Journal Home > Volume 2 , Issue 2
Cancer Innovation 2023, 2(2): 114-130 https://doi.org/10.1002/cai2.59
Review | Open Access | Issue | Published: 05 March 2023

Progress in phase Ⅲ clinical trials of molecular targeted therapy and immunotherapy for glioblastoma

Show Author's Information Yuekun Wang1,  Shenglan Li2,  Yichen Peng2,  Wenbin Ma1,  Yu Wang1( ),  Wenbin Li2 ( )
Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Department of Neuro‐oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

Yuekun Wang, Shenglan Li, and Yu Wang contributed equally to this work and shared the first authorship.

Keywords:
immunotherapy, glioblastoma, phase Ⅲ clinical trial, target therapy
Cite this article:
Wang Y, Li S, Peng Y, et al. Progress in phase Ⅲ clinical trials of molecular targeted therapy and immunotherapy for glioblastoma. Cancer Innovation, 2023, 2(2): 114-130. https://doi.org/10.1002/cai2.59
Download citation
EndNote(RIS)
BibTeX

394

Views

21

Downloads

Citations

0

Crossref

N/A

WoS

0

Scopus

N/A

CSCD

Abstract Full text About this article

Glioblastoma (GBM) is the most common primary central nervous system tumor, whose prognosis remains poor under the sequential standard of care, such as neurosurgery followed by concurrent temozolomide radiochemotherapy and adjuvant temozolomide chemotherapy in the presence or absence of tumor treating fields. Accordingly, the advent of molecular targeted therapy and immunotherapy has opened a new era of tumor management. A diverse range of targeted drugs have been tested in patients with GBM in phase Ⅲ clinical trials. However, these drugs are ineffective for all patients, as evidenced by the fact that only a minority of patients in these trials showed prolonged survival. Furthermore, there are several published phase Ⅲ clinical trials that involve immune checkpoint inhibitors, peptide vaccines, dendritic cell vaccines, and virotherapy. Accordingly, this review comprehensively overviews existing studies of targeted drugs and immunotherapy for glioma and discusses the challenge and perspective of targeted drugs and immunotherapy for glioma to clarify future directions.


menu
Abstract
Full text
Outline
About this article

Progress in phase Ⅲ clinical trials of molecular targeted therapy and immunotherapy for glioblastoma

Show Author's information Yuekun Wang1, Shenglan Li2, Yichen Peng2, Wenbin Ma1, Yu Wang1( ), Wenbin Li2 ( )
Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Department of Neuro‐oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

Yuekun Wang, Shenglan Li, and Yu Wang contributed equally to this work and shared the first authorship.

Abstract

Glioblastoma (GBM) is the most common primary central nervous system tumor, whose prognosis remains poor under the sequential standard of care, such as neurosurgery followed by concurrent temozolomide radiochemotherapy and adjuvant temozolomide chemotherapy in the presence or absence of tumor treating fields. Accordingly, the advent of molecular targeted therapy and immunotherapy has opened a new era of tumor management. A diverse range of targeted drugs have been tested in patients with GBM in phase Ⅲ clinical trials. However, these drugs are ineffective for all patients, as evidenced by the fact that only a minority of patients in these trials showed prolonged survival. Furthermore, there are several published phase Ⅲ clinical trials that involve immune checkpoint inhibitors, peptide vaccines, dendritic cell vaccines, and virotherapy. Accordingly, this review comprehensively overviews existing studies of targeted drugs and immunotherapy for glioma and discusses the challenge and perspective of targeted drugs and immunotherapy for glioma to clarify future directions.

Keywords: immunotherapy, glioblastoma, phase Ⅲ clinical trial, target therapy

References(117)

1

Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz‐Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011‐2015. Neuro‐Oncology. 2018;20(suppl_4):iv1–iv86. https://doi.org/10.1093/neuonc/noy131
DOI Google Scholar
2

Preusser M, Lim M, Hafler DA, Reardon DA, Sampson JH. Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol. 2015;11(9):504–14. https://doi.org/10.1038/nrneurol.2015.139
DOI Google Scholar
3

Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase Ⅲ study: 5‐year analysis of the EORTC‐NCIC trial. Lancet Oncol. 2009;10(5):459–66. https://doi.org/10.1016/S1470-2045(09)70025-7
DOI Google Scholar
4

