Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Current Neurology and Neuroscience Reports
Published in: Current Neurology and Neuroscience Reports 5/2024

Open Access 05-04-2024 | Glioblastoma | Review

Strategies to Improve Drug Delivery Across the Blood–Brain Barrier for Glioblastoma

Authors: Kazim H. Narsinh, Edgar Perez, Alexander F. Haddad, Jacob S. Young, Luis Savastano, Javier E. Villanueva-Meyer, Ethan Winkler, John de Groot

Published in: Current Neurology and Neuroscience Reports | Issue 5/2024

Login to get access

Abstract

Purpose of Review

Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed.

Recent Findings

We discuss how the blood–brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody–drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood–brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design.

Summary

New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.
Literature
1.
Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2014–2018. Neuro-Oncol. 2021 Oct 5;23(12 Suppl 2):iii1–105.
2.
Kaka N, Hafazalla K, Samawi H, Simpkin A, Perry J, Sahgal A, et al. Progression-free but no overall survival benefit for adult patients with bevacizumab therapy for the treatment of newly diagnosed glioblastoma: a systematic review and meta-analysis. Cancers. 2019;11(11):1723.PubMedPubMedCentralCrossRef
3.
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.PubMedCrossRef
4.
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.PubMedCrossRef
5.
Chaichana KL, Jusue-Torres I, Navarro-Ramirez R, Raza SM, Pascual-Gallego M, Ibrahim A, et al. Establishing percent resection and residual volume thresholds affecting survival and recurrence for patients with newly diagnosed intracranial glioblastoma. Neuro-Oncol. 2014;16(1):113–22.PubMedCrossRef
6.
Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95(2):190–8.PubMedCrossRef
7.
Wick W, Gorlia T, Bendszus M, Taphoorn M, Sahm F, Harting I, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017;377(20):1954–63.PubMedCrossRef
8.
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.PubMedCrossRef
9.
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.PubMedPubMedCentralCrossRef
10.
Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318(23):2306–16.PubMedPubMedCentralCrossRef
11.
Hochberg FH, Linggood R, Wolfson L, Baker WH, Kornblith P. Quality and duration of survival in glioblastoma multiforme: combined surgical, radiation, and lomustine therapy. JAMA. 1979;241(10):1016–8.PubMedCrossRef
12.
Walker MD, Alexander E, Hunt WE, MacCarty CS, Mahaley MS, Mealey J, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial. J Neurosurg. 1978;49(3):333–43.PubMedCrossRef
13.
Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1. Cancer Cell. 2010;17(1):98.PubMedPubMedCentralCrossRef
14.
Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344(6190):1396–401.PubMedPubMedCentralCrossRef
15.
Sottoriva A, Spiteri I, Piccirillo SGM, Touloumis A, Collins VP, Marioni JC, et al. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci U S A. 2013;110(10):4009–14.PubMedPubMedCentralCrossRef
16.
Chen HM, Nikolic A, Singhal D, Gallo M. Roles of chromatin remodelling and molecular heterogeneity in therapy resistance in glioblastoma. Cancers. 2022;14(19):4942.PubMedPubMedCentralCrossRef
17.
18.
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.PubMedPubMedCentralCrossRef
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.PubMedCrossRef
20.
Burster T, Gärtner F, Bulach C, Zhanapiya A, Gihring A, Knippschild U. Regulation of MHC I molecules in glioblastoma cells and the sensitizing of NK cells. Pharmaceuticals. 2021;14(3):236.PubMedPubMedCentralCrossRef
21.
Zagzag D, Salnikow K, Chiriboga L, Yee H, Lan L, Ali MA, et al. Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain. Lab Invest. 2005;85(3):328–41.PubMedCrossRef
22.
Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350(6257):207–11.PubMedPubMedCentralCrossRef
23.
Valero C, Lee M, Hoen D, Wang J, Nadeem Z, Patel N, et al. The association between tumor mutational burden and prognosis is dependent on treatment context. Nat Genet. 2021;53(1):11–5.PubMedPubMedCentralCrossRef
24.
Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51(2):202–6.PubMedPubMedCentralCrossRef
25.
