Glioblastoma: future therapeutic perspectives
DOI:
https://doi.org/10.24197/cl.30.2025.70-86Keywords:
glioblastoma, immunotherapy, blood-brain barrier, targeted therapy, biomarkersAbstract
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor of the central nervous system. It exhibits high genetic and phenotypic heterogeneity, which complicates early diagnosis and limits therapeutic efficacy. Its incidence is approximately 3-4 cases per 100,000 inhabitants per year, with a higher prevalence in older adults. This type of tumor is associated with high mortality due to its rapid progression, tumor resistance, and the blood-brain barrier, which restricts drug access. This paper highlights the low efficacy of conventional therapeutic strategies, such as surgical resection, radiotherapy, and chemotherapy with temozolomide, and reviews therapies currently under investigation, including immunotherapy, personalized vaccines, viral vectors, CAR-T cells, and nanotechnology. The role of molecular biomarkers in prognosis and the selection of individualized therapies is also considered. The information comes from recent preclinical studies and clinical trials, providing a comprehensive overview of current knowledge and innovations in development to improve the treatment of GBM.
Downloads
References
Ferlay J, Ervik M, Lam F, Laversanne M, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F (2024).
Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Available
from: https://gco.iarc.who.int/today, accessed [01 Abril 2025].
Glioblastoma | UCSF Brain Tumor Center [Internet]. [citado 10 de julio de 2025]. Disponible en: https://braintumorcenter.ucsf.edu/condition/glioblastoma
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. 2 de agosto de 2021;23(8):1231-51.
Wang B, Lv L, Wang Z, Jiang Y, Lv W, Liu X, et al. Improved anti-glioblastoma efficacy by IL-13Rα2 mediated copolymer nanoparticles loaded with paclitaxel. Sci Rep. 16 de noviembre de 2015;5:16589.
Wu W, Klockow JL, Zhang M, Lafortune F, Chang E, Jin L, et al. Glioblastoma multiforme (GBM): An overview of current therapies and mechanisms of resistance. Pharmacological Research. septiembre de 2021;171:105780.
Grupo Español de Investigación en Neurooncología (GEINO). Documento de consenso: Perspectivas IDH. Madrid: GEINO; 2023.
Yang F, Wang L, Zhao W, Wang S, Li J, Sun A, et al. Meta‑Analysis on the Effectiveness. Neurology India. 2024;72(4).
Heiland DH, Masalha W, Franco P, Machein MR, Weyerbrock A. Progression-free and overall survival in patients with recurrent Glioblastoma multiforme treated with last-line bevacizumab versus bevacizumab/lomustine. J Neurooncol. febrero de 2016;126(3):567-75.
Jin Y, Wei J, Weng Y, Feng J, Xu Z, Wang P, et al. Adjuvant Therapy With PD1/PDL1 Inhibitors for Human Cancers: A Systematic Review and Meta-Analysis. Front Oncol. 25 de febrero de 2022;12:732814.
Liu Y, Zhou F, Ali H, Lathia JD, Chen P. Immunotherapy for glioblastoma: current state, challenges, and future perspectives. Cell Mol Immunol. 15 de octubre de 2024;21(12):1354-75.
Reardon DA, Kim TM, Frenel JS, Simonelli M, Lopez J, Subramaniam DS, et al. Treatment with pembrolizumab in programmed death ligand 1–positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial. Cancer. 2021;127(10):1620-9.
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. 15 de febrero de 2021;27(4):1048-57.
Maj T, Wang W, Crespo J, Zhang H, Wang W, Wei S, et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol. diciembre de 2017;18(12):1332-41.
A Set of Transcriptomic Changes Is Associated with Anti–PD-1 Resistance. Cancer Discov. 1 de mayo de 2016;6(5):472.
Kim JE, Patel MA, Mangraviti A, Kim ES, Theodros D, Velarde E, et al. Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas. Clin Cancer Res. 1 de enero de 2017;23(1):124-36.
