activation in the presence of adjuvant temozolomide. OncoImmunology. 2018;7(4):e1412901. https://doi.org/10.1080/2162402x.2017.1412901.CrossRefPubMedPubMedCentral

161.

Mathewson ND, Ashenberg O, Tirosh I, Gritsch S, Perez EM, Marx S, et al. Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis. Cell. 2021;184(5):1281-98.e26. https://doi.org/10.1016/j.cell.2021.01.022.CrossRefPubMedPubMedCentral

162.

Kane JR, Zhao J, Tsujiuchi T, Laffleur B, Arrieta VA, Mahajan A, et al. CD8+ T-cell–mediated immunoediting influences genomic evolution and immune evasion in murine gliomas. Clin Cancer Res. 2020;26(16):4390–401. https://doi.org/10.1158/1078-0432.ccr-19-3104.CrossRefPubMedPubMedCentral

163.

Gangoso E, Southgate B, Bradley L, Rus S, Galvez-Cancino F, McGivern N, et al. Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion. Cell. 2021;184(9):2454-70.e26. https://doi.org/10.1016/j.cell.2021.03.023.CrossRefPubMedPubMedCentral

164.

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. Can Res. 2006;66(6):3294–302. https://doi.org/10.1158/0008-5472.can-05-3773.CrossRef

165.

Chang AL, Miska J, Wainwright DA, Dey M, Rivetta CV, Yu D, et al. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Can Res. 2016;76(19):5671–82. https://doi.org/10.1158/0008-5472.can-16-0144.CrossRef

166.

Cao J-Y, Guo Q, Guan G-F, Zhu C, Zou C-Y, Zhang L-Y, et al. Elevated lymphocyte specific protein 1 expression is involved in the regulation of leukocyte migration and immunosuppressive microenvironment in glioblastoma. Aging. 2020;12(2):1656–84. https://doi.org/10.18632/aging.102706.CrossRefPubMedPubMedCentral

167.

Ferguson SD, Srinivasan VM, Heimberger AB. The role of STAT3 in tumor-mediated immune suppression. J Neurooncol. 2015;123(3):385–94. https://doi.org/10.1007/s11060-015-1731-3.CrossRefPubMed

168.

Piperi C, Papavassiliou KA, Papavassiliou AG. Pivotal role of STAT3 in shaping glioblastoma immune microenvironment. Cells. 2019;8(11):1398. https://doi.org/10.3390/cells8111398.CrossRefPubMedCentral

169.

Ott M, Kassab C, Marisetty A, Hashimoto Y, Wei J, Zamler D, et al. Radiation with STAT3 blockade triggers dendritic cell–T cell interactions in the glioma microenvironment and therapeutic efficacy. Clin Cancer Res. 2020;26(18):4983–94. https://doi.org/10.1158/1078-0432.ccr-19-4092.CrossRefPubMed

170.

Miska J, Lee-Chang C, Rashidi A, Muroski ME, Chang AL, Lopez-Rosas A, et al. HIF-1α Is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma. Cell Rep. 2019;27(1):226-37.e4. https://doi.org/10.1016/j.celrep.2019.03.029.CrossRefPubMedPubMedCentral

171.

Wainwright DA, Balyasnikova IV, Chang AL, Ahmed AU, Moon K-S, Auffinger B, et al. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res. 2012;18(22):6110–21. https://doi.org/10.1158/1078-0432.ccr-12-2130.CrossRefPubMedPubMedCentral

172.

Sordillo PP, Sordillo LA, Helson L. The kynurenine pathway: a primary resistance mechanism in patients with glioblastoma. Anticancer Res. 2017;37(5):2159–71. https://doi.org/10.21873/anticanres.11551.CrossRefPubMed

173.

Bagley SJ, Desai AS, Linette GP, June CH, O’Rourke DM. CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges. Neuro Oncol. 2018;20(11):1429–38. https://doi.org/10.1093/neuonc/noy032.CrossRefPubMedPubMedCentral

174.

