Advancing the Glioma Treatment Paradigm With Immunotherapy and Novel Strategies

Nicholas Blondin, MD, provides an in-depth discussion on the evolving role of immunotherapy in the treatment of primary and metastatic brain tumors.

The treatment of aggressive gliomas, including glioblastoma, remains a significant challenge in oncology. While standard therapies like radiation and temozolomide offer some benefit, the prognosis for these patients remains poor, necessitating the development of novel therapeutic strategies.

Nicholas Blondin, MD, assistant professor of Clinical Neurology at Yale School of Medicine, spoke with CancerNetwork® about critical insights into the current state of glioma treatment and the emerging role of cutting-edge approaches.

Blondin addressed the historical limitations of immunotherapy in treating primary brain tumors, particularly glioblastoma, and highlighted the disappointing results seen with strategies like PD-1 inhibition. However, he focused on the promising potential of CAR T-cell therapy, emphasizing the early stages of development in this field for brain tumors. He underscored the encouraging preliminary data in specific glioblastoma subtypes, such as those with EGFRvIII mutations.

Additionally, Blondin discussed the phase 2/3 GBM AGILE clinical trial (NCT03970447), a platform study designed to accelerate the evaluation of multiple novel agents in glioblastoma. This trial design is necessary to develop new treatment strategies, and the accompanying biobanking efforts draw parallels to the successful paradigm shift observed in lung cancer treatment.

CancerNetwork: How is the role of immunotherapy evolving in the treatment of primary and metastatic brain tumors?

Blondin: Primary brain tumors, in particular glioblastoma, are the most common malignant tumors in adults. Immunotherapies have generally been unsuccessful. To date, there have been exciting advances in immunotherapy and other cancer types, particularly metastatic melanoma and some forms of lung cancer. For glioblastoma, these immunotherapy strategies, such as PD-1 inhibition, have generally been ineffective. However, a new immunotherapy approach called CAR T-cell therapy is being developed at several centers around the US. It’s a form of a T cell, an important cell in the immune system that can be designed through scientific methods to specifically target cancer cells and eradicate them. This therapy is still in its early days. CAR T-cell therapy treatments are now FDA approved for the treatment of [different] forms of lymphoma, multiple myeloma, and types of blood cancers, and there’s an early development for brain cancer. There appear to be promising results in these early studies.

What are the most promising emerging therapeutic strategies beyond standard chemotherapy and radiation for aggressive gliomas?

For aggressive gliomas like glioblastoma and grade 3 and 4 gliomas, typical therapy would entail radiation treatment along with temozolomide chemotherapy. Temozolomide has been in use for over 20 years. It does have anti-cancer effectiveness, but it’s not a very powerful drug. This is good and bad in that the adverse effect [AE] profile is relatively benign. It has relatively low AEs compared with other chemotherapies, but it’s also not highly effective. Several years ago, another treatment modality called tumor treating fields, or TTFields, became available for the treatment of patients with glioblastoma, and the device was recently upgraded in this past year, with the arrays, the portion of the device that’s applied to the patient scalp, have been redesigned and updated with a larger surface, delivering the electrical fields per array. In models that were developed, these newer arrays seem to be more powerful in generating anti-cancer TTFields through the patient, and, with the new designs, they may be more comfortable for patients to wear. Generally, there’s less skin toxicity seen with the new arrays compared with the older arrays. That’s an important advance in the last year that’s occurred, and I encourage all of my glioblastoma patients who could be eligible for TTFields to strongly consider adding it to their treatment. Beyond that, there haven’t been any other major advances in the last year in terms of glioblastoma therapies.

In the context of advanced neuroimaging techniques like diffusion tensor imaging and magnetic resonance spectroscopy, how can oncology clinicians best collaborate with neuroradiologists to optimize tumor characterization, differentiate true progression from pseudoprogression, and inform treatment decisions?

They have continued to advance over the last several years with neuroimaging, but unfortunately, there remains no completely sensitive and specific way to differentiate true progression from pseudo-progression. There are strategies like cerebral blood volume mapping and other MRI software techniques to help give some hint of true vs pseudoprogression. It remains not completely adequate for full clinical use. Making treatment decisions is still generally based on the change of MRI over time and what treatment effects the patient has or could be experiencing.

Here at Yale, we’re developing another MRI technique called metabolic imaging, and the idea is to have patients drink a glucose solution where the hydrogen in the glucose molecule has been replaced by an isotope called deuterium, and that allows the MRI to image the glucose molecule as it is converted into lactate in cancer cells. Glioblastoma cells have an altered metabolism, and they use sugar in an altered way from normal tissue, which breaks down sugar into carbon dioxide and water. Cancer cells convert sugar into lactate, and 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, using glucose as fuel to make lactate. We’ve been recruiting patients for the last several years on this effort to try to image lesions like contrast-enhancing lesions in the brain and determine if they’re generating lactate or not. We’re hopeful that this may ultimately be a low-cost solution to determining tumor metabolism and the presence or absence of tumors in the brain and other patients. This is an exciting project, and there’s more to come in the next couple of years.

