Abstract
Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches. Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication. Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma. Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments.
Highlights
Glioblastoma multiforme is the most aggressive intracranial tumor; histologically considered as a malignant glioma arising from an astrocytic lineage (WHO classification: astrocytoma grade IV), and it represents the most common malignant primary brain tumor in adults [1,2]
The other treatment modality that has shown improved overall survival (OS) in glioblastoma patients is the addition of tumor treating field (TTF) to the current standard of care (Stupp protocol), which is a device worn by the patient on the scalp, and works by delivering alternating electrical fields that disrupt the microtubules in the mitotic spindle leading to tumor cell death [8]
To better explain the current challenges in implementing effective immunotherapies for glioblastoma, it is imperative to understand the cross-talk between malignant cells of glioblastoma and immune cells and the immunosuppressive nature of the tumor. Several factors govern this interaction, and can be classified into the following: (1) factors related to blood brain barrier (BBB); (2) factors related to the immunosuppressive microenvironment; (3) factors related to tumor heterogeneity and genetic signature of glioblastoma subtypes; and (4) extrinsic factors related to the modulating effect of previous systemic treatment
Summary
Glioblastoma multiforme is the most aggressive intracranial tumor; histologically considered as a malignant glioma arising from an astrocytic lineage (WHO classification: astrocytoma grade IV), and it represents the most common malignant primary brain tumor in adults [1,2]. The other treatment modality that has shown improved OS in glioblastoma patients is the addition of tumor treating field (TTF) to the current standard of care (Stupp protocol), which is a device worn by the patient on the scalp, and works by delivering alternating electrical fields that disrupt the microtubules in the mitotic spindle leading to tumor cell death [8] This treatment has proved to be challenging for patients given the low compliance rates with its use and high cost [9]. As the majority of glioblastoma recur during or after treatment, it is imperative to develop therapeutic drugs that could offer clinical benefit to these patients to improve survival, and decrease disease associated morbidity and complications This unmet need has led to extensive preclinical research to further characterize the molecular and genetic alterations that control tumor growth, as well as the interaction between the immune system and glioblastoma in order to identify candidate targets for effective drug development. Several factors govern this interaction, and can be classified into the following: (1) factors related to BBB; (2) factors related to the immunosuppressive microenvironment; (3) factors related to tumor heterogeneity and genetic signature of glioblastoma subtypes; and (4) extrinsic factors related to the modulating effect of previous systemic treatment
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