Wen PY, Weller M, Lee EQ, Alexander BM, Barnholtz‐Sloan JS, Barthel FP, et al. Glioblastoma in adults: a Society for Neuro‐Oncology (SNO) and European Society of Neuro‐Oncology (EANO) consensus review on current management and future directions. Neuro‐Oncology. 2020;22(8):1073–113. https://doi.org/10.1093/neuonc/noaa106
DOI Google Scholar
5

Ostrom QT, Price M, Neff C, Cioffi G, Waite KA, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2015‐2019. Neuro‐Oncology. 2022;24(suppl_4):v1–v95. https://doi.org/10.1093/neuonc/noac202
DOI Google Scholar
6

Morgan LL. The epidemiology of glioma in adults: a “state of the science” review. Neuro‐Oncology. 2015;17(4):623–4. https://doi.org/10.1093/neuonc/nou358
DOI Google Scholar
7

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97–109. https://doi.org/10.1007/s00401-007-0243-4
DOI Google Scholar
8

Berger TR, Wen PY, Lang‐Orsini M, Chukwueke UN. World Health Organization 2021 classification of central nervous system tumors and implications for therapy for adult‐type gliomas: a review. JAMA Oncol. 2022;8(10):1493–501. https://doi.org/10.1001/jamaoncol.2022.2844
DOI Google Scholar
9

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
DOI Google Scholar
10

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‐Oncology. 2021;23(8):1231–51. https://doi.org/10.1093/neuonc/noab106
DOI Google Scholar
11

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: a randomized clinical trial. JAMA. 2015;314(23):2535–43. https://doi.org/10.1001/jama.2015.16669
DOI Google Scholar
12

Ronellenfitsch MW, Zeiner PS, Mittelbronn M, Urban H, Pietsch T, Reuter D, et al. Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma. Acta Neuropathol Commun. 2018;6(1):81. https://doi.org/10.1186/s40478-018-0583-4
DOI Google Scholar
13

Marin BM, Porath KA, Jain S, Kim M, Conage‐Pough JE, Oh JH, et al. Heterogeneous delivery across the blood‐brain barrier limits the efficacy of an EGFR‐targeting antibody drug conjugate in glioblastoma. Neuro‐Oncology. 2021;23(12):2042–53. https://doi.org/10.1093/neuonc/noab133
DOI Google Scholar
14

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
DOI Google Scholar
15

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
DOI Google Scholar
16

Sandmann T, Bourgon R, Garcia J, Li C, Cloughesy T, Chinot OL, et al. Patients with proneural glioblastoma may derive overall survival benefit from the addition of bevacizumab to first‐line radiotherapy and temozolomide: retrospective analysis of the AVAglio trial. J Clin Oncol. 2015;33(25):2735–44. https://doi.org/10.1200/JCO.2015.61.5005
DOI Google Scholar
17

Weller M, Nabors LB, Gorlia T, Leske H, Rushing E, Bady P, et al. Cilengitide in newly diagnosed glioblastoma: biomarker expression and outcome. Oncotarget. 2016;7(12):15018–32. https://doi.org/10.18632/oncotarget.7588
DOI Google Scholar
18

Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071‐22072 study): a multicentre, randomised, open‐label, phase 3 trial. Lancet Oncol. 2014;15(10):1100–8. https://doi.org/10.1016/S1470-2045(14)70379-1
DOI Google Scholar
19

Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the CheckMate 143 phase 3 randomized clinical trial. JAMA Oncol. 2020;6(7):1003–10. https://doi.org/10.1001/jamaoncol.2020.1024
DOI Google Scholar
20

Omuro A, Brandes AA, Carpentier AF, Idbaih A, Reardon DA, Cloughesy T, et al. Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: an international randomized phase Ⅲ trial. Neuro‐Oncology. 2023;25(1):123–34. https://doi.org/10.1093/neuonc/noac099
DOI Google Scholar
21

Lim M, Weller M, Idbaih A, Steinbach J, Finocchiaro G, Raval RR, et al. Phase Ⅲ trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Neuro‐Oncology. 2022;24(11):1935–49. https://doi.org/10.1093/neuonc/noac116
DOI Google Scholar
22

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
DOI Google Scholar
23

Narita Y, Arakawa Y, Yamasaki F, Nishikawa R, Aoki T, Kanamori M, et al. A randomized, double‐blind, phase Ⅲ trial of personalized peptide vaccination for recurrent glioblastoma. Neuro‐Oncology. 2019;21(3):348–59. https://doi.org/10.1093/neuonc/noy200
DOI Google Scholar
24