Stock S, Schmitt M, Sellner L. Optimizing manufacturing protocols of chimeric antigen receptor T cells for improved anticancer immunotherapy. Int J Mol Sci. 2019;20(24):6223. https://doi.org/10.3390/ijms20246223.CrossRefPubMedCentral

175.

Van Der Stegen SJC, Hamieh M, Sadelain M. The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov. 2015;14(7):499–509. https://doi.org/10.1038/nrd4597.CrossRefPubMedPubMedCentral

176.

Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48. https://doi.org/10.1056/nejmoa1709866.CrossRefPubMedPubMedCentral

177.

Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, Mcguirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56. https://doi.org/10.1056/nejmoa1804980.CrossRefPubMed

178.

Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang W-C, et al. Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin Cancer Res. 2015;21(18):4062–72. https://doi.org/10.1158/1078-0432.ccr-15-0428.CrossRefPubMedPubMedCentral

179.

Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375(26):2561–9. https://doi.org/10.1056/nejmoa1610497.CrossRefPubMedPubMedCentral

180.

Goff SL, Morgan RA, Yang JC, Sherry RM, Robbins PF, Restifo NP, et al. Pilot trial of adoptive transfer of chimeric antigen receptor–transduced T cells targeting EGFRvIII in patients with glioblastoma. J Immunother. 2019;42(4):126–35. https://doi.org/10.1097/cji.0000000000000260.CrossRefPubMedPubMedCentral

181.

Zhang C, Burger MC, Jennewein L, Genßler S, Schönfeld K, Zeiner P, et al. Specific NK cells for targeted therapy of glioblastoma. JNCI: J Natl Cancer Inst. 2016;108(5):djv375. https://doi.org/10.1093/jnci/djv375.CrossRef

182.

Ahmed N, Brawley V, Hegde M, Bielamowicz K, Kalra M, Landi D, et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma. JAMA Oncol. 2017;3(8):1094. https://doi.org/10.1001/jamaoncol.2017.0184.CrossRefPubMedPubMedCentral

183.

Weiss T, Weller M, Guckenberger M, Sentman CL, Roth P. NKG2D-based CAR T cells and radiotherapy exert synergistic efficacy in glioblastoma. Can Res. 2018;78(4):1031–43. https://doi.org/10.1158/0008-5472.can-17-1788.CrossRef

184.

Yang D, Sun B, Dai H, Li W, Shi L, Zhang P, et al. T cells expressing NKG2D chimeric antigen receptors efficiently eliminate glioblastoma and cancer stem cells. J Immunother Cancer. 2019;7(1):1–13. https://doi.org/10.1186/s40425-019-0642-9.CrossRef

185.

O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, et al. 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. 2017;9(399):eaaa0984. https://doi.org/10.1126/scitranslmed.aaa0984.CrossRefPubMedPubMedCentral

186.

Agliardi G, Liuzzi AR, Hotblack A, De Feo D, Núñez N, Stowe CL, et al. Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma. Nat Commun. 2021;12(1):1–11. https://doi.org/10.1038/s41467-020-20599-x.CrossRef

187.

Choi BD, Yu X, Castano AP, Darr H, Henderson DB, Bouffard AA, et al. CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma. J immunother Cancer. 2019;7(1):1–8. https://doi.org/10.1186/s40425-019-0806-7.CrossRef

188.

Nakazawa T, Natsume A, Nishimura F, Morimoto T, Matsuda R, Nakamura M, et al. Effect of CRISPR/Cas9-mediated PD-1-disrupted primary human third-generation CAR-T cells targeting EGFRvIII on in vitro human glioblastoma cell growth. Cells. 2020;9(4):998. https://doi.org/10.3390/cells9040998.CrossRefPubMedCentral

189.

Wang D, Starr R, Chang W-C, Aguilar B, Alizadeh D, Wright SL, et al. Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Sci Transl Med. 2020;12(533):eaaw2672. https://doi.org/10.1126/scitranslmed.aaw2672.CrossRefPubMedPubMedCentral

190.

