Advancing the Fight Against Glioblastoma with Emerging Therapies and Clinical Trials

Glioblastoma is one of the deadliest and most challenging cancers to treat, and it is the leading cause of brain cancer-related death in adults. Despite ongoing research, the standard treatments for glioblastoma, including surgery, radiation, and chemotherapy, have only slightly improved outcomes. Median survival remains just over one year, and few patients survive beyond five years.^1,2 However, emerging treatment options are beginning to offer new hope. Advances such as precision-targeted therapies, immunotherapies, and novel drug delivery techniques that cross the blood–brain barrier are gradually reshaping the treatment landscape.

At Private Health Management (PHM), our clinicians and researchers stay at the forefront of the latest scientific research and have helped clients diagnosed with glioblastoma to access cutting-edge treatments. According to our latest cancer whitepaper, PHM clients with advanced glioblastoma survived 5 months longer on average than patients in the National Cancer Institute registries.³ To better understand why treating glioblastoma is so complex, it’s important to first understand what this aggressive cancer is and how it behaves in the brain.

What is Glioblastoma?
Glioblastoma is the most common and deadliest type of brain cancer in adults. It arises from cells that support and protect nerves in the brain, and tends to grow quickly, spreading into nearby brain tissue.⁴ Most cases are diagnosed in adults between the ages of 55 and 75, and the disease is more common in men and in Caucasians.⁵ Symptoms vary depending on where the tumor forms in the brain, but often include headaches, memory or personality changes, speech difficulties, and seizures. Diagnosis is usually confirmed with brain imaging followed by a biopsy or surgery to remove part of the tumor.^4,6

Treatment challenges
Treatment typically begins with surgery to remove as much of the tumor as safely possible, followed by radiation and chemotherapy. Even with this comprehensive approach, glioblastoma almost always returns, resulting in poor survival.^1,2

Several factors make glioblastoma especially difficult to treat:

• It’s not one-size-fits-all. Glioblastoma tumors often evolve to form a diverse mixture of cells, even within the same tumor; some of these cells pose the biggest challenge.^4,7
• Some tumor cells are especially resistant. The most resistant cells, called “glioma stem cells” can survive treatment and fuel the tumor’s return. These cells are hard to eliminate with standard chemotherapy or radiation.^4,8
• The brain’s protective barrier limits treatment. The blood-brain barrier, which normally helps protect the brain from harmful substances, also blocks many cancer drugs from reaching the tumor.^1,4

Innovative treatments are emerging
Promising new developments are beginning to transform the therapeutic landscape of glioblastoma, offering cautious optimism to patients and their families. While many of these approaches are still in early stages, they represent important progress against a disease that has long resisted treatment.  

TARGETED THERAPIES
Researchers are increasingly using advanced genetic testing to personalize glioblastoma treatment. These tests analyze the unique genetic makeup of each patient’s tumor to identify specific mutations. This enables doctors to pair tumors with newer, highly targeted therapies that precisely exploit the tumor’s specific weaknesses. This personalized approach offers exciting new opportunities for treatments that were once unimaginable, providing a tailored strategy for each patient, such as:

• Combination treatment with dabrafenib and trametinib, which has shown impressive efficacy in glioblastomas harboring BRAF V600E mutations.
• Novel agents such as larotrectinib and entrectinib that target neurotrophic tyrosine receptor kinase (NTRK) gene fusions are in development.
• Vorasidenib, a promising new treatment recently approved for gliomas with isocitrate dehydrogenase (IDH) mutations.
• Therapies directed at the epidermal growth factor receptor (EGFR), including the antibody–drug conjugate AMG 596 and the brain-penetrant inhibitor ERAS-801, are entering clinical trials and opening new therapeutic avenues.

Unfortunately, these tumor-specific molecular changes are relatively rare, underscoring the critical need for treatment strategies that address a broader spectrum of patients. The future of glioblastoma therapy likely lies in combining precision medicine with scalable approaches that incorporate immunotherapy, novel delivery systems, and biomarker-driven patient stratification to optimize outcomes across diverse tumor profiles.

IMMUNOTHERAPIES
Immunotherapy is also advancing rapidly, offering new treatment avenues, such as therapeutic cancer vaccines and other strategies that help the patient’s own immune system to identify and attack cancer cells.