Liau LM, Ashkan K, Brem S, Campian JL, Trusheim JE, Iwamoto FM, et al. Association of autologous tumor lysate‐loaded dendritic cell vaccination with extension of survival among patients with newly diagnosed and recurrent glioblastoma: a phase 3 prospective externally controlled cohort trial. JAMA Oncol. 2023;9(1):112–21. https://doi.org/10.1001/jamaoncol.2022.5370
DOI Google Scholar
25

Rainov NG. A phase Ⅲ clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther. 2000;11(17):2389–401. https://doi.org/10.1089/104303400750038499
DOI Google Scholar
26

Westphal M, Ylä‐Herttuala S, Martin J, Warnke P, Menei P, Eckland D, et al. 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. 2013;14(9):823–33. https://doi.org/10.1016/S1470-2045(13)70274-2
DOI Google Scholar
27

Cloughesy TF, Brenner A, de Groot JF, Butowski NA, Zach L, Campian JL, et al. A randomized controlled phase Ⅲ study of VB‐111 combined with bevacizumab vs bevacizumab monotherapy in patients with recurrent glioblastoma (GLOBE). Neuro‐Oncology. 2020;22(5):705–17. https://doi.org/10.1093/neuonc/noz232
DOI Google Scholar
28

Szabo E, Schneider H, Seystahl K, Rushing EJ, Herting F, Weidner KM, et al. Autocrine VEGFR1 and VEGFR2 signaling promotes survival in human glioblastoma models in vitro and in vivo. Neuro‐Oncology. 2016;18(9):1242–52. https://doi.org/10.1093/neuonc/now043
DOI Google Scholar
29

Estrada CC, Maldonado A, Mallipattu SK. Therapeutic inhibition of VEGF signaling and associated nephrotoxicities. J Am Soc Nephrol. 2019;30(2):187–200. https://doi.org/10.1681/ASN.2018080853
DOI Google Scholar
30

Sorensen AG, Emblem KE, Polaskova P, Jennings D, Kim H, Ancukiewicz M, et al. Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res. 2012;72(2):402–7. https://doi.org/10.1158/0008-5472.CAN-11-2464
DOI Google Scholar
31

Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti‐VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun. 2005;333(2):328–35. https://doi.org/10.1016/j.bbrc.2005.05.132
DOI Google Scholar
32

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
DOI Google Scholar
33

Gilbert MR, Pugh SL, Aldape K, Sorensen AG, Mikkelsen T, Penas‐Prado M, et al. NRG oncology RTOG 0625: a randomized phase Ⅱ trial of bevacizumab with either irinotecan or dose‐dense temozolomide in recurrent glioblastoma. J Neurooncol. 2017;131(1):193–9. https://doi.org/10.1007/s11060-016-2288-5
DOI Google Scholar
34

Erdem‐Eraslan L, van den Bent MJ, Hoogstrate Y, Naz‐Khan H, Stubbs A, van der Spek P, et al. Identification of patients with recurrent glioblastoma who may benefit from combined bevacizumab and CCNU therapy: a report from the BELOB trial. Cancer Res. 2016;76(3):525–34. https://doi.org/10.1158/0008-5472.CAN-15-0776
DOI Google Scholar
35

Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST‐1): a multicentre, randomised, placebo‐controlled phase 3 trial. Lancet. 2013;381(9861):125–32. https://doi.org/10.1016/S0140-6736(12)61134-9
DOI Google Scholar
36

Ma DJ, Galanis E, Anderson SK, Schiff D, Kaufmann TJ, Peller PJ, et al. A phase Ⅱ trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K. Neuro‐Oncology. 2015;17(9):1261–9. https://doi.org/10.1093/neuonc/nou328
DOI Google Scholar
37

Brennan CW, Verhaak RGW, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462–77. https://doi.org/10.1016/j.cell.2013.09.034
DOI Google Scholar
38

Kelly WJ, Shah NJ, Subramaniam DS. Management of brain metastases in epidermal growth factor receptor mutant non‐small‐cell lung cancer. Front Oncol. 2018;8:208. https://doi.org/10.3389/fonc.2018.00208
DOI Google Scholar
39

De Witt Hamer PC. Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies. Neuro‐Oncology. 2010;12(3):304–16. https://doi.org/10.1093/neuonc/nop068
DOI Google Scholar
40

