Recent Advances in the Treatment of Glioblastoma Multiforme
Recent advances in the treatment of stage 4 glioblastoma, or Glioblastoma Multiforme (GBM), have shown promise in improving outcomes for this aggressive and often treatment-resistant cancer. Here are some of the most notable developments:
1. Ultrasound Technology: This interesting technology had its beginnings in 1954 with the application of focused ultrasound (FUS) to create focal lesions in feline brains leaving the surrounding tissue essentially unharmed. This pioneering work was developed by the Fry brothers who went on to demonstrate the reversibility of neuroanatomical changes induced by low-power FUS. Additionally, they have established the threshold ultrasound doses necessary for different levels of neuromodulation in mammalian brains.
There were several other milestones along the way until 2021 when researchers at the University of Maryland demonstrated in the Phase 0 clinical trial (NCT03322813), the ability of microbubble-enhanced focused ultrasound (MB-FUS) to achieve safe, localized, and controlled blood-brain barrier (BBB) opening. It underscores the potential of this technology to enhance surgical and pharmacological treatments for brain tumors.
In a landmark discovery, researchers at Northwestern Medicine have pioneered the use of ultrasound technology to disrupt the blood-brain barrier (BBB), allowing for the delivery of a chemotherapy and immunotherapy drug cocktail directly to the brain tumor. This innovative approach has been shown to enhance the immune system’s ability to recognize and attack cancer cells, potentially paving the way for new treatment strategies for GBM. The ultrasound method involves focused ultrasound waves that temporarily open the BBB, which is typically a significant obstacle in delivering effective treatments to brain tumors.
3D rendering of the focused ultrasound beam targeting the blood-brain barrier,
illustrating the precision and interaction of the beam with the barrier in a medical context.
2. According to www.clinicaltrial.gov, there are currently six (6) clinical trials which are or will be conducted using focused ultrasound as a therapeutic modality as well as a diagnostic aid to determine the presence of biomarkers and sonodynamic therapy (SDT) which introduces a nontoxic drug intravenously before tumor resection. A device is then attached to the patient’s skull to deliver low-dose focused ultrasound that activates the drug and targets only the tumor cells.
3. Nanoparticle-based Treatment: Traditional treatments, such as surgery, radiation, and chemotherapy, often fall short due to the tumor’s resilience and the difficulty of delivering therapeutic agents across the blood-brain barrier (BBB). Nanotechnology offers a promising solution to these challenges through the development of highly targeted and effective treatments.
A collaborative effort between researchers from Yale and the University of Connecticut has led to the development of a nanoparticle-based treatment specifically designed for GBM. These bioadhesive nanoparticles adhere to the tumor site and gradually release synthesized peptide nucleic acids, which target and disrupt the cancer cells. This targeted delivery system aims to improve the precision and efficacy of treatment while minimizing damage to surrounding healthy tissue.
In addition, other recent advances in nanotechnology have led to the development of multifunctional nanoparticles that combine therapeutic and diagnostic functions, also known as theranostic (personalized) nanoparticles. These particles can:
· Deliver Multiple Drugs: Nanoparticles can be loaded with a combination of drugs, such as chemotherapeutics, immune checkpoint inhibitors, and radiosensitizers, to target several aspects of tumor growth and survival.
· Imaging and Monitoring: Nanoparticles can be tagged with imaging agents, such as fluorescent dyes or magnetic nanoparticles, allowing for real-time monitoring of drug delivery and tumor response using techniques like magnetic resonance imaging (MRI) or fluorescence imaging.
Several clinical trials are underway to explore the efficacy and safety of nanoparticle-based treatments for GBM. These studies are investigating diverse types of nanoparticles, drug combinations, and delivery methods:
· Liposomal Nanoparticles: Liposomes are spherical vesicles that can encapsulate drugs, protecting them from degradation and enhancing their delivery to the tumor site. Clinical trials are testing liposomal formulations of chemotherapeutic agents like doxorubicin and temozolomide.
- Polymeric Nanoparticles: These nanoparticles can be designed to release drugs when exposed to specific triggers, such as changes in pH within the tumor microenvironment. Trials are exploring their use in delivering targeted therapies to GBM.
4.
