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Jin, K. Glioblastoma Immunotherapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/7337 (accessed on 17 November 2024).
Jin K. Glioblastoma Immunotherapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/7337. Accessed November 17, 2024.
Jin, Ketao. "Glioblastoma Immunotherapy" Encyclopedia, https://encyclopedia.pub/entry/7337 (accessed November 17, 2024).
Jin, K. (2021, February 17). Glioblastoma Immunotherapy. In Encyclopedia. https://encyclopedia.pub/entry/7337
Jin, Ketao. "Glioblastoma Immunotherapy." Encyclopedia. Web. 17 February, 2021.
Glioblastoma Immunotherapy
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This entry is adapted from the peer-reviewed paper 10.3390/cancers13020229

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor with dismal survival and poor response to conventional therapies. Therefore, the development of immunotherapy for GBM treatment is necessary. 

brain tumor glioblastoma immunotherapy adenosine CD73 CD39

1. Introduction

Brain tumors are heterogeneous tumors that can be classified into two general categories based on their origin. The primary brain tumors stem from the brain, while the origins of metastatic types are other organs that have metastasized to the brain [1][2]. Approximately 80% of brain malignancies originate from glial cells and are called gliomas [3]. According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System, diffused gliomas are categorized into different types, including Astrocytomas, Oligoastrocytomas, Oligodendrogliomas, and Glioblastoma [4]. In this updated classification, molecular parameters are combined with the histological patterns. For instance, the mutation status of isocitrate dehydrogenase (IDH)-1/2 gene and 1p/19q codeletion status are two molecular parameters in classifications of gliomas [4][5][6]. The classification of brain tumors is thoroughly reviewed in [4][5][6]. Glioblastoma multiforme (GBM) is the most malignant and common type of brain tumor in adults. GBM can arise from astrocyte, oligodendrocyte, and even neural stem cells, and therefore, is not classified in a specific category of gliomas [7]. The word multiforme indicates the heterogeneity of this tumor in terms of molecular markers, physiopathology, clinical manifestations, and response to treatment [8].

The average survival in GBM without treatment is three months and with current treatments it is 12–19 months [9][10]. Standard treatment includes surgery, radiotherapy, and chemotherapy [9]. Temozolomide (TMZ) is the gold-standard chemotherapy used in GBM due to its high permeability to the blood–brain barrier (BBB). TMZ is usually given after surgery for six weeks with radiotherapy [11]. Despite these multiple treatments, the recurrence rate of GBM is very high, with 2-year and 5-year survivals of 26.5% and 7%, respectively [10][12]. Steroids are also used to reduce cervical edema [9]. Recently, two other treatments for GBM have been approved in the United States: (I) bevacizumab, a monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF) receptor [13], and (II) tumor-treating fields [14]. However, the effectiveness of both treatments remains controversial. Accelerated approval of bevacizumab in GBM by the FDA indicates the urgent need for advanced and targeted treatment. Due to the ineffectiveness of current treatments on GBM, various types of targeted therapies, such as immunotherapy, raised hopes in the treatment of GBM.

2. Glioblastoma Immunotherapy

It was initially believed that the central nervous system (CNS) was an immune-privileged organ. Studies on CNS autoimmune diseases such as multiple sclerosis and encephalitis, the discovery of the CNS lymphatic system, and successful treatment of brain metastases, have shown that the CNS has an immunological activity [15]. However, some unique features of the CNS, such as the presence of the BBB, the use of corticosteroids for cerebral edema, and the immunosuppressive mechanisms of brain tumors, caused problems in immunotherapy [16]. Regarding the heterogeneous glioblastoma microenvironment (GME), severe immunosuppression, low mutational burden, and decreased antigen presentation, GBM is very poorly responsive to immunotherapy so far [16] (Table 1). Immune checkpoint inhibitors (ICIs) have become a promising immunotherapy approach in the treatment of many solid tumors (reviewed in [17]). In this method, inhibitory ICs that cause immune exhaustion are blocked, thereby restoring the immune cells’ ability to induce antitumor responses [17][18]. The prerequisite of ICI treatment is the overexpression of ICs in the tumor microenvironment (TME). Overexpression of ICs has been reported only in some subtypes of GBMs [19]. Clinical trials on GBMs have demonstrated that ICIs do not have a significant advantage over other therapies such as bevacizumab, radiotherapy, and chemotherapy. Hence, they proposed a combination of therapies or ICI applications as a neoadjuvant therapy before surgery [20][21][22]. The combined use of several ICIs, although improving the response to treatment, increases their toxicity and the likelihood of CNS autoimmunity [23][24].

Table 1. Advantages and disadvantages of the current immunotherapies in GBM.

Immunotherapy

Advantage

Disadvantage

Refs.

