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Microbes & Immunity Glioblastoma therapy: Immunotherapy and inhibitors

potential to express GBM tumor-specific antigens and to highly adaptive and neuroprotective property, the highly
mediate an eventual antitumor immune response. 71,72 selective permeability of the tight junctions and endothelial
Two other forms of vaccine that have demonstrated cells forming the external lining of the CNS, preserved by
moderate efficacy in numerous clinical trials are autologous astrocytes and pericytes, prevents the entry of drugs into the
and peptide vaccines. Autologous vaccination involves brain. Furthermore, the ample presence of P-glycoprotein
the use of a patient’s peripheral blood mononuclear cells and multidrug resistance proteins in the BBB anatomical
(PBMC) to stimulate the cells with known glioma tumor structure prevents the build-up of the necessary amount
antigens, and the subsequent infusion of the primed of pharmacokinetically active drug in the CNS, preventing
PBMC cells back into the patient. Peptide vaccines the activation of the drug’s physiological cascade. 79,80
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are short protein sequences with active immunogenic Another major challenge in the drug delivery of GBMs
mutations present in GBM introduced to patients to evoke is the lack of breadth the drugs carry to counteract the
an antitumor immune response against the neoplastic highly diffusive and infiltrative tumor cells that migrate
cells that shelter the known mutation. For instance, far past the point of origin. Existing therapeutic drugs can
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EGFR variant III (EGFRvIII) is a known antigenic only reach a few millimeters of the delivery site of interest
variant widely expressed in GBM and absent in normal surrounding the brain parenchyma. Furthermore, lack of
tissue. Moreover, EGFRvIII mutation also encodes an diffusion during drug delivery can cause substantial local
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active tyrosine kinase known to amplify tumor growth cytotoxicity at the delivery site. 81,82
and migration 75-77 and instigate tumor resistance against
radiation and conventional chemotherapeutic agents. The third challenge arises from the intrinsic nature
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Furthermore, expression levels of EGFRvIII mutation have of GBM tumor cells: highly heterogeneous genome, with
served as an independent negative prognostic criterion of unpredictable patterns of amplification, dysregulation,
overall survival in GBM patients. Hence, multiple lines of and mutational activation of growth factor signaling;
evidence corroborate the EGFRvIII mutation sequence receptor tyrosine kinase genes; tumor suppressor genes;
as a highly promising target for GBM peptide vaccine O6-methylguanine-DNA methyltransferase methylation;
immunotherapy. 74,78 Summary of emerging vaccination and various other molecular pathways of interconnected
therapy for glioblastoma is summarized in Table 2. and interdependent influence that require patient-
specific stratification to advance our understanding of
6. GBM drug delivery and medicinal pharmacokinetics in GBMs. 83-85 Drug delivery is further
chemistry: challenges and advances challenged by GBM’s highly indistinct tumor margins,
highly angiogenic properties that enhance vascular
6.1. Challenges proliferation and hyperplasia, and rapidly adaptive and
Despite decades of substantial progress in pharmacokinetics, evasive interaction of the tumor with its surrounding
medicinal chemistry, and nanomedicine, drug delivery in microenvironment, such as overexpression of VEGF,
GBM remains a fundamental challenge for several reasons. acting as a hypoxia-induced promoter of tumor cell
A principal challenge is that of the BBB. Despite being a invasion and migration into healthy parenchyma. 86-88

Table 2. Summary of emerging vaccination therapy for glioblastoma
Vaccine modality Mechanism of action
Dendritic cell-based vaccines Employing patient-derived dendritic cells pulsed with glioblastoma-specific antigens to prime CD8+ T-cell
responses. This approach capitalizes on the innate ability of dendritic cells to present tumor antigens and
stimulate a robust cytotoxic T-lymphocyte response against heterogeneous tumor cells. An example is the
ICT-107 vaccine that targets antigens such as WT1, MAGE-1, and HER2.
Heat shock protein (HSP)-based vaccines Leveraging HSP70 and HSP90 as molecular chaperones that bind and display tumor-specific antigens. These
chaperones activate antigen-presenting cells, inducing a cytotoxic immune response. HSP vaccines exploit
the reliance of tumor cells on HSPs for survival and metastasis in hypoxic microenvironments.
Autologous tumor-derived vaccines Deriving patient-specific tumor lysates to pulse antigen-presenting cells or peripheral blood mononuclear
cells, thereby creating a personalized vaccine that reflects the specific antigenic landscape of the patient’s
tumor. This approach directly addresses the challenge of intratumoral heterogeneity. An example is the
HSPPC-96 derived from patient tumor lysates, demonstrating promise in clinical trials.
Peptide vaccines Targeting neoantigens or mutated epitopes, such as EGFRvIII, to induce a focused immune response.
These vaccines are designed to overcome tumor immune evasion mechanisms by presenting peptides
highly specific to glioblastoma cells, thereby sparing normal tissues. An example is rindopepimut, an
EGFRvIII-specific peptide vaccine.

Volume 2 Issue 4 (2025) 136 doi: 10.36922/mi.5075