Immunotherapy for Malignant Gliomas: Overcoming Barriers and Defining Prospects for Integrated Approaches
https://doi.org/10.24060/2076-3093-2024-14-4-351-359
Abstract
In recent years significant advancements have been made in immunotherapy and its application in various types of malignancies. However, standard treatment methods for malignant gliomas, including glioblastoma, have not undergone substantial transformations. The main barriers to the application of immunotherapy in these tumors are associated with the specific characteristics of the tumor microenvironment, immunosuppressive status of the central nervous system, protective function of the blood-brain barrier, and challenges in interpreting neuroimaging data. Additionally, gliomas are characterized by low PD-L1 expression, low mutational burden, and high heterogeneity, which limits the effectiveness of immunotherapy. Nevertheless, clinical studies demonstrate promising results with the use of immune checkpoint inhibitors, viral therapies, vaccination, and adoptive T-cell therapy. The integration of immunotherapy with radiation therapy to enhance the immune response obtains high potential for managing oncological issues. Further research in this area, including the development of glioblastoma-specific biomarkers and adaptation of immunotherapy to the characteristics of tumor microenvironment will significantly improve the treatment outcomes for malignant gliomas.
About the Authors
O. A. BeylerliRussian Federation
Ozal A. Beylerli — Cand. Sci. (Med.), Senior Researcher
Ufa
E. R. Musaev
Russian Federation
Elmar R. Musaev — Dr. Sci. (Med.), Prof., Corresponding Member of the Russian Academy of Sciences, Department of Oncology
Moscow
A. A. Bukhvostov
Russian Federation
Alexander A. Bukhvostov — Cand. Sci. (Biol.), Assoc. Prof., Department of Medical Nanobiotechnology, Faculty of Biomedical
Moscow
References
1. Abdel-Rahman S.A., Gabr M. Small molecule immunomodulators as next-generation therapeutics for glioblastoma. Cancers (Basel). 2024;16(2):435. DOI: 10.3390/cancers16020435
2. Yuan F., Wang Y., Ma C. Current WHO Guidelines and the critical role of genetic parameters in the classification of glioma: opportunities for immunotherapy. Curr Treat Options Oncol. 2022;23(2):188–98. DOI: 10.1007/s11864-021-00930-4
3. McDuff S.G.R., Dietrich J., Atkins K.M., Oh K.S., Loeffler J.S., Shih H.A. Radiation and chemotherapy for high-risk lower grade gliomas: Choosing between temozolomide and PCV. Cancer Med. 2020;9(1):3–11. DOI: 10.1002/cam4.2686
4. Hart M.G., Garside R., Rogers G., Stein K., Grant R. Temozolomide for high grade glioma. Cochrane Database Syst Rev. 2013;2013(4):CD007415. DOI: 10.1002/14651858.CD007415.pub2
5. Sahoo L., Paikray S.K., Tripathy N.S., Fernandes D., Dilnawaz F. Advancements in nanotheranostics for glioma therapy. Naunyn Schmiedebergs Arch Pharmacol. 2024 Oct 31. DOI: 10.1007/s00210-024-03559-w
6. van den Bent M.J., Baumert B., Erridge S.C., Vogelbaum M.A., Nowak A.K., Sanson M., et al. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet. 2017;390(10103):1645–53. DOI: 10.1016/S0140-6736(17)31442-3. Erratum in: Lancet. 2017;390(10103):1644. DOI: 10.1016/S0140-6736(17)32438-8
7. Rodríguez-Camacho A., Flores-Vázquez J.G., Moscardini-Martelli J., Torres-Ríos J.A., Olmos-Guzmán A., Ortiz-Arce C.S., et al. Glioblastoma treatment: state-of-the-art and future perspectives. Int J Mol Sci. 2022;23(13):7207. DOI: 10.3390/ijms23137207
8. Rock K., McArdle O., Forde P., Dunne M., Fitzpatrick D., O’Neill B., et al. A clinical review of treatment outcomes in glioblastoma multiforme--the validation in a non-trial population of the results of a randomised Phase III clinical trial: has a more radical approach improved survival? Br J Radiol. 2012;85(1017):e729–33. DOI: 10.1259/bjr/83796755
9. Rocha Pinheiro S.L., Lemos F.F.B., Marques H.S., Silva Luz M., de Oliveira Silva L.G., Faria Souza Mendes Dos Santos C., et al. Immunotherapy in glioblastoma treatment: Current state and future prospects. World J Clin Oncol. 2023;14(4):138–59. DOI: 10.5306/wjco.v14.i4.138
10. Arvanitis C.D., Ferraro G.B., Jain R.K. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer. 2020;20(1):26–41. DOI: 10.1038/s41568-019-0205-x
11. Dapash M., Castro B., Hou D., Lee-Chang C. Current immunotherapeutic strategies for the treatment of glioblastoma. Cancers (Basel). 2021;13(18):4548. DOI: 10.3390/cancers13184548
12. Abid H., Watthanasuntorn K., Shah O., Gnanajothy R. Efficacy of pembrolizumab and nivolumab in crossing the blood brain barrier. Cureus. 2019;11(4):e4446. DOI: 10.7759/cureus.4446
13. Mangel L., Vönöczky K., Hanzély Z., Kiss T., Agoston P., Somogy A., et al. CT densitometry of the brain: a novel method for early detection and assessment of irradiation induced brain edema. Neoplasma. 2002;49(4):237–42.