Crane CA, Ahn BJ, Han SJ, Parsa AT. Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy. Neuro-Oncol. 2012;14(5):584–95.PubMedPubMedCentralCrossRef
26.
DiDomenico J, Lamano JB, Oyon D, Li Y, Veliceasa D, Kaur G, et al. The immune checkpoint protein PD-L1 induces and maintains regulatory T cells in glioblastoma. Oncoimmunology. 2018;7(7):e1448329.PubMedPubMedCentralCrossRef
27.
Lamano JB, Lamano JB, Li YD, DiDomenico JD, Choy W, Veliceasa D, et al. Glioblastoma-derived IL-6 induces immunosuppressive peripheral myeloid cell PD-L1 and promotes tumor growth. Clin Cancer Res Off J Am Assoc Cancer Res. 2019;25(12):3643–57.CrossRef
28.
Wainwright DA, Balyasnikova IV, Chang AL, Ahmed AU, Moon KS, Auffinger B, et al. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin Cancer Res Off J Am Assoc Cancer Res. 2012;18(22):6110–21.CrossRef
29.
Zhai L, Lauing KL, Chang AL, Dey M, Qian J, Cheng Y, et al. The role of IDO in brain tumor immunotherapy. J Neurooncol. 2015;123(3):395–403.PubMedCrossRef
30.
Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol. 2018;15(7):422–42.PubMedCrossRef
31.
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.PubMedPubMedCentralCrossRef
32.
Woroniecka KI, Rhodin KE, Chongsathidkiet P, Keith KA, Fecci PE. T-cell dysfunction in glioblastoma: applying a new framework. Clin Cancer Res Off J Am Assoc Cancer Res. 2018;24(16):3792–802.CrossRef
33.
34.
Alban TJ, Alvarado AG, Sorensen MD, Bayik D, Volovetz J, Serbinowski E, et al. Global immune fingerprinting in glioblastoma patient peripheral blood reveals immune-suppression signatures associated with prognosis. JCI Insight. 2018 Nov 7;3(21).
35.
Gustafson MP, Lin Y, New KC, Bulur PA, O’Neill BP, Gastineau DA, et al. Systemic immune suppression in glioblastoma: the interplay between CD14+HLA-DRlo/neg monocytes, tumor factors, and dexamethasone. Neuro-Oncol. 2010;12(7):631–44.PubMedPubMedCentralCrossRef
36.
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. Cancer Res. 2006;66(6):3294–302.PubMedCrossRef
37.
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 Hagerstown Md 1997. 2019 May;42(4):126–35.
38.
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.PubMedCrossRef
39.
Haddad AF, Young JS, Mummaneni NV, Kasahara N, Aghi MK. Immunologic aspects of viral therapy for glioblastoma and implications for interactions with immunotherapies. J Neurooncol. 2021;152(1):1–13.PubMedPubMedCentralCrossRef
40.
Todo T, Ito H, Ino Y, Ohtsu H, Ota Y, Shibahara J, et al. Intratumoral oncolytic herpes virus G47∆ for residual or recurrent glioblastoma: a phase 2 trial. Nat Med. 2022;28(8):1630–9.PubMedPubMedCentralCrossRef
41.
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. 2022;17:E1–10.
42.
Portnow J, Badie B, Chen M, Liu A, Blanchard S, Synold TW. The neuropharmacokinetics of temozolomide in patients with resectable brain tumors: potential implications for the current approach to chemoradiation. Clin Cancer Res. 2009;15(22):7092–8.PubMedPubMedCentralCrossRef
43.
Ostermann S, Csajka C, Buclin T, Leyvraz S, Lejeune F, Decosterd LA, et al. Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients. Clin Cancer Res. 2004;10(11):3728–36.PubMedCrossRef
44.
Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and trojan horses. Clin Cancer Res. 2007;13(6):1663–74.PubMedCrossRef
45.
Stewart DJ, Lu K, Benjamin RS, Leavens ME, Luna M, Yap HY, et al. Concentrations of vinblastine in human intracerebral tumor and other tissues. J Neurooncol. 1983;1(2):139–44.PubMedCrossRef
46.
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.PubMedCrossRef
47.