Curigliano G, Gelderblom H, Mach N, Doi T, Tai D, Forde PM, et al. Phase I/Ib Clinical Trial of Sabatolimab, an Anti-TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti-PD-1 Antibody, in Advanced Solid Tumors. Clin Cancer Res. 1 de julio de 2021;27(13):3620-9.
Harris-Bookman S, Mathios D, Martin AM, Xia Y, Kim E, Xu H, et al. Expression of LAG-3 and efficacy of combination treatment with anti-LAG-3 and anti-PD-1 monoclonal antibodies in glioblastoma. Int J Cancer. 15 de diciembre de 2018;143(12):3201-8.
Bunse L, Pusch S, Bunse T, Sahm F, Sanghvi K, Friedrich M, et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med. agosto de 2018;24(8):1192-203.
Kumar A, Watkins R, Vilgelm AE. Cell Therapy With TILs: Training and Taming T Cells to Fight Cancer. Front Immunol. 1 de junio de 2021;12:690499.
Yao Y, Chen D, Tang C, Ji C, Li Z, Qian Q. Safety, efficacy, and biomarker analysis of response to engineered tumor-infiltrating lymphocytes secreting anti-PD-1 antibody in recurrent glioblastoma: An open-label, two-arms, phase 1 study. JCO. 1 de junio de 2023;41(16_suppl):2042-2042.
Söderberg-Nauclér C, Johnsen JI. Cytomegalovirus in human brain tumors: Role in pathogenesis and potential treatment options. World J Exp Med. 20 de febrero de 2015;5(1):1-10.
Thompson J, Inamdar A, Jahan N, Doniger J, Rosenthal LJ. Localization and Sequence Analysis of Morphological Transforming Region III within Human Cytomegalovirus Strain Towne. Intervirology. 29 de julio de 2008;36(3):121-7.
Soroceanu L, Cobbs CS. Is HCMV a tumor promoter? Virus Res. mayo de 2011;157(2):193-203.
Shen Y, Zhu H, Shenk T. Human cytomagalovirus IE1 and IE2 proteins are mutagenic and mediate «hit-and-run» oncogenic transformation in cooperation with the adenovirus E1A proteins. Proc Natl Acad Sci U S A. 1 de abril de 1997;94(7):3341-5.
Schuessler A, Smith C, Beagley L, Boyle GM, Rehan S, Matthews K, et al. Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer Res. 1 de julio de 2014;74(13):3466-76.
Thompson EM, Ashley DM, Ayasoufi K, Norberg P, Archer G, Buckley ED, et al. A peptide vaccine targeting the CMV antigen pp65 in children and young adults with recurrent high-grade glioma and medulloblastoma: a phase 1 trial. Nat Cancer. 12 de junio de 2025;
Brown CE, Hibbard JC, Alizadeh D, Blanchard MS, Natri HM, Wang D, et al. Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial. Nat Med. abril de 2024;30(4):1001-12.
Bagley SJ, Desai AS, Fraietta JA, Silverbush D, Chafamo D, Freeburg NF, et al. Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial. Nat Med. agosto de 2025;31(8):2778-87.
O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 19 de julio de 2017;9(399):eaaa0984.
Bagley SJ, Binder ZA, Lamrani L, Marinari E, Desai AS, Nasrallah MP, et al. Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial. Nat Cancer. marzo de 2024;5(3):517-31.
Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol. 2007;25:267-96.
Bezu L, Kepp O, Cerrato G, Pol J, Fucikova J, Spisek R, et al. Trial watch: Peptide-based vaccines in anticancer therapy. Oncoimmunology. 2018;7(12):e1511506.
Schuster J, Lai RK, Recht LD, Reardon DA, Paleologos NA, Groves MD, et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol. junio de 2015;17(6):854-61.
Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. marzo de 2011;13(3):324-33.
Malkki H. Trial Watch: Glioblastoma vaccine therapy disappointment in Phase III trial. Nat Rev Neurol. abril de 2016;12(4):190.
Fenstermaker RA, Ciesielski MJ, Qiu J, Yang N, Frank CL, Lee KP, et al. Clinical study of a survivin long peptide vaccine (SurVaxM) in patients with recurrent malignant glioma. Cancer Immunol Immunother. noviembre de 2016;65(11):1339-52.