Tang X, Zhao S, Zhang Y, Wang Y, Zhang Z, Yang M, et al. B7–H3 as a novel CAR-T therapeutic target for glioblastoma. Mol Ther Oncol. 2019;14:279–87. https://doi.org/10.1016/j.omto.2019.07.002.CrossRef

191.

Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management. Blood Rev. 2019;34:45–55. https://doi.org/10.1016/j.blre.2018.11.002.CrossRefPubMed

192.

Gust J, Hay KA, Hanafi L-A, Li D, Myerson D, Gonzalez-Cuyar LF, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404–19. https://doi.org/10.1158/2159-8290.cd-17-0698.CrossRefPubMedPubMedCentral

193.

Wu S-Y, Fu T, Jiang Y-Z, Shao Z-M. Natural killer cells in cancer biology and therapy. Mol Cancer. 2020;19(1):1–26. https://doi.org/10.1186/s12943-020-01238-x.CrossRefPubMedPubMedCentral

194.

Castriconi R, Daga A, Dondero A, Zona G, Poliani PL, Melotti A, et al. NK cells recognize and kill human glioblastoma cells with stem cell-like properties. J Immunol. 2009;182(6):3530–9. https://doi.org/10.4049/jimmunol.0802845.CrossRefPubMed

195.

Avril T, Vauleon E, Hamlat A, Saikali S, Etcheverry A, Delmas C, et al. Human glioblastoma stem-like cells are more sensitive to allogeneic NK and T cell-mediated killing compared with serum-cultured glioblastoma cells. Brain Pathol. 2012;22(2):159–74. https://doi.org/10.1111/j.1750-3639.2011.00515.x.CrossRefPubMed

196.

Shaim H, Shanley M, Basar R, Daher M, Gumin J, Zamler DB, et al. Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells. J Clin Investig. 2021. https://doi.org/10.1172/jci142116.CrossRefPubMedPubMedCentral

197.

Lee SJ, Kang WY, Yoon Y, Jin JY, Song HJ, Her JH, et al. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. BMC Cancer. 2015;15(1):1–13. https://doi.org/10.1186/s12885-015-2034-y.CrossRef

198.

Friebel E, Kapolou K, Unger S, Núñez NG, Utz S, Rushing EJ, et al. Single-cell mapping of human brain cancer reveals tumor-specific instruction of tissue-invading leukocytes. Cell. 2020;181(7):1626-42.e20. https://doi.org/10.1016/j.cell.2020.04.055.CrossRefPubMed

199.

Flüh C, Chitadze G, Adamski V, Hattermann K, Synowitz M, Kabelitz D, et al. NKG2D ligands in glioma stem-like cells: expression in situ and in vitro. Histochem Cell Biol. 2018;149(3):219–33. https://doi.org/10.1007/s00418-018-1633-5.CrossRefPubMed

200.

Close HJ, Stead LF, Nsengimana J, Reilly KA, Droop A, Wurdak H, et al. Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma. Clin Exp Immunol. 2020;200(1):33–44. https://doi.org/10.1111/cei.13403.CrossRefPubMed

201.

Crane CA, Austgen K, Haberthur K, Hofmann C, Moyes KW, Avanesyan L, et al. Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients. Proc Natl Acad Sci. 2014;111(35):12823–8. https://doi.org/10.1073/pnas.1413933111.CrossRefPubMedPubMedCentral

202.

Lang FF, Conrad C, Gomez-Manzano C, Yung WKA, Sawaya R, Weinberg JS, et al. Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol. 2018;36(14):1419–27. https://doi.org/10.1200/jco.2017.75.8219.CrossRefPubMedPubMedCentral

203.

Martikainen M, Essand M. Virus-Based Immunotherapy of Glioblastoma. Cancers. 2019;11(2):186. https://doi.org/10.3390/cancers11020186.CrossRefPubMedCentral

204.

Bartee E, Li Z. In vivo and in situ programming of tumor immunity by combining oncolytics and PD-1 immune checkpoint blockade. Exp Hematol Oncol. 2017;6:15. https://doi.org/10.1186/s40164-017-0075-4.CrossRefPubMedPubMedCentral

205.