14. Huang B., Zhang H., Gu L., Ye B., Jian Z., Stary C., et al. Advances in immunotherapy for glioblastoma multiforme. J Immunol Res. 2017;2017:3597613. DOI: 10.1155/2017/3597613
15. Maxwell R., Luksik A.S., Garzon-Muvdi T., Hung A.L., Kim E.S., Wu A., et al. Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system. Oncoimmunology. 2018;7(12):e1500108. DOI: 10.1080/2162402X.2018.1500108
16. Garant A., Guilbault C., Ekmekjian T., Greenwald Z., Murgoi P., Vuong T. Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with hematologic or solid neoplasms: A systematic review. Crit Rev Oncol Hematol. 2017;120:86–92. DOI: 10.1016/j.critrevonc.2017.10.009
17. Fujii T., Colen R.R., Bilen M.A., Hess K.R., Hajjar J., Suarez-Almazor M.E., et al. Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience. Invest New Drugs. 2018;36(4):638–46. DOI: 10.1007/s10637-017-0534-0
18. Aquino D., Gioppo A., Finocchiaro G., Bruzzone M.G., Cuccarini V. MRI in glioma immunotherapy: evidence, pitfalls, and perspectives. J Immunol Res. 2017;2017:5813951. DOI: 10.1155/2017/5813951
19. Okan Cakir M., Kirca O., Gunduz S., Ozdogan M. Hyperprogression after immunotherapy: A comprehensive review. J BUON. 2019;24(6):2232–41
20. Brandsma D., Stalpers L., Taal W., Sminia P., van den Bent M.J. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol. 2008;9(5):453–61. DOI: 10.1016/S1470-2045(08)70125-6
21. Young J.S., Al-Adli N., Scotford K., Cha S., Berger M.S. Pseudoprogression versus true progression in glioblastoma: what neurosurgeons need to know. J Neurosurg. 2023;139(3):748–59. DOI: 10.3171/2022.12.JNS222173
22. Gatson N.T.N., Makary M., Bross S.P., Vadakara J., Maiers T., Mongelluzzo G.J., et al. Case series review of neuroradiologic changes associated with immune checkpoint inhibitor therapy. Neurooncol Pract. 2020;8(3):247–58. DOI: 10.1093/nop/npaa079
23. Cuoco J.A., Klein B.J., Busch C.M., Guilliams E.L., Olasunkanmi A.L., Entwistle J.J. Corticosteroid-Induced Regression of Glioblastoma: A Radiographic Conundrum. Front Oncol. 2019;9:1288. DOI: 10.3389/fonc.2019.01288
24. Chen D., Zhang R., Huang X., Ji C., Xia W., Qi Y., et al. MRI-derived radiomics assessing tumor-infiltrating macrophages enable prediction of immune-phenotype, immunotherapy response and survival in glioma. Biomark Res. 2024;12(1):14. DOI: 10.1186/s40364-024-00560-6
25. Srivastava S., Jackson C., Kim T., Choi J., Lim M. A Characterization of dendritic cells and their role in immunotherapy in glioblastoma: from preclinical studies to clinical trials. Cancers (Basel). 2019;11(4):537. DOI: 10.3390/cancers11040537
26. Xu S., Tang L., Li X., Fan F., Liu Z. Immunotherapy for glioma: Current management and future application. Cancer Lett. 2020;476:1–12. DOI: 10.1016/j.canlet.2020.02.002
27. Huang R., Lu X., Sun X., Wu H. A novel immune cell signature for predicting glioblastoma after radiotherapy prognosis and guiding therapy. Int J Immunopathol Pharmacol. 2024;38:3946320241249395. DOI: 10.1177/03946320241249395
28. Martikainen M., Essand M. Virus-based immunotherapy of glioblastoma. Cancers (Basel). 2019;11(2):186. DOI: 10.3390/cancers11020186