Neyns B, Sadones J, Joosens E, Bouttens F, Verbeke L, Baurain JF, et al. Stratified phase Ⅱ trial of cetuximab in patients with recurrent high‐grade glioma. Ann Oncol. 2009;20(9):1596–603. https://doi.org/10.1093/annonc/mdp032
DOI Google Scholar
41

Gan HK, Burgess AW, Clayton AHA, Scott AM. Targeting of a conformationally exposed, tumor‐specific epitope of EGFR as a strategy for cancer therapy. Cancer Res. 2012;72(12):2924–30. https://doi.org/10.1158/0008-5472.CAN-11-3898
DOI Google Scholar
42

Lassman AB, van den Bent MJ, Gan HK, Reardon DA, Kumthekar P, Butowski N, et al. Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR‐amplified, recurrent glioblastoma: results from an international phase Ⅰ multicenter trial. Neuro‐Oncology. 2019;21(1):106–14. https://doi.org/10.1093/neuonc/noy091
DOI Google Scholar
43

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‐Oncology. 2015;17(6):854–61. https://doi.org/10.1093/neuonc/nou348
DOI Google Scholar
44

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
DOI Google Scholar
45

Drilon A. TRK inhibitors in TRK fusion‐positive cancers. Ann Oncol. 2019;30(Suppl_8):viii23–30. https://doi.org/10.1093/annonc/mdz282
DOI Google Scholar
46

Kaley T, Touat M, Subbiah V, Hollebecque A, Rodon J, Lockhart AC, et al. BRAF inhibition in BRAF(V600)‐mutant gliomas: results from the VE‐BASKET Study. J Clin Oncol. 2018;36(35):3477–84. https://doi.org/10.1200/JCO.2018.78.9990
DOI Google Scholar
47

Wen P, Stein A, van den Bent M, De Greve J, Dietrich S, De Vos F, et al. ACTR‐30. Updated efficacy and safety of dabrafenib plus trametinib in patients with recurrent/refractory braf V600E‐mutated high‐grade glioma (HGG) and low‐grade glioma (LGG). Neuro‐Oncology. 2019;21(Suppl_6):vi19–20. https://doi.org/10.1093/neuonc/noz175.073
DOI Google Scholar
48

Lombardi G, De Salvo GL, Brandes AA, Eoli M, Rudà R, Faedi M, et al. Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open‐label, randomised, controlled, phase 2 trial. Lancet Oncol. 2019;20(1):110–9. https://doi.org/10.1016/S1470-2045(18)30675-2
DOI Google Scholar
49

Alexander BM, Ba S, Berger MS, Berry DA, Cavenee WK, Chang SM, et al. Adaptive global innovative learning environment for glioblastoma: GBM AGILE. Clin Cancer Res. 2018;24(4):737–43. https://doi.org/10.1158/1078-0432.CCR-17-0764
DOI Google Scholar
50

Schnell O, Krebs B, Carlsen J, Miederer I, Goetz C, Goldbrunner RH, et al. Imaging of integrin αvβ3 expression in patients with malignant glioma by [18F] Galacto‐RGD positron emission tomography. Neuro‐Oncology. 2009;11(6):861–70. https://doi.org/10.1215/15228517-2009-024
DOI Google Scholar
51

Mikkelsen T, Brodie C, Finniss S, Berens ME, Rennert JL, Nelson K, et al. Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule‐dependency. Int J Cancer. 2009;124(11):2719–27. https://doi.org/10.1002/ijc.24240
DOI Google Scholar
52

Gerstner ER, Ye X, Duda DG, Levine MA, Mikkelsen T, Kaley TJ, et al. A phase Ⅰ study of cediranib in combination with cilengitide in patients with recurrent glioblastoma. Neuro‐Oncology. 2015;17(10):1386–92. https://doi.org/10.1093/neuonc/nov085
DOI Google Scholar
53

Gilbert MR, Kuhn J, Lamborn KR, Lieberman F, Wen PY, Mehta M, et al. Cilengitide in patients with recurrent glioblastoma: the results of NABTC 03‐02, a phase Ⅱ trial with measures of treatment delivery. J Neurooncol. 2012;106(1):147–53. https://doi.org/10.1007/s11060-011-0650-1
DOI Google Scholar
54

Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O'Neill A, Plotkin S, et al. Randomized phase Ⅱ study of cilengitide, an integrin‐targeting arginine‐glycine‐aspartic acid peptide, in recurrent glioblastoma multiforme. J. Clin. Oncol. 2008;26(34):5610–7. https://doi.org/10.1200/JCO.2008.16.7510
DOI Google Scholar
55