Yamahara T, Numa Y, Oishi T, Kawaguchi T, Seno T, Asai A, et al. Morphological and flow cytometric analysis of cell infiltration in glioblastoma: a comparison of autopsy brain and neuroimaging. Brain Tumor Pathol. 2010;27(2):81–7.PubMedCrossRef
48.
Barajas RF, Phillips JJ, Parvataneni R, Molinaro A, Essock-Burns E, Bourne G, et al. Regional variation in histopathologic features of tumor specimens from treatment-naive glioblastoma correlates with anatomic and physiologic MR Imaging. Neuro-Oncol. 2012;14(7):942–54.PubMedPubMedCentralCrossRef
49.
Randall EC, Emdal KB, Laramy JK, Kim M, Roos A, Calligaris D, et al. Integrated mapping of pharmacokinetics and pharmacodynamics in a patient-derived xenograft model of glioblastoma. Nat Commun. 2018;9(1):4904.PubMedPubMedCentralCrossRef
50.
Haas-Kogan DA, Prados MD, Tihan T, Eberhard DA, Jelluma N, Arvold ND, et al. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst. 2005;97(12):880–7.PubMedCrossRef
51.
Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353(19):2012–24.PubMedCrossRef
52.
Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol. 2004;22(1):133–42.PubMedCrossRef
53.
Franceschi E, Cavallo G, Lonardi S, Magrini E, Tosoni A, Grosso D, et al. Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Br J Cancer. 2007;96(7):1047–51.PubMedPubMedCentralCrossRef
54.
Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, et al. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol. 2009;27(4):579–84.PubMedCrossRef
55.
de Groot JF, Gilbert MR, Aldape K, Hess KR, Hanna TA, Ictech S, et al. Phase II study of carboplatin and erlotinib (Tarceva, OSI-774) in patients with recurrent glioblastoma. J Neurooncol. 2008;90(1):89–97.PubMedPubMedCentralCrossRef
56.
Reardon DA, Groves MD, Wen PY, Nabors L, Mikkelsen T, Rosenfeld S, et al. A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma. Clin Cancer Res. 2013;19(4):900–8.PubMedCrossRef
57.
Wen PY, Cloughesy TF, Olivero AG, Morrissey KM, Wilson TR, Lu X, et al. First-in-human phase I study to evaluate the brain-penetrant PI3K/mTOR inhibitor GDC-0084 in patients with progressive or recurrent high-grade glioma. Clin Cancer Res. 2020;26(8):1820–8.PubMedCrossRef
58.
Wen PY, de Groot JF, Battiste J, Goldlust SA, Garner JS, Friend J, et al. Paxalisib in patients with newly diagnosed glioblastoma with unmethylated MGMT promoter status: final phase 2 study results. J Clin Oncol. 2022 Jun 1;40(16_suppl):2047–2047.
59.
Drappatz J, Brenner A, Wong ET, Eichler A, Schiff D, Groves MD, et al. Phase I study of GRN1005 in recurrent malignant glioma. Clin Cancer Res. 2013;19(6):1567–76.PubMedCrossRef
60.
Kumthekar P, Tang SC, Brenner AJ, Kesari S, Piccioni DE, Anders C, et al. ANG1005, a brain-penetrating peptide-drug conjugate, shows activity in patients with breast cancer with leptomeningeal carcinomatosis and recurrent brain metastases. Clin Cancer Res Off J Am Assoc Cancer Res. 2020;26(12):2789–99.CrossRef
61.
62.
Mullard A. FDA approves ADC Therapeutics’ loncastuximab tesirine, ushering in a new cytotoxic payload. Nat Rev Drug Discov. 2021;20(6):414–14.PubMed
63.
64.
Chau CH, Steeg PS, Figg WD. Antibody–drug conjugates for cancer. The Lancet. 2019;394(10200):793–804.CrossRef
65.
Van Den Bent M, Eoli M, Sepulveda JM, Smits M, Walenkamp A, Frenel JS, 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-Oncol. 2020;22(5):684–93.PubMedCrossRef
66.
67.
Hamblett KJ, Kozlosky CJ, Siu S, Chang WS, Liu H, Foltz IN, et al. AMG 595, an anti-EGFRvIII antibody–drug conjugate, induces potent antitumor activity against EGFRvIII-expressing glioblastoma. Mol Cancer Ther. 2015;14(7):1614–24.PubMedCrossRef
68.