Therapeutic cancer vaccines
What started as simple vaccines targeting a single part of a tumor has now grown into much more advanced and personalized treatments, including:

• A vaccine made from a patient’s own tumor and immune cells (DCVax-L), is an early-stage innovation that has opened the door to more personalized brain tumor vaccines.
• New vaccines that now target shared tumor features, such as the Survivin protein, used in SurVaxM, to stimulate a broader immune response.
• Highly personalized vaccines that use genetic analysis to train the immune system to recognize patient-specific tumor mutations—an approach led by companies like CeGaT with encouraging early survival results.

CAR T-cell Therapies
Chimeric antigen receptor (CAR) T-cell therapies, a form of treatment that uses a patient’s own immune cells to fight cancer, are another promising frontier.

• CAR-T therapies reprogram a patient’s immune cells to recognize glioblastoma-specific markers like IL13Rα2 and EGFR/EGFRvIII, with early trials showing tumor shrinkage in some cases.
• Responses to the current CAR-T therapies are often short-lived, as tumors frequently return, underscoring the need for next-generation CAR-T approaches that can overcome the tumor’s immune resistance and provide longer-lasting effects.

Immune Checkpoint Inhibitors
Novel approaches involving immune checkpoint inhibitors (ICI), a type of immunotherapy that works by blocking specific proteins on immune cells, are also being explored.

• Administering immunotherapy before surgery has shown benefits by boosting the body’s anti-tumor immune response and improving the effectiveness of later treatments.
• These approaches represent a growing focus in cancer care on harnessing the immune system through both broad and highly personalized strategies.

ONCOLYTIC VIRUS THERAPY
Another emerging area of research is oncolytic virus therapy, which uses viruses to selectively infect and destroy cancer cells while sparing healthy cells. These treatments, which are still early in development, represent a growing trend of using genetically modified viruses to both kill tumor cells and boost the immune system. Though clinical results are promising, most oncolytic virus therapies are still in early-stage trials or limited regulatory pathways. Promising viral-based therapies include:

• A modified poliovirus that targets tumor cells and stimulates immune responses (PVSRIPO), earning FDA “breakthrough therapy” status.
• An oncolytic adenovirus (DNX-2401) that works especially well when combined with immune checkpoint inhibitors.
• A herpesvirus-derived therapy, G47Δ (Delytact), has shown strong clinical results and received regulatory approval in Japan, highlighting the growing impact of oncolytic viruses in glioblastoma treatment.
• An investigational herpesvirus-based therapy from the University of Alabama at Birmingham is gaining attention for showing early promise in clinical studies.

INNOVATIVE DEVICES AND DELIVERY TECHNOLOGIES
Innovative medical devices and delivery technologies are also contributing to the glioblastoma treatment landscape.

• Tumor Treating Fields (TTFields) use low-intensity electric fields to disrupt cancer cell division and have been FDA-approved for extending survival in glioblastoma patients.
• Innovative technologies such as focused ultrasound (e.g., SonoCloud-9) temporarily open the blood–brain barrier to enhance chemotherapy delivery, while Alpha DaRT and LITT offer targeted radiation and minimally invasive tumor ablation, often paired with immunotherapy.
• Emerging tools such as GammaTiles and proton beam therapy provide precise radiation delivery with better tumor control and less damage to healthy tissue.

These advancements represent important scientific progress and hold potential to improve outcomes in the future, even as most remain in early stages of development. While significant challenges persist, these emerging therapies offer real hope, improving patient care today while driving critical progress through ongoing clinical trials and translational research. Each innovation not only extends the therapeutic frontier but also deepens our understanding of this formidable disease.

References

1. McBenedict, B. et al. Approaches in Adult Glioblastoma Treatment: A Systematic Review of Emerging Therapies. Cureus (2024) doi:10.7759/cureus.67856.
2. Rong, L., Li, N. & Zhang, Z. Emerging therapies for glioblastoma: current state and future directions. J Exp Clin Cancer Res 41, 142 (2022).
3. Improving Cancer Survival: PHM’s Impact on Cancer Care. Private Health Management https://solutions.privatehealth.com/phm-impact-on-cancer-survival.
4. Obrador, E. et al. Glioblastoma Therapy: Past, Present and Future. IJMS 25, 2529 (2024).
5. Khiabani, N. A. et al. Glioblastoma therapy: State of the field and future prospects. Life Sciences 359, 123227 (2024).
6. Adult Central Nervous System Tumors Treatment – NCI. https://www.cancer.gov/types/brain/patient/adult-brain-treatment-pdq (2024).
7. Verhaak, R. G. W. et al. Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).
8. Khiabani, N. A. et al. Glioblastoma therapy: State of the field and future prospects. Life Sciences 359, 123227 (2024).