Eisele G, Wick A, Eisele AC, Clément PM, Tonn J, Tabatabai G, et al. Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression. J Neurooncol. 2014;117(1):141–5. https://doi.org/10.1007/s11060-014-1365-x
DOI Google Scholar
56

Nabors LB, Fink KL, Mikkelsen T, Grujicic D, Tarnawski R, Nam DH, et al. Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open‐label, controlled, randomized phase Ⅱ CORE study. Neuro‐Oncology. 2015;17(5):708–17. https://doi.org/10.1093/neuonc/nou356
DOI Google Scholar
57

Stupp R, Hegi ME, Neyns B, Goldbrunner R, Schlegel U, Clement PMJ, et al. Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010;28(16):2712–8. https://doi.org/10.1200/JCO.2009.26.6650
DOI Google Scholar
58

Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071‐22072 study): a multicentre, randomised, open‐label, phase 3 trial. Lancet Oncol. 2014;15(10):1100–8. https://doi.org/10.1016/S1470-2045(14)70379-1
DOI Google Scholar
59

Goldberg AL. Protein degradation and protection against misfolded or damaged proteins. Nature. 2003;426(6968):895–9. https://doi.org/10.1038/nature02263
DOI Google Scholar
60

Narayanan S, Cai CY, Assaraf YG, Guo HQ, Cui Q, Wei L, et al. Targeting the ubiquitin‐proteasome pathway to overcome anti‐cancer drug resistance. Drug Resist Updates. 2020;48:100663. https://doi.org/10.1016/j.drup.2019.100663
DOI Google Scholar
61

Friday BB, Anderson SK, Buckner J, Yu C, Giannini C, Geoffroy F, et al. Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: a north central cancer treatment group study. Neuro‐Oncology. 2012;14(2):215–21. https://doi.org/10.1093/neuonc/nor198
DOI Google Scholar
62

Kong XT, Nguyen NT, Choi YJ, Zhang G, Nguyen HN, Filka E, et al. Phase 2 study of bortezomib combined with temozolomide and regional radiation therapy for upfront treatment of patients with newly diagnosed glioblastoma multiforme: safety and efficacy assessment. Int J Radiat Oncol Biol Phys. 2018;100(5):1195–203. https://doi.org/10.1016/j.ijrobp.2018.01.001
DOI Google Scholar
63

Bota DA, Mason W, Kesari S, Magge R, Winograd B, Elias I, et al. Marizomib alone or in combination with bevacizumab in patients with recurrent glioblastoma: phase Ⅰ/Ⅱ clinical trial data. Neurooncol Adv. 2021;3(1):vdab142. https://doi.org/10.1093/noajnl/vdab142
DOI Google Scholar
64

Van Den Bent M, Eoli M, Sepulveda JM, Smits M, Walenkamp A, Frenel J‐S, et al. INTELLANCE 2/EORTC 1410 randomized phase Ⅱ study of Depatux‐M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFR amplified glioblastoma. Neuro‐Oncology. 2019;22(5):684–93. https://doi.org/10.1093/neuonc/noz222
DOI Google Scholar
65

Chalmers AJ, Short S, Watts C, Herbert C, Morris A, Stobo J, et al. Phase I clinical trials evaluating olaparib in combination with radiotherapy (RT) and/or temozolomide (TMZ) in glioblastoma patients: results of OPARATIC and PARADIGM phase Ⅰ and early results of PARADIGM‐2. J Clin Oncol. 2018;36(15_suppl):2018. https://doi.org/10.1200/JCO.2018.36.15_suppl.2018
DOI Google Scholar
66

Khasraw M, McDonald KL, Rosenthal M, Lwin Z, Ashley DM, Wheeler H, et al. A randomized phase Ⅱ trial of veliparib (V), radiotherapy (RT) and temozolomide (TMZ) in patients (pts) with unmethylated MGMT (uMGMT) glioblastoma (GBM). J Clin Oncol. 2019;37(15_suppl):2011. https://doi.org/10.1200/JCO.2019.37.15_suppl.2011
DOI Google Scholar
67

Piotrowski A, Puduvalli V, Wen P, Campian J, Colman H, Pearlman M, et al. ACTR‐39. Pamiparib in combination with radiation therapy (RT) and/or temozolomide (TMZ) in patients with newly diagnosed or recurrent/refractory (R/R) glioblastoma (GBM); phase 1B/2 study update. Neuro‐Oncology. 2019;21(Suppl_6):vi21–22. https://doi.org/10.1093/neuonc/noz175.081
DOI Google Scholar
68