Rosenthal M, Curry R, Reardon DA, Rasmussen E, Upreti VV, Damore MA, et al. Safety, tolerability, and pharmacokinetics of anti-EGFRvIII antibody–drug conjugate AMG 595 in patients with recurrent malignant glioma expressing EGFRvIII. Cancer Chemother Pharmacol. 2019;84(2):327–36.PubMedCrossRef
69.
Offenhäuser C, Al-Ejeh F, Puttick S, Ensbey KS, Bruce ZC, Jamieson PR, et al. EphA3 pay-loaded antibody therapeutics for the treatment of glioblastoma. Cancers. 2018;10(12):519.PubMedPubMedCentralCrossRef
70.
Zalutsky MR, Reardon DA, Akabani G, Coleman RE, Friedman AH, Friedman HS, et al. Clinical experience with α-Particle–emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6. J Nucl Med Off Publ Soc Nucl Med. 2008;49(1):30–8.
71.
Schumacher T, Hofer S, Eichhorn K, Wasner M, Zimmerer S, Freitag P, et al. Local injection of the 90Y-labelled peptidic vector DOTATOC to control gliomas of WHO grades II and III: an extended pilot study. Eur J Nucl Med Mol Imaging. 2002;29(4):486–93.PubMedCrossRef
72.
Casacó A, López G, García I, Rodríguez JA, Fernández R, Figueredo J, et al. Phase I single-dose study of intracavitary-administered nimotuzumab labeled with 188 Re in adult recurrent high-grade glioma. Cancer Biol Ther. 2008;7(3):333–9.PubMedCrossRef
73.
Li L, Quang TS, Gracely EJ, Kim JH, Emrich JG, Yaeger TE, et al. A Phase II study of anti–epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme: clinical article. J Neurosurg. 2010;113(2):192–8.PubMedCrossRef
74.
Li Y, Marcu LG, Hull A, Bezak E. Radioimmunotherapy of glioblastoma multiforme - current status and future prospects. Crit Rev Oncol Hematol. 2021;163:103395.PubMedCrossRef
75.
Zawadzki M, Walecki J, Kostkiewicz B, Kostyra K, Pearl MS, Solaiyappan M, et al. Republished: Real-time MRI guidance for intra-arterial drug delivery in a patient with a brain tumor: technical note. J NeuroInterventional Surg. 2019;11(8):e3–e3.CrossRef
76.
Tyler JL, Yamamoto YL, Diksic M, Théron J, Villemure JG, Worthington C, et al. Pharmacokinetics of superselective intra-arterial and intravenous [11C]BCNU evaluated by PET. J Nucl Med Off Publ Soc Nucl Med. 1986;27(6):775–80.
77.
Neuwelt EA, Glasberg M, Diehl J, Frenkel EP, Barnett P. Osmotic blood-brain barrier disruption in the posterior fossa of the dog. J Neurosurg. 1981;55(5):742–8.PubMedCrossRef
78.
Neuwelt EA, Frenkel EP, D’Agostino AN, Carney DN, Minna JD, Barnett PA, et al. Growth of human lung tumor in the brain of the nude rat as a model to evaluate antitumor agent delivery across the blood-brain barrier. Cancer Res. 1985;45(6):2827–33.PubMed
79.
Uluc K, Ambady P, McIntyre MK, Tabb JP, Kersch CN, Nerison CS, et al. Safety of intra-arterial chemotherapy with or without osmotic blood–brain barrier disruption for the treatment of patients with brain tumors. Neuro-Oncol Adv. 2022 Jan 1;4(1):vdac104.
80.
81.
82.
Lidar Z, Mardor Y, Jonas T, Pfeffer R, Faibel M, Nass D, et al. Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study. J Neurosurg. 2004;100(3):472–9.PubMedCrossRef
83.
Bruce JN, Fine RL, Canoll P, Yun J, Kennedy BC, Rosenfeld SS, et al. Regression of recurrent malignant gliomas with convection-enhanced delivery of topotecan. Neurosurgery. 2011;69(6):1272–80.PubMedCrossRef
84.
Spinazzi EF, Argenziano MG, Upadhyayula PS, Banu MA, Neira JA, Higgins DMO, et al. Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial. Lancet Oncol. 2022;23(11):1409–18.PubMedPubMedCentralCrossRef
85.