Zhu S, Zhang T, Zheng L, Liu H, Song W, Liu D, et al. Combination strategies to maximize the benefits of cancer immunotherapy. J Hematol Oncol. 2021;14(1):156. https://doi.org/10.1186/s13045-021-01164-5.CrossRefPubMedPubMedCentral

206.

Nwagwu CD, Immidisetti AV, Bukanowska G, Vogelbaum MA, Carbonell A-M. Convection-enhanced delivery of a first-in-class anti-β1 integrin antibody for the treatment of high-grade glioma utilizing real-time imaging. Pharmaceutics. 2020;13(1):40. https://doi.org/10.3390/pharmaceutics13010040.CrossRefPubMedPubMedCentral

207.

Farrera-Sal M, Moya-Borrego L, Bazan-Peregrino M, Alemany R. Evolving status of clinical immunotherapy with oncolytic adenovirus. Clin Cancer Res. 2021;27(11):2979–88. https://doi.org/10.1158/1078-0432.ccr-20-1565.CrossRefPubMed

208.

Zhu Z, Mesci P, Bernatchez JA, Gimple RC, Wang X, Schafer ST, et al. Zika virus targets glioblastoma stem cells through a SOX2-integrin α. Cell Stem Cell. 2020;26(2):187-204.e10. https://doi.org/10.1016/j.stem.2019.11.016.CrossRefPubMed

209.

Nair S, Mazzoccoli L, Jash A, Govero J, Bais SS, Hu T, et al. Zika virus oncolytic activity requires CD8+ T cells and is boosted by immune checkpoint blockade. JCI Insight. 2021;6(1):e144619. https://doi.org/10.1172/jci.insight.144619.CrossRefPubMedCentral

210.

Desjardins A, Gromeier M, Herndon JE, Beaubier N, Bolognesi DP, Friedman AH, et al. Recurrent glioblastoma treated with recombinant poliovirus. N Engl J Med. 2018;379(2):150–61. https://doi.org/10.1056/nejmoa1716435.CrossRefPubMedPubMedCentral

211.

Lupo KB, Matosevic S. CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma. J Hematol Oncol. 2020;13(1):1–10. https://doi.org/10.1186/s13045-020-00913-2.CrossRef

212.

Fueyo J, Gomez-Manzano C, Alemany R, Lee PS, Mcdonnell TJ, Mitlianga P, et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene. 2000;19(1):2–12. https://doi.org/10.1038/sj.onc.1203251.CrossRefPubMed

213.

Geletneky K, Huesing J, Rommelaere J, Schlehofer JR, Leuchs B, Dahm M, et al. Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol. BMC Cancer. 2012;12(1):99. https://doi.org/10.1186/1471-2407-12-99.CrossRefPubMedPubMedCentral

214.

Geletneky K, Hajda J, Angelova AL, Leuchs B, Capper D, Bartsch AJ, et al. Oncolytic H-1 parvovirus shows safety and signs of immunogenic activity in a first phase I/IIa glioblastoma trial. Mol Ther. 2017;25(12):2620–34. https://doi.org/10.1016/j.ymthe.2017.08.016.CrossRefPubMedPubMedCentral

215.

Markert JM, Razdan SN, Kuo H-C, Cantor A, Knoll A, Karrasch M, et al. A phase 1 trial of oncolytic HSV-1, G207, Given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol Ther. 2014;22(5):1048–55. https://doi.org/10.1038/mt.2014.22.CrossRefPubMedPubMedCentral

216.

Friedman GK, Johnston JM, Bag AK, Bernstock JD, Li R, Aban I, et al. Abstract CT018: phase I immunovirotherapy trial of oncolytic HSV-1 G207 alone or combined with radiation in pediatric high-grade glioma. Cancer Res. 2021;81(13):CT018. https://doi.org/10.1158/1538-7445.am2021-ct018.CrossRef

217.

Friedman GK, Johnston JM, Bag AK, Bernstock JD, Li R, Aban I, et al. Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas. N Engl J Med. 2021;384(17):1613–22. https://doi.org/10.1056/nejmoa2024947.CrossRefPubMedPubMedCentral

218.

