Keywords
PD-1 inhibitors
PD-L1 inhibitors
PD-L2 inhibitors
CTLA-4 inhibitors
overall survival
progression free survival
How to Cite
Abstract
Background: Immune checkpoint inhibitors (ICIs) have shown promise in the treatment of many cancers but have faced many challenges in treating glioblastoma (GBM) due to the tumor’s unique immune microenvironment.
Methods: This literature review was conducted to explore the role of ICIs in GBM, focusing on PD-1 and PD-L1 inhibitors, and their potential in combination therapies. Studies were retrieved from PubMed, Web of Science, and a total of 26 articles were included for data extraction after applying inclusion and exclusion criteria.
Results: ICIs in GBM has demonstrated limited clinical benefit despite the strong biological rationale. Large phase III trials showed that PD-1 inhibition with agents like nivolumab has not improved overall or progression-free survival, largely due to the tumor heterogeneity, immunosuppressive tumor microenvironment, and low tumor mutational burden. CTLA-4 inhibitors like ipilimumab and tremelimumab have shown limited efficacy as monotherapy, though combination or salvage strategies following failure of PD-1 showed some results, particularly in replication-repair–deficient or hypermutated gliomas. Standard chemoradiotherapy with temozolomide remains the standard of treatment, with MGMT promoter methylation as the strongest predictive biomarker. Adn PD-L2 remains underexplored as a target.
Conclusion: Overall, the evidence shows that monotherapy with ICIs is insufficient in GBM, and future approaches for these agents will require case-studied patient selection, combination strategies, and integration with existing standard therapies.
References
Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: The CheckMate 143 Phase 3 Randomized Clinical Trial. https://pubmed.ncbi.nlm.nih.gov/32437507/
Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: An international randomized phase III trial (CheckMate-498). https://pubmed.ncbi.nlm.nih.gov/35419607/
Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter (CheckMate-548). https://pubmed.ncbi.nlm.nih.gov/35511454/
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. https://pubmed.ncbi.nlm.nih.gov/15758009/
Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. https://pubmed.ncbi.nlm.nih.gov/25355681/
Neurocognitive, symptom, and health-related quality of life outcomes of a randomized trial of bevacizumab for newly diagnosed glioblastoma (NRG/RTOG 0825). https://pubmed.ncbi.nlm.nih.gov/33515019/
O(6)-methylguanine DNA-methyltransferase methylation status can change between first surgery for newly diagnosed glioblastoma and second surgery for recurrence: clinical implications. https://pubmed.ncbi.nlm.nih.gov/20167816/
Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients. https://pubmed.ncbi.nlm.nih.gov/38060340/
Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. https://pubmed.ncbi.nlm.nih.gov/28844499/
Combined Immunotherapy Improves Outcome for Replication-Repair-Deficient (RRD) High-Grade Glioma Failing Anti-PD-1 Monotherapy: A Report from the International RRD Consortium. https://pubmed.ncbi.nlm.nih.gov/37823831/
Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. https://pubmed.ncbi.nlm.nih.gov/29260225/
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. https://pubmed.ncbi.nlm.nih.gov/19269895/
Lessons learned from phase 3 trials of immunotherapy for glioblastoma: Time for longitudinal sampling?. https://pubmed.ncbi.nlm.nih.gov/37995317/
Prospects of immune checkpoint modulators in the treatment of glioblastoma. https://pubmed.ncbi.nlm.nih.gov/35976319/
Immune Checkpoint Inhibitors in Glioblastoma IDHwt Treatment: A Systematic Review. https://pubmed.ncbi.nlm.nih.gov/39766048/
Checkpoint inhibitor immunotherapy for glioblastoma: current progress, challenges and future outlook. https://pubmed.ncbi.nlm.nih.gov/32862726/
The landscape of immune checkpoint inhibitor clinical trials in glioblastoma: A systematic review. https://pubmed.ncbi.nlm.nih.gov/39534539/
PD-1 inhibitors: Do they have a future in the treatment of glioblastoma?. https://pmc.ncbi.nlm.nih.gov/articles/PMC7682636/
PD-1/PD-L1 immune checkpoint inhibitors in glioblastoma: clinical studies, challenges and potential. https://pmc.ncbi.nlm.nih.gov/articles/PMC7899692/
Checkpoint: Inspecting the Barriers in Glioblastoma Immunotherapies. https://pmc.ncbi.nlm.nih.gov/articles/PMC9363531/
Current Immunotherapies for Glioblastoma Multiforme. https://pmc.ncbi.nlm.nih.gov/articles/PMC7986847/
Present and Future of Immunotherapy in Patients With Glioblastoma: Limitations and Opportunities. https://pmc.ncbi.nlm.nih.gov/articles/PMC10994265/
Immune checkpoint inhibitors for glioblastoma: emerging science, clinical advances, and future directions. https://pmc.ncbi.nlm.nih.gov/articles/PMC12188872/
Unlocking Hope: Anti-VEGFR inhibitors and their potential in glioblastoma treatment. https://pubmed.ncbi.nlm.nih.gov/38677355/
Immunosuppression in Gliomas via PD-1/PD-L1 Axis and Adenosine Pathway. https://pmc.ncbi.nlm.nih.gov/articles/PMC7919594/
PD-1/PD-L1 immune-checkpoint inhibitors in glioblastoma: A concise review. https://pubmed.ncbi.nlm.nih.gov/30819441/