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Microbes & Immunity Glioblastoma therapy: Immunotherapy and inhibitors

tumor volume by total gross resection holds extremely low 5. Immunotherapy
efficacy as a treatment option. Furthermore, in many cases,
surgical intervention into the neocortex, basal ganglia, and 5.1. Mechanisms of immunosuppression in
the brainstem is either unfeasible or comes at a significant glioblastoma
cost to quality of life. 26,27 Over the past decade, our understanding of

Following safe surgical resection of the tumor, patients immunosurveillance within the CNS has substantially
begin a radiotherapeutic intervention concomitant shifted. The notion that the brain and spinal cord are
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with temozolomide (TMZ) (Temodar ), an alkylating immune-privileged has been radically discredited by the
chemotherapeutic agent. Post-radiotherapy, patients are substantial literature demonstrating a robust immune
28
given adjuvant TMZ alone as a course of chemotherapy. response generated by B- and T-cell adaptive immunogens
Other chemotherapeutic agents that have shown moderate during inflammation-derived conditions such as
efficacy are anti-angiogenic agents such as bevacizumab common intracerebral infections, multiple sclerosis, and
(an anti-vascular endothelial growth factor [VEGF] encephalitis. 33,34 This emerging shift in paradigm to view
monoclonal antibody) and gefitinib and erlotinib (anti- the brain as immunologically robust, with distinct and
epidermal growth factor receptor [EGFR] tyrosine kinase active lymphatic channels capable of priming B- and
inhibitors [TKIs]). 29,30 T-lymphocytes, presents a promising venture in developing
novel immunotherapeutics for the treatment of GBM.
35
Alternating electric field therapy, also referred to as Unlike chemotherapy, immunotherapy carries non-
TTF, is an emergent FDA-approved therapy, serving as a existent cellular and genetic toxicity, low side effects, and a
concurrent treatment option for newly diagnosed GBM or highly selective, patient-stratified therapeutic strategy that
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recurrent GBM alongside TMZ. The TTF device, Optune , counteracts the highly heterogeneous genome of GBM
works by a battery-powered device that delivers alternating cells.
electrical fields of low intensity to disrupt cell division and
cause eventual apoptosis. TTF is a relatively safe mode of Local and systemic immunosuppression is a consistent
treatment as the induction frequency can be selectively characteristic of GBM, recapitulated by immunosuppressive
adjusted to target GBM tumor cells, characterized by rapid factors present in cervical lymph nodes, blood, bone marrow,
cell divisions. 31,32 The major challenges in the treatment of and spleen. Common mechanisms of immunosuppression
glioblastoma are summarized in Table 1. by the tumor cell include elimination of self-presenting

Table 1. Major challenges in the treatment of glioblastoma

Challenge Mode of resistance
BBB The BBB’s highly selective endothelial tight junctions and P-glycoprotein efflux transporters prevent
therapeutic agents from achieving effective concentrations in the central nervous system. This restricts
the bioavailability of even highly potent drugs. Strategies such as nanoparticle-mediated delivery and
focused ultrasound are being investigated to transiently disrupt the BBB for drug delivery.
Tumor infiltration and recurrence Glioblastoma cells invade healthy brain parenchyma using white matter tracts, blood vessels, and the
leptomeningeal space. This results in indistinct tumor margins and inevitable recurrence even after
gross total resection. Novel intraoperative imaging techniques and localized drug delivery systems aim
to address this challenge.
Genetic and molecular heterogeneity GBM tumors exhibit patient-specific genomic landscapes, including mutations in EGFR, PTEN,
and TP53, as well as IDH status. This heterogeneity renders one-size-fits-all therapies ineffective,
necessitating personalized and stratified treatment approaches.
Immunosuppressive tumor microenvironment The GBM microenvironment is characterized by hypoxia, upregulated VEGF, and infiltrating
immunosuppressive cells such as TAMs, Tregs, and MDSCs. These factors collectively inhibit effector
T-cell activity and promote tumor proliferation. Strategies targeting PD-L1, IDO, and TGF-β are being
developed to modulate the tumor microenvironment.
Therapeutic resistance Resistance mechanisms include MGMT-mediated repair of alkylating damage by TMZ, overexpression
of efflux pumps, and activation of compensatory signaling pathways such as PI3K/AKT and MAPK.
Combination therapies targeting these pathways are under investigation to overcome resistance.
Abbreviations: BBB: Blood-brain barrier; EGFR: Epidermal growth factor receptor; GBM: Glioblastoma multiforme; IDH: Isocitrate
dehydrogenase; IDO: Indoleamine 2,3-dioxygenase; MAPK: mitogen-activated protein kinase; MDSCs: Myeloid-derived suppressor cells;
MGMT: O6-Methylguanine-DNA methyltransferase; PD-L1: Programmed cell death ligand 1; PI3K/AKT: phosphatidylinositol 3-kinase/protein kinase B;
PTEN: Phosphatase and tensin homolog; TAMs: Tumor-associated macrophages; TGF-β: Transforming growth factor beta; TMZ: Temozolomide;
Tregs: Regulatory T-cells; VEGF: Vascular endothelial growth factor.

Volume 2 Issue 4 (2025) 134 doi: 10.36922/mi.5075