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
DOI Google Scholar
69

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
DOI Google Scholar
70

Sokratous G, Polyzoidis S, Ashkan K. Immune infiltration of tumor microenvironment following immunotherapy for glioblastoma multiforme. Hum Vaccin Immunother. 2017;13(11):2575–82. https://doi.org/10.1080/21645515.2017.1303582
DOI Google Scholar
71

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
DOI Google Scholar
72

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‐Oncology. 2017;19(8):1047–57. https://doi.org/10.1093/neuonc/nox026
DOI Google Scholar
73

Zhao J, Chen AX, Gartrell RD, Silverman AM, Aparicio L, Chu T, et al. Immune and genomic correlates of response to anti‐PD‐1 immunotherapy in glioblastoma. Nat Med. 2019;25(3):462–9. https://doi.org/10.1038/s41591-019-0349-y
DOI Google Scholar
74

Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, et al. Neoadjuvant anti‐PD‐1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med. 2019;25(3):477–86. https://doi.org/10.1038/s41591-018-0337-7
DOI Google Scholar
75

Swartz AM, Batich KA, Fecci PE, Sampson JH. Peptide vaccines for the treatment of glioblastoma. J. Neurooncology. 2015;123(3):433–40. https://doi.org/10.1007/s11060-014-1676-y
DOI Google Scholar
76

Huang PH, Mukasa A, Bonavia R, Flynn RA, Brewer ZE, Cavenee WK, et al. Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma. Proc Natl Acad Sci. 2007;104(31):12867–72. https://doi.org/10.1073/pnas.0705158104
DOI Google Scholar
77

Heimberger AB, Crotty LE, Archer GE, Hess KR, Wikstrand CJ, Friedman AH, et al. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin. Cancer Res. 2003;9(11):4247–54.
Google Scholar
78

Tsuda N, Mochizuki K, Harada M, Sukehiro A, Kawano K, Yamada A, et al. Vaccination with predesignated or evidence‐based peptides for patients with recurrent gynecologic cancers. J Immunother. 2004;27(1):60–72. https://doi.org/10.1097/00002371-200401000-00006
DOI Google Scholar
79

Yajima N, Yamanaka R, Mine T, Tsuchiya N, Homma J, Sano M, et al. Immunologic evaluation of personalized peptide vaccination for patients with advanced malignant glioma. Clin Cancer Res. 2005;11(16):5900–11. https://doi.org/10.1158/1078-0432.CCR-05-0559
DOI Google Scholar
80

Terasaki M, Shibui S, Narita Y, Fujimaki T, Aoki T, Kajiwara K, et al. Phase I trial of a personalized peptide vaccine for patients positive for human leukocyte antigen‐A24 with recurrent or progressive glioblastoma multiforme. J Clin Oncol. 2011;29(3):337–44. https://doi.org/10.1200/JCO.2010.29.7499
DOI Google Scholar
81

Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, Giovannone AJ, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T‐cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005;11(15):5515–25. https://doi.org/10.1158/1078-0432.CCR-05-0464
DOI Google Scholar
82

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):142. https://doi.org/10.1186/s12967-018-1507-6
DOI Google Scholar
83

Preusser M, van den Bent MJ. Autologous tumor lysate‐loaded dendritic cell vaccination (DCVax‐L) in glioblastoma: breakthrough or fata morgana. Neuro‐Oncology. 2022:noac281. https://doi.org/10.1093/neuonc/noac281
DOI Google Scholar
84

Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, Yong WH, et al. Gene expression profile correlates with T‐cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res. 2011;17(6):1603–15. https://doi.org/10.1158/1078-0432.CCR-10-2563
DOI Google Scholar
85

Wollmann G, Ozduman K, van den Pol AN. Oncolytic virus therapy for glioblastoma multiforme: concepts and candidates. Cancer J. 2012;18(1):69–81. https://doi.org/10.1097/PPO.0b013e31824671c9
DOI Google Scholar
86

Saha D, Martuza RL, Rabkin SD. Curing glioblastoma: oncolytic HSV‐IL12 and checkpoint blockade. Oncoscience. 2017;4(7‐8):67–9. https://doi.org/10.18632/oncoscience.359
DOI Google Scholar
87

