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Microbes & Immunity Glioblastoma therapy: Immunotherapy and inhibitors

of all CNS neoplasms. As the most malignant primary and clinical classifications of high-grade astrocytomas.
1,2
12
brain tumor, GBM has an incidence rate of 3.2/100,000 Patients with IDH1 mutation-linked gliomas tend to have
people in the United States, with a median age of 64. substantially better clinical outcomes, longer survival, and
3
The disease affects males 1.6-fold more frequently than more favorable response to treatment than those harboring
females and Caucasians two-fold more frequently than wild-type IDH1. 13
African-Americans. Glioblastoma remains one of the
4
most deadly diagnoses of all cancer types that affect the 3. Pathogenesis
5
human body, with an abysmal median survival rate of Most GBMs present supratentorially, affect the white matter
15 months after therapeutic interventions and a 3-month of cerebral hemispheres, infiltrate the corpus callosum,
6
survival rate in untreated patients. Despite substantial and result in bilateral hemispheric involvement of the
7
advances in angiogenesis, chemotherapy, radiotherapy, tumor. The aggressive nature of GBMs is characterized
14
immunotherapy, and gene therapy, GBM remains one by its rapid and diffuse infiltration of brain parenchyma,
of oncology’s most challenging and treatment-resistant high metabolic demands, and substantial angiogenesis,
diagnoses. The current paper aims to review the basic coupled with uncontrolled proliferation and deregulation
8
pathophysiology and tumorigenicity of GBM, the of a highly heterogeneous tumor genome. 15-18 As a
current challenges and advances in treatment and drug high-grade astrocytic tumor, GBM exhibits microscopic
discovery, and the potential role of immunotherapy and features resembling those of the highly undifferentiated
small-molecule inhibitors (SMIs) as effective therapeutic neoplastic astrocytes, comprises glial fibrillary acidic
strategies. protein, and presents vascular proliferations and extensive
2. Histological grading: primary versus interaction with the endothelium of the blood-brain
GBM cells infiltrate and invade healthy
barrier (BBB).
19,20
secondary GBM tissues using pre-existing routes such as the parenchymal
Historically, glioblastoma was classified by the World tract, perivascular space, white-matter tracts, and the
Health Organization (WHO) based on macroscopic leptomeningeal space. 21,22 What makes GBM particularly
and microscopic histopathology, using a grading scale pernicious is the tumor cell’s tendency to extort existing
of I (most benign) to IV (most malignant) astrocytoma. cell types such as reactive astrocytes, glial and neural
GBM classification by the WHO now takes into account progenitors, stem cells, mitogens, and ligands in the brain
genetic mutations, molecular and cellular morphology, microenvironment to induce further tumor proliferation
23
and historically well-known histological alterations and invasion of the parenchyma. For instance, tumor cells
characteristic of astrocytomas. GBMs are bifurcated require more oxygen during rapid proliferation and growth
8,9
into primary and secondary GBMs. Primary GBMs stages. A hypoxic microenvironment prevents rapid growth
feature the presence of de novo, wild-type isocitrate of the tumor and induces necrosis of surrounding tissue.
dehydrogenase (IDH) enzyme, accounting for 90% of all To evade the adverse hypoxic microenvironment, tumor
GBM cases, and tend to afflict older patient populations cells spread to healthy parenchyma, produce angiogenic
(mean age = 55 years). Furthermore, primary GBMs are factors that induce vascular proliferation, and eventually
characterized by extensive tissue necrosis, worse clinical reclaim the high-oxygen microenvironment. Hence, the
outcomes, and substantially lower survival rates. Secondary hypoxic environment induces tumor cell invasion. 24
GBMs encompass lower-grade astrocytomas such as
grade II diffuse astrocytoma and grade III anaplastic 4. Treatment
astrocytoma, according to the WHO classification. Despite substantial advances in tumor resection surgeries,
Secondary GBMs feature the presence of mutant-type IDH chemotherapy, radiotherapy, immunotherapy, and tumor-
enzyme, accounting for 10% of all GBMs and predominantly treating fields (TTFs), glioblastoma remains an incurable
afflicting younger populations (mean age = 40 years). condition and poses a tremendous challenge to clinical
25
Furthermore, secondary GBMs are characterized by limited oncology. Neurosurgical tumor resection remains the first
tissue necrosis, better clinical outcomes, and higher survival line of intervention for GBMs. The efficacy of total gross
rates. 9-11 Out of the many genetic signatures characteristic resection of the tumor through surgery largely depends on
of GBMs, IDH1 mutation has shown substantial promise the size of invading tumor cell lines and the location of the
as a highly predictive biomarker for distinguishing lobes involved. Furthermore, the highly infiltrative nature
secondary GBMs from primary GBMs. Furthermore, of GBMs into the surrounding parenchyma presages the
11
patient IDH1 status presents a far more accurate overall recurrence of the tumor within 2 – 4 cm of the initial
survival prognosis than traditional histological grading resection site. Hence, even an ideal removal of 99% of

Volume 2 Issue 4 (2025) 133 doi: 10.36922/mi.5075