Matthew Kenny

Background: Glioblastoma (GBM) is the most common primary tumor of the central nervous system in adults.^1-4 The prognosis is poor, with the median survival averaging 14 months after diagnosis and the overall survival of patients beyond five years being less than 5%.³ Current treatment of GBM is combinational therapy of maximal safe resection, radiation therapy, and temozolomide chemotherapy.¹ Current therapy is ineffective at curing GBM, and the field is currently investigating novel treatment modalities to treat GBM, including modulation of the tumor microenvironment (TME) and increasing the immune system’s ability to suppress tumor growth.3 Different approaches to immune checkpoint blockade (ICB) therapy have shown success when combined with other drugs.⁴

Objective: In this review, different strategies of ICB administration were analyzed for their mechanism and success in the treatment of Glioblastoma.

Search Methods: The PubMed online data based was utilized to aggregate the information used for this analysis. All articles were published between 2017 and 2023, with keywords including “Glioblastoma”, “ICB therapy”, and “PD-1 Blockade”.

Results: The results from the collected primary research indicate that there is progress in the successful treatment of glioblastoma when using combinational immune checkpoint blockade therapy. One trial identified biomarkers linked to anti-PD-1 therapy edema: matrix-metalloproteases 1&2.⁵ Controlling for ICB-induced edema with coadministration of Losartan decreased vascular leakage, reverses the immunosuppressive tumor microenvironment (TME) and improved overall immune infiltration into the tumor and overall survival of the trial subjects. Similarly, limiting T-cell regulator activity showed results that were indicative of immune system memory when subjects were able to successfully survive tumor rechallenge.⁵ Other studies examined novel methods of therapeutic administration of ICB therapy. Intracerebral administration of nivolumab and ipilimumab demonstrated improved access to the tumor in the immune-privileged site. Reduced the number of adverse effects associated with intravenous administration of ICB therapy. Results showed the mode of therapy was safe and feasible, and showed an improvement in overall survival. Intracranial administration study also showed reduced lymphocyte exhaustion.⁶ Immune checkpoint therapy was also combined with chimeric antigen receptor T cell therapy to improve overall survival. This combinational therapy identified a glioblastoma-specific biomarker, Il-13Ra2, then generated CAR therapy to target the protein. When IL13Ra2 was combined with ICB, tumor infiltration was improved, and tumor growth was suppressed.⁷ Studies also found that the aggressive nature and immunosuppressive environment of Glioblastoma were due in part to the hypoxic TME and resulting oxidative stress. Oxidative stress upregulated a nuclear receptor, Nr4a2, which is specific to cancerous tissue. Pharmacologic knockout of the nuclear receptor improved overall survival. When the knockout was combined with ICB therapy, the study subjects demonstrated tumor regression and increased overall survival.⁸ ICB therapy can also be co-administered with an oncolytic virus, Delta-24-ACT, to infiltrate growing glioblastoma, prevent lymphocyte exhaustion, and improve overall survival while conferring immunological memory.⁹

Conclusion: Glioblastoma is a remarkably complex disease with heterogeneity of tumor cells existing throughout the tumor. Combinational therapy is already the existing standard of care, adjuvant treatment with ICB ought to take the same approach when attempting to change the environment to increase the effectiveness of treatment. Combinational therapy in the use of ICB confers an advantage in overall survival and offers a unique pathway to treat a malignancy that has thus far demonstrated an unrelenting and devastating prognosis.

Works Cited.

1. McKinnon C, Nandhabalan M, Murray SA, Plaha P. Glioblastoma: clinical presentation, diagnosis, and management. BMJ. 2021;374:n1560. Published 2021 Jul 14. doi:10.1136/bmj.n1560
2. Ye Z, Ai X, Yang K, et al. Targeting Microglial Metabolic Rewiring Synergizes with Immune Checkpoint Blockade Therapy for Glioblastoma [published online ahead of print, 2023 Jan 17]. Cancer Discov. 2023;CD-22-0455. doi:10.1158/2159-8290.CD-22-0455
3. Yang K, Wu Z, Zhang H, et al. Glioma targeted therapy: insight into future of molecular approaches. Mol Cancer. 2022;21(1):39. Published 2022 Feb 8. doi:10.1186/s12943-022-01513-z
4. Biserova K, Jakovlevs A, Uljanovs R, Strumfa I. Cancer Stem Cells: Significance in Origin, Pathogenesis and Treatment of Glioblastoma. Cells. 2021;10(3):621. Published 2021 Mar 11. doi:10.3390/cells10030621
5. Rajaratnam V, Islam MM, Yang M, Slaby R, Ramirez HM, Mirza SP. Glioblastoma: Pathogenesis and Current Status of Chemotherapy and Other Novel Treatments. Cancers (Basel). 2020;12(4):937. Published 2020 Apr 10. doi:10.3390/cancers12040937
6. Datta M, Chatterjee S, Perez EM, et al. Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models. Proc Natl Acad Sci U S A. 2023;120(6):e2219199120. doi:10.1073/pnas.2219199120
7. Duerinck J, Schwarze JK, Awada G, et al. Intracerebral administration of CTLA-4 and PD-1 immune checkpoint blocking monoclonal antibodies in patients with recurrent glioblastoma: a phase I clinical trial. J Immunother Cancer. 2021;9(6):e002296. doi:10.1136/jitc-2020-002296
8. Yin Y, Boesteanu AC, Binder ZA, et al. Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas. Mol Ther Oncolytics. 2018;11:20-38. Published 2018 Aug 28. doi:10.1016/j.omto.2018.08.002
9. Puigdelloses M, Garcia-Moure M, Labiano S, et al. CD137 and PD-L1 targeting with immunovirotherapy induce a potent and durable antitumor immune response in glioblastoma models [published correction appears in J Immunother Cancer. 2021 Aug;9(8):1]. J Immunother Cancer. 2021;9(7):e002644. doi:10.1136/jitc-2021-002644