Fares J, Ahmed AU, Ulasov IV, Sonabend AM, Miska J, Lee-Chang C, et al. Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial. Lancet Oncol. 2021;22(8):1103–14. https://doi.org/10.1016/S1470-2045(21)00245-X.CrossRefPubMed

219.

Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, et al. Neural stem cells display extensive tropism for pathology in adult brain: Evidence from intracranial gliomas. Proc Natl Acad Sci. 2000;97(23):12846–51. https://doi.org/10.1073/pnas.97.23.12846.CrossRefPubMedPubMedCentral

220.

Kim S-K, Kim SU, Park IH, Bang JH, Aboody KS, Wang K-C, et al. Human neural stem cells target experimental intracranial medulloblastoma and deliver a therapeutic gene leading to tumor regression. Clin Cancer Res. 2006;12(18):5550–6. https://doi.org/10.1158/1078-0432.ccr-05-2508.CrossRefPubMed

221.

Kieran MW, Goumnerova L, Manley P, Chi SN, Marcus KJ, Manzanera AG, et al. Phase I study of gene-mediated cytotoxic immunotherapy with AdV-tk as adjuvant to surgery and radiation for pediatric malignant glioma and recurrent ependymoma. Neuro Oncol. 2019;21(4):537–46. https://doi.org/10.1093/neuonc/noy202.CrossRefPubMedPubMedCentral

222.

Stavrakaki E, Dirven CMF, Lamfers MLM. Personalizing oncolytic virotherapy for glioblastoma in search of biomarkers for response. Cancers. 2021;13(4):614. https://doi.org/10.3390/cancers13040614.CrossRefPubMedPubMedCentral

223.

Andrews DW, Resnicoff M, Flanders AE, Kenyon L, Curtis M, Merli G, et al. Results of a pilot study involving the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor in malignant astrocytomas. J Clin Oncol. 2001;19(8):2189–200. https://doi.org/10.1200/jco.2001.19.8.2189.CrossRefPubMed

224.

Tirrò E, Massimino M, Romano C, Martorana F, Pennisi MS, Stella S, et al. Prognostic and therapeutic roles of the insulin growth factor system in glioblastoma. Front Oncol. 2020;10:612385. https://doi.org/10.3389/fonc.2020.612385.CrossRefPubMed

225.

Andrews DW, Judy KD, Scott CB, Garcia S, Harshyne LA, Kenyon L, et al. Phase Ib clinical trial of IGV-001 for patients with newly diagnosed glioblastoma. Clin Cancer Res. 2021;27(7):1912–22. https://doi.org/10.1158/1078-0432.ccr-20-3805.CrossRefPubMed

226.

Reardon DA, Brem S, Desai AS, Bagley SJ, Kurz SC, Fuente MIDL, et al. INO-5401 and INO-9012 delivered intramuscularly (IM) with electroporation (EP) in combination with cemiplimab (REGN2810) in newly diagnosed glioblastoma (GBM): interim results. J Clin Oncol. 2020;38(15_suppl):2514. https://doi.org/10.1200/JCO.2020.38.15_suppl.2514.CrossRef

227.

Lee Y, Koh J, Kim S-I, Won JK, Park C-K, Choi SH, et al. The frequency and prognostic effect of TERT promoter mutation in diffuse gliomas. Acta Neuropathol Commun. 2017;5(1):1–11. https://doi.org/10.1186/s40478-017-0465-1.CrossRef

228.

Lee S, Kambhampati M, Yadavilli S, Gordish-Dressman H, Santi M, Cruz CR, et al. Differential expression of wilms’ tumor protein in diffuse intrinsic pontine glioma. J Neuropathol Exp Neurol. 2019;78(5):380–8. https://doi.org/10.1093/jnen/nlz021.CrossRefPubMedPubMedCentral

229.