29. Alban T.J., Alvarado A.G., Sorensen M.D., 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;3(21):e122264. DOI: 10.1172/jci.insight.122264
30. Ladomersky E., Zhai L., Lauing K.L., Bell A., Xu J., Kocherginsky M., et al. Advanced Age Increases Immunosuppression in the Brain and Decreases Immunotherapeutic Efficacy in Subjects with Glioblastoma. Clin Cancer Res. 2020;26(19):5232–45. DOI: 10.1158/1078-0432.CCR-19-3874
31. Filley A.C., Henriquez M., Dey M. Recurrent glioma clinical trial, CheckMate-143: the game is not over yet. Oncotarget. 2017;8(53):91779–94. DOI: 10.18632/oncotarget.21586
32. Wang X., Guo G., Guan H., Yu Y., Lu J., Yu J. Challenges and potential of PD-1/PD-L1 checkpoint blockade immunotherapy for glioblastoma. J Exp Clin Cancer Res. 2019;38(1):87. DOI: 10.1186/s13046-019-1085-3
33. Bouffet E., Larouche V., Campbell B.B., Merico D., de Borja R., Aronson M., et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J Clin Oncol. 2016;34(19):2206–11. DOI: 10.1200/JCO.2016.66.6552
34. Cloughesy T.F., Landolfi J., Vogelbaum M.A., Ostertag D., Elder J.B., Bloomfield S., et al. Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. Neuro Oncol. 2018;20(10):1383–92. DOI: 10.1093/neuonc/noy075
35. Mahmoud A.B., Ajina R., Aref S., Darwish M., Alsayb M., Taher M., et al. Advances in immunotherapy for glioblastoma multiforme. Front Immunol. 2022;13:944452. DOI: 10.3389/fimmu.2022.944452
36. Sampson J.H., Archer G.E., Mitchell D.A., Heimberger A.B., Herndon J.E. 2nd, Lally-Goss D., et al. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther. 2009;8(10):2773–9. DOI: 10.1158/1535-7163.MCT-09-0124
37. Liau L.M., Ashkan K., Tran D.D., Campian J.L., Trusheim J.E., Cobbs C.S., et al. 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):142. DOI: 10.1186/s12967-018-1507-6. Erratum in: J Transl Med. 2018;16(1):179. DOI: 10.1186/s12967-018-1552-1
38. Weller M., Butowski N., Tran D.D., Recht L.D., 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. DOI: 10.1016/S1470-2045(17)30517-X
39. Filley A.C., Henriquez M., Dey M. CART immunotherapy: development, success, and translation to malignant gliomas and other solid tumors. Front Oncol. 2018;8:453. DOI: 10.3389/fonc.2018.00453
40. O’Rourke D.M., Nasrallah M.P., Desai A., Melenhorst J.J., Mansfield K., Morrissette J.J.D., 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. 2017;9(399):eaaa0984. DOI: 10.1126/scitranslmed.aaa0984
41. Zhou L., Liu Y., Wu Y., Yang X., Spring Kong F.M., Lu Y., et al. Low-dose radiation therapy mobilizes antitumor immunity: New findings and future perspectives. Int J Cancer. 2024;154(7):1143–57. DOI: 10.1002/ijc.34801
42. Yang M., Oh I.Y., Mahanty A., Jin W.L., Yoo J.S. Immunotherapy for glioblastoma: current state, challenges, and future perspectives. Cancers (Basel). 2020;12(9):2334. DOI: 10.3390/cancers12092334
Review
For citations:
Beylerli O.A., Musaev E.R., Bukhvostov A.A. Immunotherapy for Malignant Gliomas: Overcoming Barriers and Defining Prospects for Integrated Approaches. Creative surgery and oncology. 2024;14(4):351-359. (In Russ.) https://doi.org/10.24060/2076-3093-2024-14-4-351-359