Daubon T, Hemadou A, Romero Garmendia I, Saleh M. Glioblastoma immune landscape and the potential of new immunotherapies. Front Immunol. 2020;11:585616. https://doi.org/10.3389/fimmu.2020.585616
DOI Google Scholar
88

Liu P, Wang Y, Wang Y, Kong Z, Chen W, Li J, et al. Effects of oncolytic viruses and viral vectors on immunity in glioblastoma. Gene Ther. 2022;29(3‐4):115–26. https://doi.org/10.1038/s41434-020-00207-9
DOI Google Scholar
89

Sandmair AM, Loimas S, Puranen P, Immonen A, Kossila M, Puranen M, et al. Thymidine kinase gene therapy for human malignant glioma, using replication‐deficient retroviruses or adenoviruses. Hum Gene Ther. 2000;11(16):2197–205. https://doi.org/10.1089/104303400750035726
DOI Google Scholar
90

Cloughesy TF, Landolfi J, Hogan DJ, Bloomfield S, Carter B, Chen CC, et al. Phase 1 trial of vocimagene amiretrorepvec and 5‐fluorocytosine for recurrent high‐grade glioma. Sci Transl Med. 2016;8(341):341ra75. https://doi.org/10.1126/scitranslmed.aad9784
DOI Google Scholar
91

Cloughesy TF, Petrecca K, Walbert T, Butowski N, Salacz M, Perry J, et al. Effect of vocimagene amiretrorepvec in combination with flucytosine vs standard of care on survival following tumor resection in patients with recurrent high‐grade glioma: a randomized clinical trial. JAMA Oncol. 2020;6(12):1939–46. https://doi.org/10.1001/jamaoncol.2020.3161
DOI Google Scholar
92

Brenner AJ, Peters KB, Vredenburgh J, Bokstein F, Blumenthal DT, Yust‐Katz S, et al. Safety and efficacy of VB‐111, an anticancer gene therapy, in patients with recurrent glioblastoma: results of a phase Ⅰ/Ⅱ study. Neuro‐Oncology. 2020;22(5):694–704. https://doi.org/10.1093/neuonc/noz231
DOI Google Scholar
93

Desjardins A, Gromeier M, Herndon JE 2nd, 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
DOI Google Scholar
94

Todo T, Ito H, Ino Y, et al. Intratumoral oncolytic herpes virus G47∆ for residual or recurrent glioblastoma: a phase 2 trial. Nat Med. 2022;28:1630–1639. https://doi.org/10.1038/s41591-022-01897-x
DOI Google Scholar
95

Wen PY, Reardon DA, Forst DA, Lee EQ, Haas B, Daoud T, et al. Evaluation of tumor responses and overall survival in patients with recurrent glioblastoma (GBM) from a phase Ⅱa trial of a CMV vaccine immunotherapeutic candidate (VBI‐1901). J Clin Oncol. 2022;40(16_suppl):2014. https://doi.org/10.1200/JCO.2022.40.16_suppl.2014
DOI Google Scholar
96

Sahakyan V, Pozzo E, Duelen R, Deprest J, Sampaolesi M. Methotrexate and valproic acid affect early neurogenesis of human amniotic fluid stem cells from myelomeningocele. Stem Cells Int. 2017;2017:6101609. https://doi.org/10.1155/2017/6101609
DOI Google Scholar
97

Liu P, Jiang C. Brain‐targeting drug delivery systems. Wiley Interdiscip Rev. Nanomed Nanobiotechnol. 2022;14(5):e1818. https://doi.org/10.1002/wnan.1818
DOI Google Scholar
98

Pinto M, Silva V, Barreiro S, Silva R, Remião F, Borges F, et al. Brain drug delivery and neurodegenerative diseases: polymeric PLGA‐based nanoparticles as a forefront platform. Ageing Res Rev. 2022;79:101658. https://doi.org/10.1016/j.arr.2022.101658
DOI Google Scholar
99

Power EA, Rechberger JS, Gupta S, Schwartz JD, Daniels DJ, Khatua S. Drug delivery across the blood‐brain barrier for the treatment of pediatric brain tumors—an update. Adv Drug Deliv Rev. 2022;185:114303. https://doi.org/10.1016/j.addr.2022.114303
DOI Google Scholar
100

Quader S, Kataoka K, Cabral H. Nanomedicine for brain cancer. Adv Drug Deliv Rev. 2022;182:114115. https://doi.org/10.1016/j.addr.2022.114115
DOI Google Scholar
101