Weaver M, Laske DW. Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas. J Neurooncol. 2003;65(1):3–13.PubMedCrossRef
86.
Weber F, Asher A, Bucholz R, Berger M, Prados M, Chang S, et al. Safety, tolerability, and tumor response of IL4-Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. J Neurooncol. 2003;64(1–2):125–37.PubMedCrossRef
87.
Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G, et al. Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro-Oncol. 2010;12(8):871–81.PubMedPubMedCentralCrossRef
88.
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.PubMedPubMedCentralCrossRef
89.
Chen C, Lee I, Tatsui C, Elder T, Sloan AE. Laser interstitial thermotherapy (LITT) for the treatment of tumors of the brain and spine: a brief review. J Neurooncol. 2021;151(3):429–42.PubMedPubMedCentralCrossRef
90.
Mohammadi AM, Hawasli AH, Rodriguez A, Schroeder JL, Laxton AW, Elson P, et al. The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: a multicenter study. Cancer Med. 2014;3(4):971–9.PubMedPubMedCentralCrossRef
91.
Mohammadi AM, Sharma M, Beaumont TL, Juarez KO, Kemeny H, Dechant C, et al. Upfront magnetic resonance imaging-guided stereotactic laser-ablation in newly diagnosed glioblastoma: a multicenter review of survival outcomes compared to a matched cohort of biopsy-only patients. Neurosurgery. 2019;85(6):762–72.PubMedCrossRef
92.
Viozzi I, Guberinic A, Overduin CG, Rovers MM, ter Laan M. Laser interstitial thermal therapy in patients with newly diagnosed glioblastoma: a systematic review. J Clin Med. 2021;10(2):355.PubMedPubMedCentralCrossRef
93.
de Groot JF, Kim AH, Prabhu S, Rao G, Laxton AW, Fecci PE, et al. Efficacy of laser interstitial thermal therapy (LITT) for newly diagnosed and recurrent IDH wild-type glioblastoma. Neuro-Oncol Adv. 2022 Dec;4(1):vdac040.
94.
Leuthardt EC, Duan C, Kim MJ, Campian JL, Kim AH, Miller-Thomas MM, et al. Hyperthermic laser ablation of recurrent glioblastoma leads to temporary disruption of the peritumoral blood brain barrier. PLoS ONE. 2016;11(2):e0148613.PubMedPubMedCentralCrossRef
95.
Srinivasan ES, Sankey EW, Grabowski MM, Chongsathidkiet P, Fecci PE. The intersection between immunotherapy and laser interstitial thermal therapy: a multipronged future of neuro-oncology. Int J Hyperthermia. 2020;37(2):27–34.PubMedCrossRef
96.
Ahmed N, Gandhi D, Melhem ER, Frenkel V. MRI guided focused ultrasound-mediated delivery of therapeutic cells to the brain: a review of the state-of-the-art methodology and future applications. Front Neurol. 2021Jun;17(12): 669449.CrossRef
97.
Arsiwala TA, Sprowls SA, Blethen KE, Adkins CE, Saralkar PA, Fladeland RA, et al. Ultrasound-mediated disruption of the blood tumor barrier for improved therapeutic delivery. Neoplasia N Y N. 2021;23(7):676–91.CrossRef
98.
Meng Y, Hynynen K, Lipsman N. Applications of focused ultrasound in the brain: from thermoablation to drug delivery. Nat Rev Neurol. 2021;17(1):7–22.PubMedCrossRef
99.
Clarke RL, ter Haar GR. Temperature rise recorded during lesion formation by high-intensity focused ultrasound. Ultrasound Med Biol. 1997;23(2):299–306.PubMedCrossRef
100.
Dewey WC. Arrhenius relationships from the molecule and cell to the clinic. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group. 2009;25(1):3–20.CrossRef
101.
Dobrotwir A, Pun E. Clinical 24 month experience of the first MRgFUS unit for treatment of uterine fibroids in Australia. J Med Imaging Radiat Oncol. 2012;56(4):409–16.PubMedCrossRef
102.