What are the key considerations and best practices for managing the unique treatment-related toxicities associated with neuro-oncologic therapies in a way that preserves patient quality of life?

In my practice, developing a strong doctor-patient relationship and developing a strong therapeutic alliance is key. I try to understand a person’s background, their living situation, their family situation, experience with cancer and treatment in the past, and get a sense of what their goals could be for treatment. How aggressive they want to be? To what degree are they willing to tolerate AEs and understand that glioblastoma is not felt to be a curable cancer, but it is a treatable cancer, and patients can potentially live for years after glioblastoma diagnosis. It’s important to recognize that most [patients] would not want to live with serious disabilities that aren’t going to ever get better. 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 also. It’s again, understanding someone’s support network, bringing in their family members or even friends to help them with their journey, and then also having a strong team in our neuro-oncology practice to adequately support our patients.

How can a multidisciplinary oncology team effectively integrate supportive care strategies, including neuro-rehabilitation, palliative care, and psychosocial support, from the time of diagnosis to address the complex needs of brain tumor patients and their caregivers?

Brain cancer is a unique form of cancer in that it is a neurological disease rather than a medical disease. As glioblastoma can worsen or progress, [patients] will develop increased cognitive impairments, inability to walk, imbalance, and generally neurological declines. That’s not seen with other cancers in the body. At our center at the main hospital and also a satellite clinic I work with, we have 2 strong teams of a navigator, social worker, nurse coordinator, and then physical therapists and cognitive rehabilitation specialists that work with my patients to optimize their quality of life, make sure that they can safely stay on treatment, tolerate treatment well, and mitigate those AEs. For patients with brain cancer, it would be generally helpful for them to seek out brain tumor centers, as most centers in the US do have these ancillary programs to support that patient population.

How are artificial intelligence and machine learning being applied to advance the field of neuro-oncology?

In some ways, this is an exciting time with the rise of AI and machine learning. There are privacy concerns about the use of AI in health care settings. On the other hand, there is a lot of opportunity for AI to help us better interpret MRIs, better understand treatment options, and in the last few months, I’ve seen some reports of AI being used to those ends. There was a recent report of AI use in pediatric brain cancer management, where it seemed like some useful conclusions were drawn from that. It’s still very early days in my actual practice. I’ve just started using AI to try to help me understand treatment options better for patients or build out treatment programs. [AI] is going to advance a lot in the next few years. Ultimately, doing this line of work of neuro-oncology and [and being a doctor is having the] doctor-patient relationship. It’ll be, hopefully, a very useful tool for me as a physician to help me take better care of my patients, and also, I hope my patients utilize AI as well and come up with their own concepts and ideas and bring that to me, and we can discuss and learn things together. Hopefully, this will all just move the field forward on how patients have better outcomes.

What are some of the key unanswered questions or areas of active investigation that hold the most promise for improving outcomes for patients with malignant brain tumors shortly?

A key question over the last 5 years in neuro-oncology and specifically for glioblastoma management, has been immunotherapy, and why immunotherapy has not worked. 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. [We’re] trying to understand more about brain tumor immunology is going to be key. It’s a critical unanswered question, and a lot of efforts in neuro-oncology are being focused now to understand what is blocking successful immunotherapy. What factors in brain tumors are inhibiting the immune system, and as CAR T-cell therapy becomes more developed, if CAR T is effective or ineffective, understanding why it's effective or ineffective will be an important way to move this forward.

The current CAR T-cell therapy being developed is for a specific subtype of glioblastoma called EGFRvIII-mutant glioblastoma. It’s around 10% to 15% of glioblastomas, so it’s not widely applicable either to patients, but the hope is that this is the starting block. We can understand if this CAR T-cell therapy works or [not] and then build from there. Another project I’m involved with is called the phase 2/3 GBM AGILE clinical trial (NCT03970447). It’s a large platform study investigating multiple new experimental therapies against glioblastoma compared with standard treatment, which is radiation and temozolomide. Patients enrolling in GBM AGILE could potentially be assigned into experimental treatment groups in addition to their standard treatment. We’re also asking patients to participate in a bio bank where they donate [resected] brain tumors and blood samples over time, so that scientists working through the GBM AGILE study can understand if treatments work better for some patients than others. This strategy was done in lung cancer about 10 to 15 years ago, and was effective in developing new EGFR inhibitors and targeted treatments for lung cancer. We’re trying to just recapitulate what was done in lung cancer treatment for brain cancer treatment. I am hopeful that the GBM AGILE trial will lead to a new treatment within the next several years.