Despite significant advances in cancer immunotherapy across multiple tumor types, the treatment of aggressive gliomas, particularly glioblastoma, remains one of oncology's most formidable challenges. While standard therapies like radiation and temozolomide provide modest benefits, prognosis remains poor for most patients, driving the urgent search for novel therapeutic approaches.
Dr. Nicholas Blondin, assistant professor of Clinical Neurology at Yale School of Medicine, recently shared critical insights into the evolving landscape of glioma treatment, highlighting both challenges and emerging opportunities in neuro-oncology.
Immunotherapy's Challenging History in Brain Tumors
Immunotherapy approaches that have revolutionized treatment in melanoma, lung cancer, and other malignancies have historically shown disappointing results in primary brain tumors. "For glioblastoma, immunotherapy strategies such as PD-1 inhibition have generally been ineffective," Blondin explained.
However, a new frontier is emerging with CAR T-cell therapy, which has already gained FDA approval for various hematologic malignancies. This approach engineers a patient's T cells to specifically target cancer cells, and early studies in brain tumors are showing promise.
"CAR T-cell therapy is being developed at several centers around the US," Blondin noted. "There appear to be promising results in these early studies, particularly for a specific subtype of glioblastoma called EGFRvIII-mutant glioblastoma, which represents approximately 10-15% of cases."
Beyond Standard Therapy: Current Treatment Landscape
The standard of care for aggressive gliomas has remained relatively unchanged for decades, consisting primarily of radiation with temozolomide chemotherapy. While temozolomide offers a relatively benign adverse effect profile compared to other chemotherapies, its efficacy is limited.
One notable advancement has been tumor treating fields (TTFields), a non-invasive therapy that uses electrical fields to disrupt cancer cell division. "The device was recently upgraded in this past year, with redesigned arrays that deliver more powerful electrical fields while potentially improving patient comfort and reducing skin toxicity," Blondin said.
He emphasized the importance of considering TTFields for eligible glioblastoma patients, noting, "I encourage all of my glioblastoma patients who could be eligible for TTFields to strongly consider adding it to their treatment."
Advanced Neuroimaging: Addressing the Pseudoprogression Challenge
One of the most persistent challenges in neuro-oncology is differentiating true tumor progression from pseudoprogression—treatment-related changes that mimic tumor growth on conventional imaging.
"Unfortunately, there remains no completely sensitive and specific way to differentiate true progression from pseudo-progression," Blondin acknowledged. "There are strategies like cerebral blood volume mapping and other MRI software techniques to help give some hint, but they remain not completely adequate for full clinical use."
Yale is developing a promising new approach called metabolic imaging, which uses deuterium-labeled glucose to track cancer cell metabolism via MRI. "Glioblastoma cells have an altered metabolism and use sugar in an altered way from normal tissue," Blondin explained. "Because we're using this different isotope of hydrogen that allows the MRI technique to identify lactate molecules that develop in the brain, we can infer that cancer cells are present."
This technique could potentially provide a low-cost solution for determining tumor metabolism and presence, with more developments expected in the coming years.
The GBM AGILE Trial: Accelerating Treatment Development
A significant initiative in the field is the phase 2/3 GBM AGILE clinical trial (NCT03970447), a platform study investigating multiple experimental therapies against standard treatment for glioblastoma.
"It's a large platform study investigating multiple new experimental therapies against glioblastoma compared with standard treatment, which is radiation and temozolomide," Blondin explained. "Patients enrolling in GBM AGILE could potentially be assigned into experimental treatment groups in addition to their standard treatment."
The trial includes a biobanking component, where patients donate resected brain tumors and blood samples over time. This approach mirrors successful strategies used in lung cancer research a decade ago, which led to the development of targeted therapies like EGFR inhibitors.
"We're trying to just recapitulate what was done in lung cancer treatment for brain cancer treatment," Blondin said. "I am hopeful that the GBM AGILE trial will lead to a new treatment within the next several years."
Holistic Patient Care: Quality of Life Considerations
Given the neurological nature of brain tumors, Blondin emphasized the importance of a multidisciplinary approach to patient care that addresses quality of life alongside treatment efficacy.
"Brain cancer is a unique form of cancer in that it is a neurological disease rather than a medical disease," he noted. "As glioblastoma can worsen or progress, patients will develop increased cognitive impairments, inability to walk, imbalance, and generally neurological declines."
Blondin stressed the value of developing strong doctor-patient relationships and understanding each patient's goals and tolerance for treatment side effects. "It's important to recognize that most patients would not want to live with serious disabilities that aren't going to ever get better," he said. "It's understanding what we can do to optimize someone's quality of life and neurological functioning, and have patients survive as long as possible, but with the best quality of life possible."
Future Directions: Understanding Immunotherapy Resistance
A key question driving current research is why immunotherapies that should theoretically work against glioblastoma have failed in clinical trials.
"Brain cancer expresses PD-L1, the target of PD-1 inhibitor immunotherapy. Based on preclinical models, immunotherapies and vaccine therapies should work against glioblastoma, but in clinical trials, they have proven that they don't," Blondin explained.
Understanding the factors in brain tumors that inhibit immune system function will be critical to advancing treatment. As CAR T-cell therapy development progresses, insights into its mechanisms of success or failure will provide valuable direction for future approaches.
With platform trials like GBM AGILE, advanced imaging techniques, and emerging immunotherapies, the field of neuro-oncology is poised for potential breakthroughs in the coming years, offering new hope for patients with these challenging malignancies.