Hesley GK, Gorny KR, Woodrum DA. MR-guided focused ultrasound for the treatment of uterine fibroids. Cardiovasc Intervent Radiol. 2013;36(1):5–13.PubMedCrossRef
103.
104.
Uchida T, Nakano M, Hongo S, Shoji S, Nagata Y, Satoh T, et al. High-intensity focused ultrasound therapy for prostate cancer. Int J Urol Off J Jpn Urol Assoc. 2012;19(3):187–201.
105.
Blana A, Walter B, Rogenhofer S, Wieland WF. High-intensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology. 2004;63(2):297–300.PubMedCrossRef
106.
Weeks EM, Platt MW, Gedroyc W. MRI-guided focused ultrasound (MRgFUS) to treat facet joint osteoarthritis low back pain—case series of an innovative new technique. Eur Radiol. 2012;22(12):2822–35.PubMedCrossRef
107.
Jeanmonod D, Werner B, Morel A, Michels L, Zadicario E, Schiff G, et al. Transcranial magnetic resonance imaging–guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain. Neurosurg Focus. 2012;32(1):E1.PubMedCrossRef
108.
Elias WJ, Lipsman N, Ondo WG, Ghanouni P, Kim YG, Lee W, et al. A randomized trial of focused ultrasound thalamotomy for essential tremor. N Engl J Med. 2016;375(8):730–9.PubMedCrossRef
109.
Magara A, Bühler R, Moser D, Kowalski M, Pourtehrani P, Jeanmonod D. First experience with MR-guided focused ultrasound in the treatment of Parkinson’s disease. J Ther Ultrasound. 2014;31(2):11.CrossRef
110.
McDannold N, Clement G, Black P, Jolesz F, Hynynen K. Transcranial MRI-guided focused ultrasound surgery of brain tumors: initial findings in three patients. Neurosurgery. 2010;66(2):323–32.PubMedCrossRef
111.
Paun L, Moiraghi A, Jannelli G, Nouri A, DiMeco F, Pallud J, et al. From focused ultrasound tumor ablation to brain blood barrier opening for high grade glioma: a systematic review. Cancers. 2021;13(22):5614.PubMedPubMedCentralCrossRef
112.
Tierney TS, Alavian KN, Altman N, Bhatia S, Duchowny M, Hyslop A, et al. Initial experience with magnetic resonance–guided focused ultrasound stereotactic surgery for central brain lesions in young adults. J Neurosurg. 2022;137(3):760–7.CrossRef
113.
Allen SP, Hall TL, Cain CA, Hernandez-Garcia L. Controlling cavitation-based image contrast in focused ultrasound histotripsy surgery. Magn Reson Med. 2015;73(1):204–13.PubMedCrossRef
114.
Gerhardson T, Sukovich JR, Pandey AS, Hall TL, Cain CA, Xu Z. Effect of frequency and focal spacing on transcranial histotripsy clot liquefaction using electronic focal steering. Ultrasound Med Biol. 2017;43(10):2302–17.PubMedPubMedCentralCrossRef
115.
Xu Z, Hall TL, Vlaisavljevich E, Lee FT. Histotripsy: the first noninvasive, non-ionizing, non-thermal ablation technique based on ultrasound. Int J Hyperth Off J Eur Soc Hyperthermic Oncol North Am Hyperth Group. 2021;38(1):561–75.CrossRef
116.
Cho H, Lee HY, Han M, Choi J ryul, Ahn S, Lee T, et al. Localized down-regulation of P-glycoprotein by focused ultrasound and microbubbles induced blood-brain barrier disruption in rat brain. Sci Rep. 2016 Aug 11;6:31201.
117.
Wei HJ, Upadhyayula PS, Pouliopoulos AN, Englander ZK, Zhang X, Jan CI, et al. Focused ultrasound-mediated blood-brain barrier opening increases delivery and efficacy of etoposide for glioblastoma treatment. Int J Radiat Oncol Biol Phys. 2021;110(2):539–50.PubMedCrossRef
118.
Anastasiadis P, Gandhi D, Guo Y, Ahmed AK, Bentzen SM, Arvanitis C, et al. Localized blood–brain barrier opening in infiltrating gliomas with MRI-guided acoustic emissions–controlled focused ultrasound. Proc Natl Acad Sci U S A. 2021;118(37):e2103280118.PubMedPubMedCentralCrossRef
119.