Immunotherapy: Immunotherapy has emerged as a powerful tool in the fight against GBM. Various strategies, including immune checkpoint blockade, chimeric antigen receptor (CAR) T-cell therapy, oncolytic virotherapy, and vaccine therapy, have shown potential in enhancing the immune system’s response to GBM. These therapies work by either directly attacking the tumor cells or by modulating the immune system to recognize and destroy cancer cells more effectively. Ongoing research is focused on combining these therapies to maximize their efficacy and reduce side effects, offering new hope for patients with GBM.
3D image of stage 4 glioblastoma, highlighting the highly malignant
brain tumor with irregular, invasive edges, areas of necrosis,
and significant vascularity.
In addition, dual-target CAR T cell therapy was recently introduced, and this immunotherapy involves targeting two proteins associated with brain tumors, rather than one. In a Phase I clinical trial, early results showed promise in reducing solid tumor growth in patients with recurrent GBM.
A unique form of CAR-T cells called CAR-TEAM for glioblastoma is designed to be injected directly into the brain. The cells are engineered to deliver TEAMs against wild-type EGFR, which is expressed in more than 80% of GBM cases.
5. Virotherapy and Cancer Vaccines: Combining immunotherapy with virotherapy, which uses oncolytic viruses (OVs) and cancer vaccines (CVs), represents a promising innovative approach in GBM treatment. Oncolytic viruses selectively infect and kill cancer cells, while cancer vaccines aim to boost the immune system’s ability to target the tumor. Recent advancements in these areas, including the development of tomotherapy, NanoTherm therapy, and other immunotherapeutic approaches, are showing significant progress in clinical trials. These combinatorial therapies are designed to enhance the overall antitumor immune response and improve patient outcomes.
As intimated above, accessing experimental treatments for Glioblastoma Multiforme (GBM) often involves participation in clinical trials. The following includes some of interesting options for treatment:
- Clinical Trials: Patients can participate in clinical trials that evaluate new treatments. These trials are usually conducted at major medical centers and require the patient to meet certain eligibility criteria.
Based on a recent review of clinical trials at www.clinicaltrials.gov, there are 114 clinical trials that are currently recruiting patients and 26 trials that have not yet begun recruiting patients. These trials cover new drugs, both small molecule and biologics, alone and in combination with known existing anti-tumor, novel resection techniques, novel radiation techniques, new biomarkers, and so on. Please note that experimental treatments can carry risks, and it is important for patients to discuss these risks and benefits with their healthcare provider before deciding to participate in a trial or access an experimental treatment.
- Expanded Access Programs: Sometimes called compassionate use, these programs allow seriously ill patients to gain access to experimental medicines. For example, the experimental vaccine SurVaxM was available through an expanded access program.
- Consult Healthcare Providers: Patients should consult with their healthcare providers about the possibility of accessing experimental treatments. Doctors and medical teams have the most up-to-date information and can guide patients on the best course of action.
- Research Institutions: Some research institutions, like the Mayo Clinic, are testing new treatments, interventions, and tests as a means to prevent, detect, treat, or manage GBM.
The recent advancements in treating stage 4 glioblastoma (GBM) offer significant hope in the battle against this formidable cancer. Ultrasound technology, with its capability to safely open the blood-brain barrier, has paved the way for more effective drug delivery directly to the brain tumor, enhancing the immune response against cancer cells. Nanoparticle-based treatments bring a new level of precision and effectiveness, allowing targeted delivery of multiple drugs and real-time monitoring, minimizing harm to healthy tissue. Immunotherapy strategies, including CAR T-cell therapy and oncolytic virotherapy, show promise in harnessing and enhancing the body’s immune system to combat GBM more effectively.
The combination of these innovative approaches underscores the potential for improved patient outcomes, offering new avenues for treatment that were previously inaccessible. Access to these experimental treatments through clinical trials, expanded access programs, and consultation with healthcare providers ensures that patients can benefit from the latest developments. As research institutions continue to innovate, the future holds promise for even more effective and personalized treatments for GBM, providing renewed hope for patients and their families.
Written By: Lawrence D. Jones, Ph.D.
Keywords: Focused ultrasound, nanoparticles, immunotherapy, GBM, CAR T-cell