Ahluwalia MS, Reardon DA, Abad AP, Curry WT, Wong ET, Figel SA, et al. Phase IIa Study of SurVaxM Plus Adjuvant Temozolomide for Newly Diagnosed Glioblastoma. J Clin Oncol. 1 de marzo de 2023;41(7):1453-65.
Migliorini D, Dutoit V, Allard M, Grandjean Hallez N, Marinari E, Widmer V, et al. Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients. Neuro Oncol. 11 de julio de 2019;21(7):923-33.
Migliorini D, Dutoit V, Allard M, Grandjean Hallez N, Marinari E, Widmer V, et al. Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients. Neuro Oncol. 11 de julio de 2019;21(7):923-33.
Zhu X, Nishimura F, Sasaki K, Fujita M, Dusak JE, Eguchi J, et al. Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models. J Transl Med. 12 de febrero de 2007;5:10.
Przepiorka D, Srivastava PK. Heat shock protein--peptide complexes as immunotherapy for human cancer. Mol Med Today. noviembre de 1998;4(11):478-84.
Bloch O, Lim M, Sughrue ME, Komotar RJ, Abrahams JM, O’Rourke DM, et al. Autologous Heat Shock Protein Peptide Vaccination for Newly Diagnosed Glioblastoma: Impact of Peripheral PD-L1 Expression on Response to Therapy. Clin Cancer Res. 15 de julio de 2017;23(14):3575-84.
Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 22 de marzo de 2012;12(4):265-77.
Galluzzi L, Senovilla L, Vacchelli E, Eggermont A, Fridman WH, Galon J, et al. Trial watch: Dendritic cell-based interventions for cancer therapy. Oncoimmunology. 1 de octubre de 2012;1(7):1111-34.
Polyzoidis S, Ashkan K. DCVax®-L--developed by Northwest Biotherapeutics. Hum Vaccin Immunother. 2014;10(11):3139-45.
Neth BJ, Webb MJ, Parney IF, Sener UT. The Current Status, Challenges, and Future Potential of Therapeutic Vaccination in Glioblastoma. Pharmaceutics. 3 de abril de 2023;15(4):1134.
Karimi-Sani I, Molavi Z, Naderi S, Mirmajidi SH, Zare I, Naeimzadeh Y, et al. Personalized mRNA vaccines in glioblastoma therapy: from rational design to clinical trials. J Nanobiotechnology. 4 de octubre de 2024;22(1):601.
Wang QT, Nie Y, Sun SN, Lin T, Han RJ, Jiang J, et al. Tumor-associated antigen-based personalized dendritic cell vaccine in solid tumor patients. Cancer Immunol Immunother. julio de 2020;69(7):1375-87.
Zhong H, Liu S, Cao F, Zhao Y, Zhou J, Tang F, et al. Dissecting Tumor Antigens and Immune Subtypes of Glioma to Develop mRNA Vaccine. Front Immunol. 2021;12:709986.
Melnick K, Dastmalchi F, Mitchell D, Rahman M, Sayour EJ. Contemporary RNA Therapeutics for Glioblastoma. Neuromolecular Med. marzo de 2022;24(1):8-12.
Batich KA, Reap EA, Archer GE, Sanchez-Perez L, Nair SK, Schmittling RJ, et al. Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination. Clin Cancer Res. 15 de abril de 2017;23(8):1898-909.
Lichty BD, Breitbach CJ, Stojdl DF, Bell JC. Going viral with cancer immunotherapy. Nat Rev Cancer. agosto de 2014;14(8):559-67.
Friedman GK, Johnston JM, Bag AK, Bernstock JD, Li R, Aban I, et al. Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas. N Engl J Med. 29 de abril de 2021;384(17):1613-22.
