Glioblastoma (GBM) is the most common and aggressive form of primary malignant brain tumor, classified as a Grade IV tumor. Arising from astrocytes, GBM cells multiply rapidly and infiltrate surrounding healthy brain tissue, making total removal nearly impossible. This invasive nature and the tumor’s genetic heterogeneity lead to a devastating prognosis. Despite treatment, the median survival remains approximately 12 to 18 months, with fewer than 10% of patients surviving five years. The universal recurrence of this disease establishes an urgent need for new, more effective therapies.
The Current Treatment Landscape
The standard of care for newly diagnosed glioblastoma patients is the multi-step Stupp Protocol. This regimen begins with maximal safe surgical resection to remove the visible tumor mass. Following surgery, patients undergo concurrent chemoradiation, involving daily radiation therapy delivered alongside the oral chemotherapy drug Temozolomide (TMZ). This initial phase is then followed by six cycles of adjuvant TMZ alone.
While this protocol offers a modest survival benefit, extending median survival by only a few months, it often fails. The primary reason is the highly infiltrative nature of GBM cells, which spread microscopically beyond the surgical margin. Additionally, the blood-brain barrier (BBB) severely limits the amount of chemotherapy drug that can reach the tumor site, ensuring microscopic disease remains and leading to recurrence in almost every patient.
Harnessing the Immune System
Immunotherapy leverages the body’s defense mechanisms against the tumor. One approach uses immune checkpoint inhibitors, which “release the brakes” on T-cells. These drugs target proteins like PD-1 or CTLA-4 that cancer cells exploit to evade immune detection, allowing T-cells to attack the tumor.
Checkpoint inhibitors have shown limited success in GBM compared to other cancers, largely due to the brain tumor’s unique immunosuppressive microenvironment. The GBM microenvironment actively fosters immune-suppressing cells, creating an “immunologically cold” tumor where T-cells struggle to mount an effective attack. Researchers are exploring strategies such as local delivery directly into the tumor bed or combining inhibitors with other treatments to overcome this suppression.
A personalized immunotherapy strategy involves Chimeric Antigen Receptor (CAR) T-cell therapy. This process modifies a patient’s T-cells in a laboratory to express a synthetic receptor that specifically recognizes a protein on the surface of glioblastoma cells. These engineered T-cells are then infused back into the patient, where they destroy cells expressing the target protein.
A common target for CAR T-cell trials is the Epidermal Growth Factor Receptor variant III (EGFRvIII). While initial trials show CAR T-cells can safely reach the brain and kill tumor cells, a challenge is antigen loss, where the tumor stops expressing the target protein. Ongoing research focuses on developing multi-targeted CAR T-cells to simultaneously attack several tumor antigens, aiming to improve persistence and mitigate tumor escape.
Precision Medicine and Targeted Therapies
Precision medicine tailors therapy to the specific genetic and molecular profile of an individual patient’s tumor. Genomic sequencing has revealed distinct molecular subtypes of glioblastoma, leading to the development of targeted drugs that interfere with specific pathways driving cancer growth.
The Isocitrate Dehydrogenase (IDH) mutation is a significant molecular marker occurring in a subset of gliomas. Gliomas with this mutation are often classified separately due to their more favorable prognosis and different biological mechanism. New small-molecule inhibitors, such as vorasidenib, are designed to block the function of the mutant IDH enzyme, which produces an abnormal metabolite that drives tumor progression.
Other targets include growth factor receptors like the Epidermal Growth Factor Receptor (EGFR), which is frequently amplified or mutated in GBM. Targeted drugs designed to block the signaling cascade initiated by these overactive receptors are being tested to halt cell proliferation. The success of any targeted drug relies heavily on its ability to bypass the Blood-Brain Barrier (BBB).
Novel drug delivery innovations are integral to targeted therapy development. Techniques like convection-enhanced delivery (CED) involve infusing the drug directly into the tumor interstitium through small catheters, bypassing the BBB entirely. Other methods utilize focused ultrasound to temporarily disrupt the BBB, allowing systemically administered drugs, often encapsulated in nanocarriers, to reach the brain tumor at therapeutic concentrations.
Viral Treatments to Destroy Cancer Cells
Oncolytic Virus Therapy (OVT) employs genetically modified viruses to selectively infect and destroy cancer cells. These viruses, such as modified herpes simplex virus or adenovirus, are engineered to replicate only within tumor cells with compromised antiviral defense mechanisms. Once inside, the virus multiplies until the cell bursts (oncolysis), releasing new viral particles to infect neighboring cancer cells.
This approach offers a powerful dual mechanism of action beyond direct destruction. Viral replication and cell lysis release tumor-associated antigens and danger signals, alerting the immune system to the cancer’s presence. This process transforms an “immunologically cold” tumor into a “hot” one, priming the immune system to launch a sustained anti-tumor response.
Oncolytic viruses are typically administered directly into the tumor cavity following surgical removal to maximize local concentration. Clinical trials are investigating various armed viruses engineered to carry therapeutic genes, such as immune-stimulating cytokines, to amplify the local immune response. This combination of direct tumor killing and immune activation establishes OVT as a promising frontier for glioblastoma treatment.