Immune checkpoint inhibitors (PD-1, CTLA-4, LAG-3, TIM-3, IDO, CD27)

  • Tolerable

  • Reinvigorate antitumor T cells

  • Promising results in preclinical and first phases of clinical studies

  • Proposed as a neoadjuvant therapy

  • Grade I-II toxicity in monotherapy

  • Grade III-IV in multi ICI therapy

  • No significant advantage (better OS and PFS) over bevacizumab or TMZ

  • Various IC expression levels in patients

  • Decreased effects in patients receiving TMZ

[19][20][21][22][25][26]

Bevacizumab (anti-VEGF)

  • FDA-approved for GBM

  • Prevents angiogenesis

  • Has an anti-edema effect

  • Accelerated approval after phase I/II

  • No outstanding results in extending PFS and OS

[27][28][29]

Cetuximab (anti-EGFR)

  • Tolerable

  • Promising results in preclinical studies

  • No significant survival benefit in the phase II trial

  • Insufficient BBB penetration due to the large size

[29][30]

  • Immunotoxins (mAbs conjugated with bacterial toxin or anti-mitotic agents) (Depatuxizumab mafodotin, Losatuxizumab vedotin, ABBV-221, ABBV-231)

  • Improved survival in combination with TMZ in the phase II trial

  • ABBV-231 is in the phase I trial

  • No significant survival benefit in the phase III trial

  • Safety concerns

  • Antigen-escape (downregulation of mAb target)

  • New generations are in the evaluation process

[31][32]

Anti-CSF-1R mAb

  • Decreases the recruitment of TAMs into the GME

  • Under investigation in the phase I/II trial in combination with ICIs

  • Might have insufficient BBB penetration due to large size

[33][34]

CAR T cell against IL13Rα2, EGFRvIII, Her-2, EphA2

  • Appreciable safety profile

  • Considerable infiltration into the GME

  • Significant clinical response

  • Relapse occurred 2–29 months after treatment

  • Immune-escape through antigen loss

  • Heterogeneity of GME made it difficult to use monoclonal CAR T cell for GBM (only one-third of GBM patients are EGFRvIII+)

  • CAR T cells targeting multiple antigens are needed

[9][35][36][37]

BiTE (against EGFR)

  • Appreciable safety profile

  • Recruits EGFR-specific T cells in the GME

  • Can override antigen-escape in combination with CAR T cells

  • Heterogeneity of GME challenges the targeting of a specific antigen in all GBM

[38]

Tumor vaccines using specific peptides (Rindopepimut, survivin) or tumor lysate

  • Tolerable

  • Low off-target effects

  • Improve OS and PFS (mOS:24 months)

  • Synergistic effect in combination with bevacizumab

  • Rindopepimut is effective only in EGFRvIII+ patients (30% of all GBM)

  • No survival benefits due to the antigen-escape

[39][40][41][42][43]

DC Vaccines (ICT-107:pulsed with six peptides)(DCVax: pulsed with tumor lysate)

  • ICT-107: Promising results in the phase II trial

  • DCVax: Improves OS to 24 months

  • Override antigen-escape

  • Personalized medicine

  • 2% serious adverse events in DC vaccines

  • Expensive process of personalized medicine

[44][45]

  • Viral gene therapy: (Toca-511: Metabolize prodrug (FC) to drug (5-FU))

  • VB-111: delivers pro-apoptotic proteins

  • Ad-RTS-hIL-12: Conditional delivering of IL-12)

  • Appreciable safety profile

  • Promising results in early trials with a 22% durable response rate

  • Synergistic effects with ICIs

  • No survival benefit in the phase III trials

[46][47][48][49][50][51]

Oncolytic virotherapy

(Adenovirus, polio-rhinovirus chimera, herpes simplex virus)

  • Safe intratumoral administration, induces innate and adaptive immune responses

  • Turns immunosuppressive to immune-active TME

  • Promising survival results in early trials

  • Evaluation in phase II trials as a monotherapy or with ICIs

[52][53][54]

Adenosinergic pathway (ARs, CD39, CD73, ADA)

  • High expression in all types of GME

  • No antigen escape

  • Turns immunosuppressive GME into immune-active GME

  • Reduces angiogenesis

  • Potentiates other immunotherapies such as ICIs, CAR T cell, and NK cell therapy

  • Synergistic effects with conventional therapies

  • Overrides chemoresistance

  • Not entered in clinical trials yet

  • mAbs might have insufficient BBB penetration

  • All pathway components should be targeted to get maximum results

  • Not effective as monotherapy and should be used as combination therapy

[55][56][57][58][59][60][61][62][63][64][65][66][67]

PD-1. Programmed cell-death protein-1; CTLA-4. cytotoxic T-lymphocyte-associated protein-4; LAG-3. Lymphocyte activation gene-3; TIM-3. T-cell immunoglobulin and mucin domain-containing protein-3; IDO. Indoleamine-2,3-dioxygenase; ICI. Immune checkpoint inhibitor; OS. Overall survival; TMZ. Temozolomide; VEGF. Vascular endothelial growth factor; GBM. Glioblastoma multiforme; PFS. Progression-free survival; EGFR. Endothelial growth factor receptor; BBB. Blood-brain barrier; mAb. Monoclonal antibody; CSF-1R. Colony stimulating factor-1 receptor; GME. GBM microenvironment; CAR. Chimeric antigen receptor; IL13Rα2. Interleukin-13 receptor α2; Her-2. Human epidermal growth factor receptor-2; BiTE. Bispecific T cell engager; mOS. Mean OS; DC. Dendritic cell; FC. Fluorocytosine; 5-FU.5-Flurouracil; ARs. Adenosine receptors; ADA. Adenosine deaminase.