Park SH, Kim MJ, Jung HH, Chang WS, Choi HS, Rachmilevitch I, et al. One-year outcome of multiple blood-brain barrier disruptions with temozolomide for the treatment of glioblastoma. Front Oncol. 2020;10:1663.PubMedPubMedCentralCrossRef
120.
Zhao SG, Chen XF, Wang LG, Yang G, Han DY, Teng L, et al. Increased expression of ABCB6 enhances protoporphyrin IX accumulation and photodynamic effect in human glioma. Ann Surg Oncol. 2013;20(13):4379–88.PubMedCrossRef
121.
Ohmura T, Fukushima T, Shibaguchi H, Yoshizawa S, Inoue T, Kuroki M, et al. Sonodynamic therapy with 5-aminolevulinic acid and focused ultrasound for deep-seated intracranial glioma in rat. Anticancer Res. 2011;31(7):2527–33.PubMed
122.
123.
Hadjipanayis CG, Widhalm G, Stummer W. What is the surgical benefit of utilizing 5-ALA for fluorescence-guided surgery of malignant gliomas? Neurosurgery. 2015;77(5):663–73.PubMedCrossRef
124.
Sanai N, Tien AC, Tovmasyan A, Chang YW, Margaryan T, Hendrickson K, et al. CTNI-23. A first-in-human Phase 0/1 clinical trial of 5-aminolevulinic acid sonodynamic therapy in recurrent glioblastoma. Neuro-Oncol. 2021 Nov 2;23(Supplement_6):vi64.
125.
Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010;28(7):1168–74.PubMedPubMedCentralCrossRef
126.
Mandel JJ, Yust-Katz S, Patel AJ, Cachia D, Liu D, Park M, et al. Inability of positive phase II clinical trials of investigational treatments to subsequently predict positive phase III clinical trials in glioblastoma. Neuro-Oncol. 2018;20(1):113–22.PubMedCrossRef
127.
Smith EJ, Naik A, Goel M, Wen PY, Lim M, Chang SM, et al. Adult neuro-oncology trials in the United States over 5 decades: analysis of trials completion rate to guide the path forward. Neuro-Oncol Adv. 2024;6(1):vdad169.
128.
Mellinghoff IK, Cloughesy TF. Balancing risk and efficiency in drug development for rare and challenging tumors: a new paradigm for glioma. J Clin Oncol. 2022;40(30):3510–9.PubMedPubMedCentralCrossRef
129.
Vogelbaum MA, Li G, Heimberger AB, Lang FF, Fueyo J, Gomez-Manzano C, et al. A window of opportunity to overcome therapeutic failure in neuro-oncology. Am Soc Clin Oncol Educ Book. 2022;42:139–46.CrossRef
130.
Di Nunno V, Franceschi E, Tosoni A, Gatto L, Lodi R, Bartolini S, et al. Glioblastoma: emerging treatments and novel trial designs. Cancers. 2021;13(15):3750.PubMedPubMedCentralCrossRef
131.
Subbiah V, Kreitman RJ, Wainberg ZA, Gazzah A, Lassen U, Stein A, et al. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. Nat Med. 2023;29(5):1103–12.PubMedPubMedCentralCrossRef
132.
Cunanan KM, Gonen M, Shen R, Hyman DM, Riely GJ, Begg CB, et al. Basket trials in oncology: a trade-off between complexity and efficiency. J Clin Oncol. 2017;35(3):271–3.PubMedCrossRef
133.
Youssef G, Wen PY. Updated response assessment in neuro-oncology (RANO) for gliomas. Curr Neurol Neurosci Rep. 2024;24(2):17–25.PubMedCrossRef
Metadata
Title
Strategies to Improve Drug Delivery Across the Blood–Brain Barrier for Glioblastoma
Authors
Kazim H. Narsinh
Edgar Perez
Alexander F. Haddad
Jacob S. Young
Luis Savastano
Javier E. Villanueva-Meyer
Ethan Winkler
John de Groot
Publication date
05-04-2024
Publisher
Springer US
Published in
Current Neurology and Neuroscience Reports / Issue 5/2024
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI
https://doi.org/10.1007/s11910-024-01338-x
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits