Keywords
Glioblastoma
Immunotherapy
CAR T-cell therapy
Submitted : 2024-11-27
Accepted : 2024-12-12
Published : 2024-12-27
Abstract
Glioblastoma is the most common and aggressive malignant brain tumor, responsible for a poor prognosis and treatment perspective. Despite advancements in investigating novel therapeutic approaches for brain tumor and glioblastoma, there is less progress in improving patients’ survival outcomes. Several hurdles hinder effective treatment, including the immunosuppressive tumor microenvironment (TME), the blood-brain barrier, and extensive heterogeneity. Despite these challenges, immunotherapies are promising and effective therapeutic breakthroughs for the therapy of brain tumor types such as gliomas. Multiple new techniques are being explored including chimeric antigen receptor T-cell therapy, oncolytic virus, cytokine-based treatment, immune checkpoint inhibitors, and vaccine-based techniques. Finally, the present review paper aims to summarize the existing developments of microglia, neutrophils, monocyte-derived macrophages, border-associated macrophages, and potential novel therapeutic options and recent advances in immunotherapies for brain tumors.
References
McFaline-Figueroa JR, Lee EQ, 2018, Brain Tumors. The American Journal of Medicine, 131(8): 874–882.
Herholz K, Langen KJ, Schiepers C, et al., 2012, Brain Tumors. Seminars in Nuclear Medicine, 42(6): 356–370.
D’Alessio A, Proietti G, Sica G, et al., 2019, Pathological and Molecular Features of Glioblastoma and Its Peritumoral Tissue. Cancers, 11(4): 469.
Alves TR, Lima FRS, Kahn SA, et al., 2011, Glioblastoma Cells: A Heterogeneous and Fatal Tumor Interacting with the Parenchyma. Life Sciences, 89(15–16): 532–539.
Emens LA, Ascierto PA, Darcy PK, et al., 2017, Cancer Immunotherapy: Opportunities and Challenges in the Rapidly Evolving Clinical Landscape. European Journal of Cancer, 2017(81): 116–129.
Redman JM, Gibney GT, Atkins MB, 2016, Advances in Immunotherapy for Melanoma. BMC Medicine, 14(1): 20.
McDermott D, Lebbe C, Hodi FS, et al., 2014, Durable Benefit and the Potential for Long-Term Survival with Immunotherapy in Advanced Melanoma. Cancer Treatment Reviews, 40(9): 1056–1064.
Mohme M, Schliffke S, Maire CL, et al., 2018, Immunophenotyping of Newly Diagnosed and Recurrent Glioblastoma Defines Distinct Immune Exhaustion Profiles in Peripheral and Tumor-Infiltrating Lymphocytes. Clinical Cancer Research, 24(17): 4187–4200.
Lu X, Li C, Xu W, et al., 2021, Malignant Tumor Purity Reveals the Driven and Prognostic Role of CD3E in Low-Grade Glioma Microenvironment. Frontiers in Oncology, 2021(11): 676124.
Vimalathas G, Kristensen BW, 2022, Expression, Prognostic Significance and Therapeutic Implications of PD-L1 in Gliomas. Neuropathology and Applied Neurobiology, 48(1): e12767.
Filippone A, Lanza M, Mannino D, et al., 2022, PD1/PD-L1 Immune Checkpoint as a Potential Target for Preventing Brain Tumor Progression. Cancer Immunology, Immunotherapy, 71(9): 2067–2075.
Kondo T, 2017, Molecular Mechanisms Involved in Gliomagenesis. Brain Tumor Pathology, 2017(34): 1–7.
Vastrad B, Vastrad C, Godavarthi A, et al., 2017, Molecular Mechanisms Underlying Gliomas and Glioblastoma Pathogenesis Revealed by Bioinformatics Analysis of Microarray Data. Medical Oncology, 2017(34): 1–30.
Appin CL, Brat DJ, 2015, Molecular Pathways in Gliomagenesis and Their Relevance to Neuropathologic Diagnosis. Advances in Anatomic Pathology, 22(1): 50–58.
Kunkle BW, Yoo C, Roy D, 2013, Reverse Engineering of Modified Genes by Bayesian Network Analysis Defines Molecular Determinants Critical to the Development of Glioblastoma. PloS One, 8(5): e64140.
Eder K, Kalman B, 2014, Molecular Heterogeneity of Glioblastoma and Its Clinical Relevance. Pathology & Oncology Research, 20(4): 777–787.
Weiss SA, Zito C, Tran T, et al., 2021, Melanoma Brain Metastases Have Lower T-cell Content and Microvessel Density Compared to Matched Extracranial Metastases. Journal of Neuro-oncology, 2021(152): 15–25.
Fischer GM, Jalali A, Kircher DA, et al., 2019, Molecular Profiling Reveals Unique Immune and Metabolic Features of Melanoma Brain Metastases. Cancer Discovery, 9(5): 628–645.
Fu M, Tang L, 2019, Chimeric Antigen Receptor T Cell Immunotherapy for Tumor: A Review of Patent Literatures. Recent Patents on Anti-Cancer Drug Discovery, 14(1): 60–69.
Francis SS, Ostrom QT, Cote DJ, et al., 2022, The Epidemiology of Central Nervous System Tumors. Hematology/Oncology Clinics, 36(1): 23–42.
Brem SS, Bierman PJ, Brem H, et al., 2011, Central Nervous System Cancers. Journal of the National Comprehensive Cancer Network, 9(4): 352–400.
Binnewies M, Roberts EW, Kersten K, et al., 2018, Understanding the Tumor Immune Microenvironment (TIME) for Effective Therapy. Nature Medicine, 24(5): 541–550.
Lubgan D, Rutzner S, Lambrecht U, et al., 2017, Stereotactic Radiotherapy as Primary Definitive or Postoperative Treatment of Intracranial Meningioma of WHO Grade II and III Leads to Better Disease Control Than Stereotactic Radiotherapy of Recurrent Meningioma. Journal of Neuro-oncology, 2017(134): 407–416.
Tzikoulis V, Gkantaifi A, Alongi F, et al., 2020, Benign Intracranial Lesions-Radiotherapy: An Overview of Treatment Options, Indications and Therapeutic Results. Reviews on Recent Clinical Trials, 15(2): 93–121.
Sharma P, Allison JP, 2015, The Future of Immune Checkpoint Therapy. Science, 348(6230): 56–61.
Pardoll DM, 2012, The Blockade of Immune Checkpoints in Cancer Immunotherapy. Nature Reviews Cancer, 12(4): 252–264.
Schwabenland M, Bruck W, Priller J, et al., 2021, Analyzing Microglial Phenotypes Across Neuropathologies: A Practical Guide. Acta Neuropathologica, 142(6): 923–936.
Mills J, Ladner L, Soliman E, et al., 2022, Cross-talk and Subset Control of Microglia and Associated Myeloid Cells in Neurological Disorders. Cells, 11(21): 3364.
Pallares-Moratalla C, Bergers G, 2024, The Ins and Outs of Microglial Cells in Brain Health and Disease. Frontiers in Immunology, 2024(15): 1305087.
Yang T, Guo R, Zhang F, 2019, Brain Perivascular Macrophages: Recent Advances and Implications in Health and Diseases. CNS Neuroscience & Therapeutics, 25(12): 1318–1328.
Da Mesquita S, Rua R, 2024, Brain Border-Associated Macrophages: Common Denominators in Infection, Aging, and Alzheimer’s Disease? Trends in Immunology, 45(5): 346–357.
Silvin A, Qian J, Ginhoux F, 2023, Brain Macrophage Development, Diversity and Dysregulation in Health and Disease. Cellular & Molecular Immunology, 20(11): 1277–1289.
Souberan A, Brustlein S, Gouarne C, et al., 2019, Effects of VEGF Blockade on the Dynamics of the Inflammatory Landscape in Glioblastoma-Bearing Mice. Journal of Neuroinflammation, 2019(16): 1–15.
Liu MQ, Zhang JW, Zhu JW, 2023, Roles of Tumor-Associated Macrophages in Tumor Environment and Strategies for Targeting Therapy. Pharmaceutical Fronts, 5(4): 254–273.
Fendl B, Berghoff A, Preusser M, et al., 2023, Macrophage and Monocyte Subsets as New Therapeutic Targets in Cancer Immunotherapy. ESMO Open, 8(1): 100776.
Klemm F, Mockl A, Salamero-Boix A, et al., 2021, Compensatory CSF2-driven Macrophage Activation Promotes Adaptive Resistance to CSF1R Inhibition in Breast-to-Brain Metastasis. Nature Cancer, 2(10): 1086–1101.
Kim DI, 2023, Defining the Roles of Macrophages in Melanoma Drug-Resistance Trajectories, thesis, Cornell University.
Song M, Graubard BI, Rabkin CS, et al., 2021, Neutrophil-to-Lymphocyte Ratio and Mortality in the United States General Population. Scientific Reports, 11(1): 464.
Yan X, Li F, Wang X, et al., 2020, Neutrophil to Lymphocyte Ratio as Prognostic and Predictive Factor in Patients with Coronavirus Disease 2019: A Retrospective Cross‐sectional Study. Journal of Medical Virology, 92(11): 2573–2581.
Tan YG, Eu EWC, Huang HH, et al., 2018, High Neutrophil‐to‐Lymphocyte Ratio Predicts Worse Overall Survival in Patients with Advanced/Metastatic Urothelial Bladder Cancer. International Journal of Urology, 25(3): 232–238.
Tan AC, Ashley DM, Lopez GY, et al., 2020, Management of Glioblastoma: State of the Art and Future Directions. CA: A Cancer Journal for Clinicians, 70(4): 299–312.
Thon N, Tonn JC, Kreth FW, 2019, The Surgical Perspective in Precision Treatment of Diffuse Gliomas. OncoTargets and Therapy, 2019(12): 1497–1508.
Kocher M, Frommolt P, Borberg SK, et al., 2008, Randomized Study of Postoperative Radiotherapy and Simultaneous Temozolomide without Adjuvant Chemotherapy for Glioblastoma. Strahlentherapie und Onkologie, 184(11): 572.
Stummer W, Meinel T, Ewelt C, et al., 2012, Prospective Cohort Study of Radiotherapy with Concomitant and Adjuvant Temozolomide Chemotherapy for Glioblastoma Patients with No or Minimal Residual Enhancing Tumor Load After Surgery. Journal of Neuro-oncology, 2012(108): 89–97.
Strobel H, Baisch T, Fitzel R, et al., 2019, Temozolomide and Other Alkylating Agents in Glioblastoma Therapy. Biomedicines, 7(3): 69.
Singh N, Miner A, Hennis L, et al., 2021, Mechanisms of Temozolomide Resistance in Glioblastoma: A Comprehensive Review. Cancer Drug Resistance, 4(1): 17.
Tomaszewski W, Sanchez-Perez L, Gajewski TF, et al., 2019, Brain Tumor Microenvironment and Host State: Implications for Immunotherapy. Clinical Cancer Research, 25(14): 4202–4210.
Hirata E, Sahai E, 2017, Tumor Microenvironment and Differential Responses to Therapy. Cold Spring Harbor Perspectives in Medicine, 7(7): a026781.
Farkona S, Diamandis EP, Blasutig IM, 2016, Cancer Immunotherapy: The Beginning of the End of Cancer? BMC Medicine, 2016(14): 1–18.
Kumar A, Swain CA, Shevde LA, 2021, Informing the New Developments and Future of Cancer Immunotherapy: Future of Cancer Immunotherapy. Cancer and Metastasis Reviews, 40(2): 549–562.
Himes BT, Geiger PA, Ayasoufi K, et al., 2021, Immunosuppression in Glioblastoma: Current Understanding and Therapeutic Implications. Frontiers in Oncology, 2021(11): 770561.
Liu B, Qu L, Yan S, 2015, Cyclooxygenase-2 Promotes Tumor Growth and Suppresses Tumor Immunity. Cancer Cell International, 2015(15): 1–6.
Islam MK, Stanslas J, 2021, Peptide-Based and Small Molecule PD-1 and PD-L1 Pharmacological Modulators in the Treatment of Cancer. Pharmacology & Therapeutics, 2021(227): 107870.
Ou A, Ott M, Fang D, et al., 2021, The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma. Cancers, 13(3): 437.
Mostofa A, Punganuru SR, Madala HR, et al., 2017, The Process and Regulatory Components of Inflammation in Brain Oncogenesis. Biomolecules, 7(2): 34.
Paolino M, Penninger JM, 2016, The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy. Cancers, 8(10): 97.
Wang Y, Wang C, Qiu J, et al., 2022, Targeting CD96 Overcomes PD-1 Blockade Resistance by Enhancing CD8+ TIL Function in Cervical Cancer. Journal for Immunotherapy of Cancer, 10(3): e003667.
Curran KJ, Pegram HJ, Brentjens RJ, 2012, Chimeric Antigen Receptors for T Cell Immunotherapy: Current Understanding and Future Directions. The Journal of Gene Medicine, 14(6): 405–415.
Abken H, 2021, Building on Synthetic Immunology and T Cell Engineering: A Brief Journey Through the History of Chimeric Antigen Receptors. Human Gene Therapy, 32(19–20): 1011–1028.
Wikstrand CJ, Hale LP, Batra SK, et al., 1995, Monoclonal Antibodies Against EGFRvIII Are Tumor Specific and React with Breast and Lung Carcinomas and Malignant Gliomas. Cancer Research, 55(14): 3140–3148.
Choi BD, Archer GE, Mitchell DA, et al., 2009, EGFRvIII‐Targeted Vaccination Therapy of Malignant Glioma. Brain Pathology, 19(4): 713–723.
Pellegatta S, Cuppini L, Finocchiaro G, 2011, Brain Cancer Immunoediting: Novel Examples Provided by Immunotherapy of Malignant Gliomas. Expert Review of Anticancer Therapy, 11(11): 1759–1774.
Zebertavage L, Bambina S, Shugart J, et al., 2019, A Microbial-Based Cancer Vaccine for Induction of EGFRvIII-Specific CD8+ T Cells and Anti-Tumor Immunity. PLOS One, 14(1): e0209153.
Han Y, Liu C, Li G, et al., 2018, Antitumor Effects and Persistence of a Novel HER2 CAR T Cells Directed to Gastric Cancer in Preclinical Models. American Journal of Cancer Research, 8(1): 106.
Forsberg EM, Lindberg MF, Jespersen H, et al., 2019, HER2 CAR-T Cells Eradicate Uveal Melanoma and T-Cell Therapy–Resistant Human Melanoma in IL2 Transgenic NOD/SCID IL2 Receptor Knockout Mice. Cancer Research, 79(5): 899–904.
Salinas RD, Durgin JS, O’Rourke DM, 2020, Potential of Glioblastoma-Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy. CNS Drugs, 34(2): 127–145.
de Sostoa J, Dutoit V, Migliorini D, 2020, Oncolytic Viruses as a Platform for the Treatment of Malignant Brain Tumors. International Journal of Molecular Sciences, 21(20): 7449.
Rius-Rocabert S, García-Romero N, Garcia A, et al., 2020, Oncolytic Virotherapy in Glioma Tumors. International Journal of Molecular Sciences, 21(20): 7604.
Fudaba H, Wakimoto H, 2023, Oncolytic Virus Therapy for Malignant Gliomas: Entering the New Era. Expert Opinion on Biological Therapy, 23(3): 269–282.
Stepanenko AA, Chekhonin VP, 2018, Recent Advances in Oncolytic Virotherapy and Immunotherapy for Glioblastoma: A Glimmer of Hope in the Search for an Effective Therapy? Cancers, 10(12): 492.
Niedbała M, Malarz K, Sharma G, et al., 2022, Glioblastoma: Pitfalls and Opportunities of Immunotherapeutic Combinations. OncoTargets and Therapy, 2022(15): 437–468.
Zhao Y, Baldin AV, Isayev O, et al., 2021, Cancer Vaccines: Antigen Selection Strategy. Vaccines, 9(2): 85.
Sioud M, 2007, An Overview of the Immune System and Technical Advances in Tumor Antigen Discovery and Validation, in Target Discovery and Validation Reviews and Protocols: Volume 1, Emerging Strategies for Targets and Biomarker Discovery. Humana Press, New Jersey, 277–318.
Liu J, Fu M, Wang M, et al., 2022, Cancer Vaccines as Promising Immuno-Therapeutics: Platforms and Current Progress. Journal of Hematology & Oncology, 15(1): 28.
Gilboa E, 2007, DC-Based Cancer Vaccines. The Journal of Clinical Investigation, 117(5): 1195–1203.
Bettonville M, Aria S, Weatherly K, et al., 2018, Long-Term Antigen Exposure Irreversibly Modifies Metabolic Requirements for T Cell Function. Elife, 2018(7): e30938.
Kim P, 2023, Defining the Role of the Hexosamine Biosynthesis Pathway in Pancreatic Cancer, thesis, University of Michigan.
Adhikaree J, Moreno-Vicente J, Kaur AP, et al., 2020, Resistance Mechanisms and Barriers to Successful Immunotherapy for Treating Glioblastoma. Cells, 9(2): 263.
Galstyan A, Markman JL, Shatolova ES, et al., 2019, Blood-Brain Barrier Permeable Nano Immunoconjugates Induce Local Immune Responses for Glioma Therapy. Nature Communications, 10(1): 3850.
Boccalatte F, Mina R, Aroldi A, et al., 2022, Advances and Hurdles in CAR T Cell Immune Therapy for Solid Tumors. Cancers, 14(20): 5108.
Andrea AE, Chiron A, Mallah S, et al., 2022, Advances in CAR-T Cell Genetic Engineering Strategies to Overcome Hurdles in Solid Tumors Treatment. Frontiers in Immunology, 2022(13): 830292.