Mochizuki AY, Hummel TR, Cripe T, Fouladi M, Pollack IF, Mitchell D, et al. Intratumoral/Peritumoral Herpes Simplex Virus-1 Mutant HSV1716 in Pediatric Patients with Refractory or Recurrent High-Grade Gliomas: A Report of the Pediatric Brain Tumor Consortium. Onco. marzo de 2025;5(1):1.
Patel DM, Foreman PM, Nabors LB, Riley KO, Gillespie GY, Markert JM. Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered HSV-1 Expressing IL-12, in Patients with Recurrent/Progressive Glioblastoma Multiforme, Anaplastic Astrocytoma, or Gliosarcoma. Hum Gene Ther Clin Dev. junio de 2016;27(2):69-78.
Lang FF, Conrad C, Gomez-Manzano C, Yung WKA, Sawaya R, Weinberg JS, et al. Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma. J Clin Oncol. 10 de mayo de 2018;36(14):1419-27.
Nassiri F, Patil V, Yefet LS, Singh O, Liu J, Dang RMA, et al. Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial. Nat Med. junio de 2023;29(6):1370-8.
Kicielinski KP, Chiocca EA, Yu JS, Gill GM, Coffey M, Markert JM. Phase 1 clinical trial of intratumoral reovirus infusion for the treatment of recurrent malignant gliomas in adults. Mol Ther. mayo de 2014;22(5):1056-62.
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. 1 de diciembre de 2020;6(12):1939-46.
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. agosto de 2013;14(9):823-33.
Habashy KJ, Dmello C, Chen L, Arrieta VA, Kim KS, Gould A, et al. Paclitaxel and Carboplatin in Combination with Low-intensity Pulsed Ultrasound for Glioblastoma. Clin Cancer Res. 15 de abril de 2024;30(8):1619-29.
Pandya H, Gibo DM, Garg S, Kridel S, Debinski W. An interleukin 13 receptor α 2-specific peptide homes to human Glioblastoma multiforme xenografts. Neuro Oncol. enero de 2012;14(1):6-18.
Régina A, Demeule M, Ché C, Lavallée I, Poirier J, Gabathuler R, et al. Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep-2. Br J Pharmacol. septiembre de 2008;155(2):185-97.
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. 15 de junio de 2020;26(12):2789-99.
Dmello C, Brenner A, Piccioni D, Wen PY, Drappatz J, Mrugala M, et al. Phase II trial of blood-brain barrier permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma. Neurooncol Adv. 2024;6(1):vdae186.
Shen Y, Pi Z, Yan F, Yeh CK, Zeng X, Diao X, et al. Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts. Int J Nanomedicine. 2017;12:5613-29.
Gould A, Zhang D, Arrieta VA, Stupp R, Sonabend AM. Delivering albumin-bound paclitaxel across the blood-brain barrier for gliomas. Oncotarget. 7 de diciembre de 2021;12(25):2474-5.
Zhang DY, Dmello C, Chen L, Arrieta VA, Gonzalez-Buendia E, Kane JR, et al. Ultrasound-mediated Delivery of Paclitaxel for Glioma: A Comparative Study of Distribution, Toxicity, and Efficacy of Albumin-bound Versus Cremophor Formulations. Clin Cancer Res. 15 de enero de 2020;26(2):477-86.
Sociedad Española de Oncología Médica (SEOM). Las cifras del cáncer en España 2024. Madrid: SEOM; 2024. ISBN: 978-84-09-58445-1. Depósito Legal: M-3222-2024
Agosti E, Garaba A, Antonietti S, Ius T, Fontanella MM, Zeppieri M, et al. CAR-T Cells Therapy in Glioblastoma: A Systematic Review on Molecular Targets and Treatment Strategies. IJMS. 29 de junio de 2024;25(13):7174.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Ángel Ugarte López, Juan de la Puente Aldea , Daniel Barriuso, Laura Senovilla
This work is licensed under a Creative Commons Attribution 4.0 International License.
The articles published at Clínica will have a Creative Commons Attribution 4.0 International License (CC BY 4.0).
The journal allows the authors to retain publishing rights. Authors may reprint their articles in other media without having to request authorization, provided they indicate that the article was originally published in Clínica.