Nakahara Y, Okamoto H, Mineta T, Tabuchi K. Expression of the Wilms’ tumor gene product WT1 in glioblastomas and medulloblastomas. Brain Tumor Pathol. 2004;21(3):113–6. https://doi.org/10.1007/bf02482185.CrossRefPubMed

230.

Holzgreve A, Biczok A, Ruf VC, Liesche-Starnecker F, Steiger K, Kirchner MA, et al. PSMA expression in glioblastoma as a basis for theranostic approaches: a retrospective, correlational panel study including immunohistochemistry, clinical parameters and PET imaging. Front Oncol. 2021;11:646387. https://doi.org/10.3389/fonc.2021.646387.CrossRefPubMedPubMedCentral

231.

Chakraborty C, Sharma AR, Bhattacharya M, Lee SS. From COVID-19 to cancer mRNA vaccines: moving from bench to clinic in the vaccine landscape. Front Immunol. 2021;12:679344. https://doi.org/10.3389/fimmu.2021.679344.CrossRefPubMedPubMedCentral

232.

Chan HY, Choi J, Jackson C, Lim M. Combination immunotherapy strategies for glioblastoma. J Neurooncol. 2021;151(3):375–91. https://doi.org/10.1007/s11060-020-03481-0.CrossRefPubMed

233.

Hung AL, Maxwell R, Theodros D, Belcaid Z, Mathios D, Luksik AS, et al. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. OncoImmunology. 2018;7:e1466769. https://doi.org/10.1080/2162402x.2018.1466769.CrossRefPubMedPubMedCentral

234.

Wu A, Maxwell R, Xia Y, Cardarelli P, Oyasu M, Belcaid Z, et al. Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment. J Neurooncol. 2019;143(2):241–9. https://doi.org/10.1007/s11060-019-03172-5.CrossRefPubMed

235.

Speranza M-C, Passaro C, Ricklefs F, Kasai K, Klein SR, Nakashima H, et al. Preclinical investigation of combined gene-mediated cytotoxic immunotherapy and immune checkpoint blockade in glioblastoma. Neuro Oncol. 2018;20(2):225–35. https://doi.org/10.1093/neuonc/nox139.CrossRefPubMed

236.

Saha D, Martuza RL, Rabkin SD. Macrophage polarization contributes to glioblastoma eradication by combination immunovirotherapy and immune checkpoint blockade. Cancer Cell. 2017;32(2):253-67.e5. https://doi.org/10.1016/j.ccell.2017.07.006.CrossRefPubMedPubMedCentral

237.

Finocchiaro G, Gentner B, Farina F, Capotondo A, Eoli M, Anghileri E, et al. A phase I-IIa study of genetically modified Tie-2 expressing monocytes in patients with glioblastoma multiforme (TEM-GBM Study). J Clin Oncol. 2021;39(15_suppl):2532. https://doi.org/10.1200/JCO.2021.39.15_suppl.2532.CrossRef

238.

Brown CE, Aguilar B, Starr R, Yang X, Chang W-C, Weng L, et al. Optimization of IL13Rα2-targeted chimeric antigen receptor T cells for improved anti-tumor efficacy against glioblastoma. Mol Ther. 2018;26(1):31–44. https://doi.org/10.1016/j.ymthe.2017.10.002.CrossRefPubMed

239.

Unger JM, Hershman DL, Fleury ME, Vaidya R. Association of patient comorbid conditions with cancer clinical trial participation. JAMA Oncol. 2019;5(3):326. https://doi.org/10.1001/jamaoncol.2018.5953.CrossRefPubMedPubMedCentral

240.

Jirka GW, Bisselou KSM, Smith LM, Shonka N. Evaluating the decisions of glioma patients regarding clinical trial participation: a retrospective single provider review. Med Oncol. 2019;36(4):1–6. https://doi.org/10.1007/s12032-019-1259-z.CrossRef

241.

Mahmud A, Zalay O, Springer A, Arts K, Eisenhauer E. Barriers to participation in clinical trials: a physician survey. Curr Oncol. 2018;25(2):119–25. https://doi.org/10.3747/co.25.3857.CrossRefPubMedPubMedCentral

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