In addition to ICIs, the use of mAbs and their derivatives such as nanobodies, single-chain variable fragment (scFv), bispecific T-cell engager (BiTE), and immunotoxins is also a routine method in immunotherapy [29][68]. Bevacizumab was the first mAb to be accelerated and approved in GBM [13]. This anti-VEGF mAb prevents angiogenesis in the TME [13]. Application of mAbs against endothelial growth factor receptor (EGFR) also yielded promising results in initial studies but was discontinued in clinical trials due to a lack of significant increase in patient survival and rising safety concerns [30][31][32]. The EGFR variants, especially EGFR class III variant (EGFRvIII), are overexpressed in a considerable part of GBM patients, making them an ideal target for immunotherapy [69]. However, the association of EGFR overexpression and mutations with the overall survival of patients is still controversial [70]. Moreover, the results of trials showed EGFRvIII downregulation following targeted therapy against EGFRvIII [35][71]. This has raised the question of whether EGFRvIII mutation represents a driver mutation, or maybe it is only a passenger mutation with no considerable impact on the survival of glioma cells. Currently, other generations of conjugated mAb are being studied in trials. The greatest challenge of mAb therapy in brain tumors is the large size of mAbs and the lack of proper penetration into the TME due to the BBB. The smaller derivatives of mAb or making the BBB permeable to these factors could enhance the treatment responses [29].

The application of autologous T cells genetically engineered with a chimeric antigen receptor (CAR) demonstrates remarkable efficiencies in many blood cancers and solid tumors [72]. These cells are against a tumor-specific antigen (TSA) and can sustain antitumor activity with the help of various costimulatory molecules [72]. The CAR T cells used in GBM were against EGFRvIII, interleukin 13 receptor-α2 (IL13Rα2), human epidermal growth factor receptor-2 (HER2), and Eph receptor-A2 (EphA2) [35][36][37][72]. The results of the trials indicate a relative response to this treatment. Given the heterogeneity and high plasticity in the GME, the use of a specific CAR T cell reduces the expression of the target antigen, and the tumor escapes the CAR T cell response [9]. Therefore, studies on the application of bivalent and trivalent CAR T cells are ongoing [37]. Another way to overcome antigen escape is to use BiTEs along with CAR T cells. Choi et al. developed an anti-EGFRvIII CAR T cell, which also expresses anti-EGFR BiTEs [38]. It initially targets positive EGFRvIII cells and then recruits T cells specific for wild-type EGFR to the TME. The initial results against heterogeneous GBMs were promising [38].

Tumor vaccines containing TSAs are another cancer immunotherapy method aiming to stimulate the patient’s adaptive immunity against TSAs [29]. Peptide vaccines containing EGFRvIII and survivin peptides in patients who were positive for these antigens raised proper responses, although the issue of antigen escape in this method is also challenging [40][41][42]. Ex vivo pulsing the patient’s autologous dendritic cells (DCs) with specific peptides (in ICT-107) or tumor lysate (in DCVax) in DC vaccines stimulates a better immune response than peptide vaccines [44][45]. This type of treatment is a personalized treatment that can overcome the high heterogeneity of GBM in patients. However, immunosuppressive GME causes pulsed DCs to become inefficient in antigen presentation. Initial clinical trials of tumor vaccines alone or in combination with bevacizumab or chemotherapy and surgery have yielded encouraging results [9][40][41].

According to initial observations of tumor regression in viral infections, viral therapy is currently used in various cancers, mostly solid tumors [73]. Viruses can be used in gene therapy, delivering the desired genes to the TME. These genes mainly produce pro-apoptotic proteins (in VB-111 vaccine), inflammatory cytokines (in Ad-RTS-hIL-12 vaccine that encodes IL12 conditionally), or enzymes that convert prodrugs to anticancer drugs (in Toca-511) [46][50][51]. Another type of virus therapy involves oncolytic viruses that selectively infect and lyse cancer cells in which antiviral responses are impaired [73]. Adenovirus, herpes simplex virus, and poliovirus are being studied in GBM and have shown a relative response in combination with other treatments [9]. Viral therapy can also stimulate innate and adaptive immune systems that enhance antitumor responses [9].

As can be seen, most of the immunotherapy methods used in GBM have been effective in the preclinical and early clinical stages but have not been very successful in the higher stages of the clinical trials (Table 1). There are several reasons for such an inadequate response in GBM patients. High heterogeneity of GBM between patients and high plasticity, even in one patient at different times, makes GBM resistant to immunotherapy [16]. Evaluation of tumor markers before treatment and development of personalized medicine can lead to overcoming GBM heterogeneity and plasticity. The severe immunosuppressive GME appears to be another barrier to immunotherapy. Immunosuppression in GME undergoes numerous and complex mechanisms so that single-arm immunotherapy cannot break this tolerance. Besides local immune suppression, GBM can suppress systemic immunity in the patient [16][74][75][76]. The GME-infiltrated T cells are mainly differentiated to regulatory T cells (Tregs) due to the high levels of tumor growth factor (TGF)-β and indoleamine-2,3-dioxygenase (IDO) in the GME [77][78]. IDO metabolizes tryptophan to kynurenine, leading to a change in the phenotype of microglial cells (CNS-resident macrophages) or tumor-associated macrophages (TAMs) to an M2 phenotype [67]. M2-TAMs promote tumor progression by further suppressing immune responses and expressing ICs [67].

On the other hand, the use of corticosteroids in GBM to reduce cerebral edema increases immunosuppression and reduces immunotherapy effects [79]. Interestingly, studies have shown that radiotherapy and chemotherapy, such as TMZ in some cases of GBM, can increase immunosuppression and decrease the effects of ICI, which challenges combination therapy [80][81]. Furthermore, the low mutational burden in GBM limits neoantigen production and presentation to the adaptive immune system [82]. All of the mentioned mechanisms make GBM an immunologically cold tumor. Knowing the different aspects of immunosuppression in GBM makes it possible to achieve a successful strategy in GBM immunotherapy by targeting several pathways simultaneously.

References

  1. Jovčevska, I.; Kočevar, N.; Komel, R. Glioma and glioblastoma-how much do we (not) know? Mol. Clin. Oncol. 2013, 1, 935–941.
  2. Qin, Z.; Zhang, X.; Chen, Z.; Liu, N. Establishment and validation of an immune-based prognostic score model in glioblastoma. Int. Immunopharmacol. 2020, 85, 106636.
  3. Goodenberger, M.L.; Jenkins, R.B. Genetics of adult glioma. Cancer Genet. 2012, 205, 613–621.
  4. Louis, D.N.; Perry, A.; Reifenberger, G.; Von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 2016, 131, 803–820.
  5. Brat, D.J.; Aldape, K.; Colman, H.; Figrarella-Branger, D.; Fuller, G.N.; Giannini, C.; Holland, E.C.; Jenkins, R.B.; Kleinschmidt-DeMasters, B.; Komori, T. cIMPACT-NOW update 5: Recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol. 2020, 139, 603–608.
  6. Brat, D.J.; Aldape, K.; Colman, H.; Holland, E.C.; Louis, D.N.; Jenkins, R.B.; Kleinschmidt-DeMasters, B.; Perry, A.; Reifenberger, G.; Stupp, R. 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, 805–810.
  7. Zong, H.; Verhaak, R.G.; Canoll, P. The cellular origin for malignant glioma and prospects for clinical advancements. Expert Rev. Mol. Diagn. 2012, 12, 383–394.
  8. Iacob, G.; Dinca, E.B. Current data and strategy in glioblastoma multiforme. J. Med. Life 2009, 2, 386.
  9. Medikonda, R.; Dunn, G.; Rahman, M.; Fecci, P.; Lim, M. A review of glioblastoma immunotherapy. J. Neuro-Oncol. 2020.
  10. Stupp, R.; Mason, W.P.; Van Den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 2005, 352, 987–996.
  11. Park, S.H.; Kim, M.J.; Jung, H.H.; Chang, W.S.; Choi, H.S.; Rachmilevitch, I.; Zadicario, E.; Chang, J.W. One-Year Outcome of Multiple Blood–Brain Barrier Disruptions with Temozolomide for the Treatment of Glioblastoma. Front. Oncol. 2020, 10, 1663.
  12. Ostrom, Q.T.; Cioffi, G.; Gittleman, H.; Patil, N.; Waite, K.; Kruchko, C.; Barnholtz-Sloan, J.S. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro-Oncology 2019, 21, v1–v100.
  13. Cohen, M.H.; Shen, Y.L.; Keegan, P.; Pazdur, R. FDA drug approval summary: Bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 2009, 14, 1131–1138.
  14. Fabian, D.; Guillermo Prieto Eibl, M.D.P.; Alnahhas, I.; Sebastian, N.; Giglio, P.; Puduvalli, V.; Gonzalez, J.; Palmer, J.D. Treatment of glioblastoma (GBM) with the addition of tumor-treating fields (TTF): A review. Cancers 2019, 11, 174.
  15. Louveau, A.; Harris, T.H.; Kipnis, J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 2015, 36, 569–577.
  16. Jackson, C.M.; Choi, J.; Lim, M. Mechanisms of immunotherapy resistance: Lessons from glioblastoma. Nat. Immunol. 2019, 20, 1100–1109.
  17. Sharma, P.; Allison, J.P. Dissecting the mechanisms of immune checkpoint therapy. Nat. Rev. Immunol. 2020, 20, 75–76.
  18. Hajifathali, A.; Parkhideh, S.; Kazemi, M.H.; Chegeni, R.; Roshandel, E.; Gholizadeh, M. Immune checkpoints in hematologic malignancies: What made the immune cells and clinicians exhausted! J. Cell. Physiol. 2020.
  19. Topalian, S.L.; Taube, J.M.; Anders, R.A.; Pardoll, D.M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 2016, 16, 275–287.
  20. Reardon, D.; Omuro, A.; Brandes, A.; Rieger, J.; Wick, A.; Sepulveda, J.; Phuphanich, S.; De Souza, P.; Ahluwalia, M.; Lim, M. OS10. 3 randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143. Neuro-Oncology 2017, 19, iii21.
  21. Phase, B.-M.S.A. CheckMate−498 Study Did Not Meet Primary Endpoint of Overall Survival with Opdivo (nivolumab) Plus Radiation in Patients with Newly Diagnosed MGMT-Unmethylated Glioblastoma Multiforme. BMS Newsroom, 5 September 2019.
  22. Cloughesy, T.F.; Mochizuki, A.Y.; Orpilla, J.R.; Hugo, W.; Lee, A.H.; Davidson, T.B.; Wang, A.C.; Ellingson, B.M.; Rytlewski, J.A.; Sanders, C.M. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat. Med. 2019, 25, 477–486.
  23. Omuro, A.; Vlahovic, G.; Lim, M.; Sahebjam, S.; Baehring, J.; Cloughesy, T.; Voloschin, A.; Ramkissoon, S.H.; Ligon, K.L.; Latek, R. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Neuro-Oncology 2018, 20, 674–686.
  24. McGinnis, G.J.; Raber, J. CNS side effects of immune checkpoint inhibitors: Preclinical models, genetics and multimodality therapy. Immunotherapy 2017, 9, 929–941.
  25. Lim, M.; Omuro, A.; Vlahovic, G.; Reardon, D.; Sahebjam, S.; Cloughesy, T.; Baehring, J.; Butowski, N.; Potter, V.; Zwirtes, R. 325ONivolumab (nivo) in combination with radiotherapy (RT)±temozolomide (TMZ): Updated safety results from CheckMate 143 in pts with methylated or unmethylated newly diagnosed glioblastoma (GBM). Ann. Oncol. 2017, 28, v109–v121.
  26. Sampson, J.H.; Vlahovic, G.; Sahebjam, S.; Omuro, A.M.P.; Baehring, J.M.; Hafler, D.A.; Voloschin, A.D.; Paliwal, P.; Grosso, J.; Coric, V. Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CHECKMATE-143. Am. Soc. Clin. Oncol. 2015.
  27. Gilbert, M.R.; Dignam, J.J.; Armstrong, T.S.; Wefel, J.S.; Blumenthal, D.T.; Vogelbaum, M.A.; Colman, H.; Chakravarti, A.; Pugh, S.; Won, M. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 2014, 370, 699–708.
  28. Chinot, O.L.; Wick, W.; Mason, W.; Henriksson, R.; Saran, F.; Nishikawa, R.; Carpentier, A.F.; Hoang-Xuan, K.; Kavan, P.; Cernea, D. Bevacizumab plus radiotherapy–temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 2014, 370, 709–722.
  29. Liu, E.K.; Sulman, E.P.; Wen, P.Y.; Kurz, S.C. Novel Therapies for Glioblastoma. Curr. Neurol. Neurosci. Rep. 2020, 20, 19.
  30. Neyns, B.; Sadones, J.; Joosens, E.; Bouttens, F.; Verbeke, L.; Baurain, J.-F.; D’Hondt, L.; Strauven, T.; Chaskis, C.; In’t Veld, P. Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann. Oncol. 2009, 20, 1596–1603.
  31. Van Den Bent, M.; Eoli, M.; Sepulveda, J.M.; Smits, M.; Walenkamp, A.; Frenel, J.-S.; Franceschi, E.; Clement, P.M.; Chinot, O.; De Vos, F. 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 2020, 22, 684–693.
  32. Phillips, A.C.; Boghaert, E.R.; Vaidya, K.S.; Falls, H.D.; Mitten, M.J.; DeVries, P.J.; Benatuil, L.; Hsieh, C.-M.; Meulbroek, J.A.; Panchal, S.C. Characterization of ABBV-221, a tumor-selective EGFR-targeting antibody drug conjugate. Mol. Cancer Ther. 2018, 17, 795–805.
  33. Coniglio, S.J.; Eugenin, E.; Dobrenis, K.; Stanley, E.R.; West, B.L.; Symons, M.H.; Segall, J.E. Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol. Med. 2012, 18, 519–527.
  34. Pyonteck, S.M.; Akkari, L.; Schuhmacher, A.J.; Bowman, R.L.; Sevenich, L.; Quail, D.F.; Olson, O.C.; Quick, M.L.; Huse, J.T.; Teijeiro, V. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 2013, 19, 1264.
  35. O’Rourke, D.M.; Nasrallah, M.P.; Desai, A.; Melenhorst, J.J.; Mansfield, K.; Morrissette, J.J.; Martinez-Lage, M.; Brem, S.; Maloney, E.; Shen, A. 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.
  36. Ahmed, N.; Brawley, V.; Hegde, M.; Bielamowicz, K.; Kalra, M.; Landi, D.; Robertson, C.; Gray, T.L.; Diouf, O.; Wakefield, A. Her2-specific chimeric antigen receptor–modified virus-specific t cells for progressive glioblastoma: A phase 1 dose-escalation trial. JAMA Oncol. 2017, 3, 1094–1101.
  37. Bielamowicz, K.; Fousek, K.; Byrd, T.T.; Samaha, H.; Mukherjee, M.; Aware, N.; Wu, M.-F.; Orange, J.S.; Sumazin, P.; Man, T.-K. Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro-Oncology 2018, 20, 506–518.
  38. Choi, B.D.; Yu, X.; Castano, A.P.; Bouffard, A.A.; Schmidts, A.; Larson, R.C.; Bailey, S.R.; Boroughs, A.C.; Frigault, M.J.; Leick, M.B. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat. Biotechnol. 2019, 37, 1049–1058.
  39. Schuster, J.; Lai, R.K.; Recht, L.D.; Reardon, D.A.; Paleologos, N.A.; Groves, M.D.; Mrugala, M.M.; Jensen, R.; Baehring, J.M.; Sloan, A. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: The ACT III study. Neuro-Oncology 2015, 17, 854–861.
  40. Weller, M.; Butowski, N.; Tran, D.D.; Recht, L.D.; Lim, M.; Hirte, H.; Ashby, L.; Mechtler, L.; Goldlust, S.A.; Iwamoto, F. 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, 1373–1385.
  41. Reardon, D.A.; Desjardins, A.; Vredenburgh, J.J.; O’Rourke, D.M.; Tran, D.D.; Fink, K.L.; Nabors, L.B.; Li, G.; Bota, D.A.; Lukas, R.V. 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, 1586–1594.
  42. Fenstermaker, R.A.; Ciesielski, M.J.; Qiu, J.; Yang, N.; Frank, C.L.; Lee, K.P.; Mechtler, L.R.; Belal, A.; Ahluwalia, M.S.; Hutson, A.D. Clinical study of a survivin long peptide vaccine (SurVaxM) in patients with recurrent malignant glioma. Cancer Immunol. Immunother. 2016, 65, 1339–1352.
  43. Ahluwalia, M.S.; Reardon, D.A.; Abad, A.P.; Curry, W.T.; Wong, E.T.; Belal, A.; Qiu, J.; Mogensen, K.; Schilero, C.; Hutson, A. SurVaxM with standard therapy in newly diagnosed glioblastoma: Phase II trial update. J. Clin. Oncol. 2019, 37, 2016.
  44. Wen, P.Y.; Reardon, D.A.; Armstrong, T.S.; Phuphanich, S.; Aiken, R.D.; Landolfi, J.C.; Curry, W.T.; Zhu, J.-J.; Glantz, M.; Peereboom, D.M. 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, 5799–5807.
  45. Liau, L.M.; Ashkan, K.; Tran, D.D.; Campian, J.L.; Trusheim, J.E.; Cobbs, C.S.; Heth, J.A.; Salacz, M.; Taylor, S.; D’Andre, S.D. 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, 1–9.
  46. Cloughesy, T.F.; Landolfi, J.; Vogelbaum, M.A.; Ostertag, D.; Elder, J.B.; Bloomfield, S.; Carter, B.; Chen, C.C.; Kalkanis, S.N.; Kesari, S. Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511+ Toca FC. Neuro-Oncology 2018, 20, 1383–1392.
  47. Cloughesy, T.F.; Landolfi, J.; Hogan, D.J.; Bloomfield, S.; Carter, B.; Chen, C.C.; Elder, J.B.; Kalkanis, S.N.; Kesari, S.; Lai, A. Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma. Sci. Transl. Med. 2016, 8, 341ra75.
  48. Cockle, J.V.; Rajani, K.; Zaidi, S.; Kottke, T.; Thompson, J.; Diaz, R.M.; Shim, K.; Peterson, T.; Parney, I.F.; Short, S. Combination viroimmunotherapy with checkpoint inhibition to treat glioma, based on location-specific tumor profiling. Neuro-Oncology 2015, 18, 518–527.
  49. Jiang, H.; Rivera-Molina, Y.; Gomez-Manzano, C.; Clise-Dwyer, K.; Bover, L.; Vence, L.M.; Yuan, Y.; Lang, F.F.; Toniatti, C.; Hossain, M.B. Oncolytic adenovirus and tumor-targeting immune modulatory therapy improve autologous cancer vaccination. Cancer Res. 2017, 77, 3894–3907.
  50. Brenner, A.J.; Peters, K.B.; Vredenburgh, J.; Bokstein, F.; Blumenthal, D.T.; Yust-Katz, S.; Peretz, I.; Oberman, B.; Freedman, L.S.; Ellingson, B.M. 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, 694–704.
  51. Chiocca, E.A.; John, S.Y.; Lukas, R.V.; Solomon, I.H.; Ligon, K.L.; Nakashima, H.; Triggs, D.A.; Reardon, D.A.; Wen, P.; Stopa, B.M. Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial. Sci. Transl. Med. 2019, 11, eaaw5680.
  52. Westphal, M.; Ylä-Herttuala, S.; Martin, J.; Warnke, P.; Menei, P.; Eckland, D.; Kinley, J.; Kay, R.; Ram, Z.; Group, A.S. 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, 823–833.
  53. Desjardins, A.; Gromeier, M.; Herndon, J.E.; Beaubier, N.; Bolognesi, D.P.; Friedman, A.H.; Friedman, H.S.; McSherry, F.; Muscat, A.M.; Nair, S. Recurrent glioblastoma treated with recombinant poliovirus. N. Engl. J. Med. 2018, 379, 150–161.
  54. Lang, F.F.; Conrad, C.; Gomez-Manzano, C.; Yung, W.A.; Sawaya, R.; Weinberg, J.S.; Prabhu, S.S.; Rao, G.; Fuller, G.N.; Aldape, K.D. Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: Replication and immunotherapeutic effects in recurrent malignant glioma. J. Clin. Oncol. 2018, 36, 1419.
  55. Ott, M.; Tomaszowski, K.-H.; Marisetty, A.; Kong, L.-Y.; Wei, J.; Duna, M.; Blumberg, K.; Ji, X.; Jacobs, C.; Fuller, G.N. Profiling of patients with glioma reveals the dominant immunosuppressive axis is refractory to immune function restoration. JCI Insight 2020, 5, e134386.
  56. Rocha, R.; Torres, Á.; Ojeda, K.; Uribe, D.; Rocha, D.; Erices, J.; Niechi, I.; Ehrenfeld, P.; San Martín, R.; Quezada, C. The adenosine A3 receptor regulates differentiation of glioblastoma stem-like cells to endothelial cells under hypoxia. Int. J. Mol. Sci. 2018, 19, 1228.
  57. Niechi, I.; Uribe-Ojeda, A.; Erices, J.I.; Torres, Á.; Uribe, D.; Rocha, J.D.; Silva, P.; Richter, H.G.; San Martín, R.; Quezada, C. Adenosine Depletion as A New Strategy to Decrease Glioblastoma Stem-Like Cells Aggressiveness. Cells 2019, 8, 1353.
  58. Torres, A.; Vargas, Y.; Uribe, D.; Jaramillo, C.; Gleisner, A.; Salazar-Onfray, F.; López, M.N.; Melo, R.; Oyarzún, C.; San Martín, R. Adenosine A3 receptor elicits chemoresistance mediated by multiple resistance-associated protein-1 in human glioblastoma stem-like cells. Oncotarget 2016, 7, 67373.
  59. Wang, J.; Matosevic, S. NT5E/CD73 as correlative factor of patient survival and natural killer cell infiltration in glioblastoma. J. Clin. Med. 2019, 8, 1526.
  60. Daniele, S.; Zappelli, E.; Natali, L.; Martini, C.; Trincavelli, M.L. Modulation of A 1 and A 2B adenosine receptor activity: A new strategy to sensitise glioblastoma stem cells to chemotherapy. Cell Death Dis. 2014, 5, e1539.
  61. Quezada, C.; Garrido, W.; Oyarzún, C.; Fernández, K.; Segura, R.; Melo, R.; Casanello, P.; Sobrevia, L.; San Martín, R. 5′-ectonucleotidase mediates multiple-drug resistance in glioblastoma multiforme cells. J. Cell. Physiol. 2013, 228, 602–608.
  62. Xu, S.; Shao, Q.-Q.; Sun, J.-T.; Yang, N.; Xie, Q.; Wang, D.-H.; Huang, Q.-B.; Huang, B.; Wang, X.-Y.; Li, X.-G. Synergy between the ectoenzymes CD39 and CD73 contributes to adenosinergic immunosuppression in human malignant gliomas. Neuro-Oncology 2013, 15, 1160–1172.