Dapash M, Hou D, Castro B, Lee‐Chang C, Lesniak MS. The interplay between glioblastoma and its microenvironment. Cells. 2021;10(9):2257. https://doi.org/10.3390/cells10092257
DOI Google Scholar
102

Radin DP, Tsirka SE. Interactions between tumor cells, neurons, and microglia in the glioma microenvironment. Int J Mol Sci. 2020;21(22):8476. https://doi.org/10.3390/ijms21228476
DOI Google Scholar
103

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
DOI Google Scholar
104

Mottini C, Napolitano F, Li Z, Gao X, Cardone L. Computer‐aided drug repurposing for cancer therapy: approaches and opportunities to challenge anticancer targets. Semin Cancer Biol. 2021;68:59–74. https://doi.org/10.1016/j.semcancer.2019.09.023
DOI Google Scholar
105

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):117. https://doi.org/10.1186/s12885-019-5308-y
DOI Google Scholar
106

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):51. https://doi.org/10.1186/s40425-018-0371-5
DOI Google Scholar
107

Mensali N, Inderberg EM. Emerging biomarkers for immunotherapy in glioblastoma. Cancers. 2022;14(8):1940. https://doi.org/10.3390/cancers14081940
DOI Google Scholar
108

Lechpammer M, Rao R, Shah S, Mirheydari M, Bhattacharya D, Koehler A, et al. Advances in immunotherapy for the treatment of adult glioblastoma: overcoming chemical and physical barriers. Cancers. 2022;14(7):1627. https://doi.org/10.3390/cancers14071627
DOI Google Scholar
109

Nayak L, Molinaro AM, Peters K, Clarke JL, Jordan JT, de Groot J, et al. Randomized phase Ⅱ and biomarker study of pembrolizumab plus bevacizumab versus pembrolizumab alone for patients with recurrent glioblastoma. Clin Cancer Res. 2021;27(4):1048–57. https://doi.org/10.1158/1078-0432.CCR-20-2500
DOI Google Scholar
110

Daniel P, Meehan B, Sabri S, Jamali F, Sarkaria JN, Choi D, et al. Detection of temozolomide‐induced hypermutation and response to PD‐1 checkpoint inhibitor in recurrent glioblastoma. Neuro‐oncol Adv. 2022;4(1):vdac076. https://doi.org/10.1093/noajnl/vdac076
DOI Google Scholar
111

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‐Oncology. 2017;19(8):1047–57. https://doi.org/10.1093/neuonc/nox026
DOI Google Scholar
112

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
DOI Google Scholar
113

Weenink B, French PJ, Sillevis Smitt PAE, Debets R, Geurts M. Immunotherapy in glioblastoma: current shortcomings and future perspectives. Cancers. 2020;12(3):751. https://doi.org/10.3390/cancers12030751
DOI Google Scholar
114

Patel V, Shah J. The current and future aspects of glioblastoma: immunotherapy a new hope? Eur J Neurosci. 2021;54(3):5120–42. https://doi.org/10.1111/ejn.15343
DOI Google Scholar
115

Arvanitis CD, Ferraro GB, Jain RK. The blood‐brain barrier and blood‐tumour barrier in brain tumours and metastases. Nat Rev Cancer. 2020;20(1):26–41. https://doi.org/10.1038/s41568-019-0205-x
DOI Google Scholar
116

Schwarze JK, Duerinck J, Dufait I, Awada G, Klein S, Fischbuch L, et al. A phase Ⅰ clinical trial on intratumoral and intracavitary administration of ipilimumab and nivolumab in patients with recurrent glioblastoma. J Clin Oncol. 2020;38(15_suppl):2534. https://doi.org/10.1200/JCO.2020.38.15_suppl.2534
DOI Google Scholar
117

Guo X, Wang S, Wang Y, Ma W. Anti‐PD‐1 plus anti‐VEGF therapy in multiple intracranial metastases of a hypermutated, IDH wild‐type glioblastoma. Neuro‐Oncology. 2021;23(4):699–701. https://doi.org/10.1093/neuonc/noab005
DOI Google Scholar
Publication history
Copyright
Acknowledgements
Rights and permissions

Publication history

Received: 18 December 2022
Accepted: 13 February 2023
Published: 05 March 2023
Issue date: April 2023

Copyright

© 2023 The Authors.

Acknowledgements

ACKNOWLEDGMENTS

None.

Rights and permissions

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Return