  63. Azambuja, J.; Schuh, R.; Michels, L.; Gelsleichter, N.; Beckenkamp, L.; Iser, I.; Lenz, G.; De Oliveira, F.; Venturin, G.; Greggio, S. Nasal administration of cationic nanoemulsions as CD73-siRNA delivery system for glioblastoma treatment: A new therapeutical approach. Mol. Neurobiol. 2020, 57, 635–649.
  64. Azambuja, J.; Schuh, R.; Michels, L.; Iser, I.; Beckenkamp, L.; Roliano, G.; Lenz, G.; Scholl, J.; Sévigny, J.; Wink, M. Blockade of CD73 delays glioblastoma growth by modulating the immune environment. Cancer Immunol. Immunother. CII 2020, 69, 1801–1812.
  65. Bahadur, S.; Pathak, K. Physicochemical and physiological considerations for efficient nose-to-brain targeting. Expert Opin. Drug Deliv. 2012, 9, 19–31.
  66. Azambuja, J.; Schuh, R.; Michels, L.; Gelsleichter, N.; Beckenkamp, L.; Lenz, G.; de Oliveira, F.; Wink, M.; Stefani, M.; Battastini, A. CD73 as a target to improve temozolomide chemotherapy effect in glioblastoma preclinical model. Cancer Chemother. Pharmacol. 2020, 85, 1177–1182.
  67. Takenaka, M.C.; Gabriely, G.; Rothhammer, V.; Mascanfroni, I.D.; Wheeler, M.A.; Chao, C.-C.; Gutierrez-Vazquez, C.; Kenison, J.; Tjon, E.C.; Barroso, A. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat. Neurosci. 2019, 22, 729–740.
  68. Barzaman, K.; Karami, J.; Zarei, Z.; Hosseinzadeh, A.; Kazemi, M.H.; Moradi-Kalbolandi, S.; Safari, E.; Farahmand, L. Breast cancer: Biology, biomarkers, and treatments. Int. Immunopharmacol. 2020, 84, 106535.
  69. Wikstrand, C.J.; McLendon, R.E.; Friedman, A.H.; Bigner, D.D. Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII. Cancer Res. 1997, 57, 4130–4140.
  70. González-Tablas, M.; Arandia, D.; Jara-Acevedo, M.; Otero, Á.; Vital, A.-L.; Prieto, C.; González-Garcia, N.; Nieto-Librero, A.B.; Tao, H.; Pascual, D. Heterogeneous EGFR, CDK4, MDM4, and PDGFRA Gene Expression Profiles in Primary GBM: No Association with Patient Survival. Cancers 2020, 12, 231.
  71. Sampson, J.H.; Heimberger, A.B.; Archer, G.E.; Aldape, K.D.; Friedman, A.H.; Friedman, H.S.; Gilbert, M.R.; Herndon, J.E. 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, 4722.
  72. Chuntova, P.; Downey, K.M.; Hegde, B.; Almeida, N.D.; Okada, H. Genetically engineered T-cells for malignant glioma: Overcoming the barriers to effective immunotherapy. Front. Immunol. 2019, 9, 3062.
  73. Li, L.; Liu, S.; Han, D.; Tang, B.; Ma, J. Delivery and Biosafety of Oncolytic Virotherapy. Front. Oncol. 2020, 10, 475.
  74. Chae, M.; Peterson, T.E.; Balgeman, A.; Chen, S.; Zhang, L.; Renner, D.N.; Johnson, A.J.; Parney, I.F. Increasing glioma-associated monocytes leads to increased intratumoral and systemic myeloid-derived suppressor cells in a murine model. Neuro-Oncology 2015, 17, 978–991.
  75. Hutter, G.; Theruvath, J.; Graef, C.M.; Zhang, M.; Schoen, M.K.; Manz, E.M.; Bennett, M.L.; Olson, A.; Azad, T.D.; Sinha, R. Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma. Proc. Natl. Acad. Sci. USA 2019, 116, 997–1006.
  76. Adhikaree, J.; Moreno-Vicente, J.; Kaur, A.P.; Jackson, A.M.; Patel, P.M. Resistance mechanisms and barriers to successful immunotherapy for treating glioblastoma. Cells 2020, 9, 263.
  77. Liu, S.; Zhang, C.; Wang, B.; Zhang, H.; Li, C.; Qin, G.; Cao, L.; Gao, Q.; Ping, Y.; Zhang, K. Regulatory T cells promote glioma cell stemness through TGF-β–NF-κB–IL6–STAT3 signaling. Eur. PMC 2020.
  78. Wainwright, D.A.; Balyasnikova, I.V.; Chang, A.L.; Ahmed, A.U.; Moon, K.-S.; Auffinger, B.; Tobias, A.L.; Han, Y.; Lesniak, M.S. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin. Cancer Res. 2012, 18, 6110–6121.
  79. Maxwell, R.; Luksik, A.S.; Garzon-Muvdi, T.; Hung, A.L.; Kim, E.S.; Wu, A.; Xia, Y.; Belcaid, Z.; Gorelick, N.; Choi, J. Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system. Oncoimmunology 2018, 7, e1500108.
  80. Mathios, D.; Kim, J.E.; Mangraviti, A.; Phallen, J.; Park, C.-K.; Jackson, C.M.; Garzon-Muvdi, T.; Kim, E.; Theodros, D.; Polanczyk, M. Anti–PD-1 antitumor immunity is enhanced by local and abrogated by systemic chemotherapy in GBM. Sci. Transl. Med. 2016, 8, ra180–ra370.
  81. Grossman, S.A.; Ye, X.; Lesser, G.; Sloan, A.; Carraway, H.; Desideri, S.; Piantadosi, S. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin. Cancer Res. 2011, 17, 5473–5480.
  82. Goodman, A.M.; Kato, S.; Bazhenova, L.; Patel, S.P.; Frampton, G.M.; Miller, V.; Stephens, P.J.; Daniels, G.A.; Kurzrock, R. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol. Cancer Ther. 2017, 16, 2598–2608.
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Ketao Jin
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