Brain cancer is the 10th leading cause of cancer death in the U.S., with the deadliest form, glioblastoma, having only a 6.9% five-year survival rate. In 2023, Stanford Cancer Institute member Reena Thomas, MD, PhD, received a $12 million award to spearhead innovation efforts for chimeric antigen receptor (CAR)-T cell therapy, when a patient’s T-cells are genetically modified to target cancer cells, to treat glioblastoma. She shed light on why glioblastoma, and brain cancer, can be challenging to treat and what innovations may help improve patients’ quality of life.
Unique challenges
The location of the cancer in the brain is critical to treatment. It may involve sensitive areas essential to neurological function and quality of life, including regions responsible for speech and movement, that can limit the ability to remove the tumor in its entirety. Tumors in sensitive areas can’t be completely removed without causing debilitating effects on the patient’s capacity to live an independent life.
Prior to surgery, neurosurgeons consider how the patient’s quality of life and independent functioning may be impacted when removing a brain tumor and how much, if any, of the tumor can be safely removed. Thomas notes that the tumor board, a team of neuro-oncologists, neurosurgeons, radiation oncologists, neuroradiologists, and neuropathologists, discuss treatment options for complex cases, including the best neurosurgical approach and complementary therapy to enhance and improve a patient’s overall survival and quality of life.
The blood-brain barrier, a network of cells and blood vessels that restricts what substances from the bloodstream can enter the brain, may also prevent some therapeutics from reaching and treating the cancer. Thomas states that immunotherapy is unique, as it’s believed that the therapy can penetrate the blood-brain barrier because it activates the immune system to attack cancer cells. However, glioblastoma tumors are heterogeneous and have several different types of drivers of the disease. Even robust immunotherapies may not be able to overcome the resistance mechanisms and immunosuppressive microenvironments.
Unlike some cancers that have identified molecular and genetic drivers, glioblastoma has no known targetable drivers sufficient to eradicate the disease. The cancer also tends to arise de novo, meaning there are no known predisposing factors. While patients tend to be older, the disease affects all ages.
The deadliness of glioblastoma
Glioblastomas are uniquely deadly among brain cancers because they have an infiltrative and aggressive growth pattern into normal brain tissue. Even with maximal surgical removal of a glioblastoma tumor, the remaining glioblastoma cells dispersed throughout normal brain tissue make recurrence with standard treatment inevitable and lead to a high mortality rate for the disease. Thomas says that even the best chemotherapy and radiation therapy tools, which are used to eradicate remaining cancer cells after surgically removing the tumor, are unable to kill all remaining glioblastoma cells.
Glioblastoma is defined at a microscopic level. After surgery, a neuropathologist examines the tumor tissue for key glioblastoma features, such as necrosis or tissue death. Thomas explains that glioblastomas create their own blood supply and grow abnormal blood vessels to acquire the nutrients needed for their rapid growth pattern. However, this quick growth can outstrip the tumor’s blood supply and cause parts of the tumor not to receive nutrients, which leads to necrosis.
The current standard of care for glioblastoma is maximal, safe surgical resection followed by chemotherapy, specifically temozolomide, with a concurrent six-week course of radiation therapy. Afterward, patients receive monthly temozolomide chemotherapy at a higher dose for five days out of each 28-day cycle, which typically continues for six cycles. In addition, Optune, an approved medical device using alternating electric field therapy to slow down or stop cancer cell division, can be worn on the scalp to complement treatment.
Innovative treatment
Researchers are looking at ways to bolster existing immunotherapies to be more effective for glioblastoma and address the disease’s unique challenges. With cancer therapies becoming more personalized, glioblastoma researchers have tried to identify genetic factors that can be used to develop treatments that block glioblastoma growth. Still, these efforts have not been as promising as seen in other solid tumors.
Thomas’s team focuses on CAR-T cell therapy. They are looking at infusing CAR-T cells precisely targeted at the glioblastoma directly into the brain and providing the therapy on a monthly basis. Thomas says this method shows significant promise for glioblastoma and other solid tumors.
“We decided to approach glioblastoma first, and it was the first solid tumor to be treated at Stanford’s adult hospital.”
Thomas explains that this approach to treating glioblastoma is informing a significant amount of future applications for directly administering CAR-T cells against solid tumors. She’s excited to learn more from her research about the unique aspects of solid tumor treatments and how to complement CAR-T therapy and other innovative immunotherapies alongside existing cancer therapies.
“Personalizing an approach will be a key aspect of cancer therapy moving forward as we learn about the unique cancer subtypes and key targetable genes. We’re also figuring out how to complement immunotherapies when treating cancer, determine the right timing of these therapies during treatment, and identify the responses that allow the immune system to have its greatest therapeutic impact.”
With the research her $12 million award funded, Thomas shares that her team has successfully treated patients in a dose escalation, phase-one clinical trial. The trial enrolled adult patients experiencing their first glioblastoma recurrence. Her team has seen early signs of successful treatment, including some patients who have regained neurological function they lost during the course of their disease.
Thomas says that her team is also gaining fundamental knowledge about this treatment approach by bringing the patient samples back to the lab to investigate the immune activation and functions triggered by the CAR-T treatment and looking at the resulting therapeutic outcomes in the patients. They capture samples throughout the course of treatment, learning from each patient in real-time. They also hope to pinpoint biomarkers that predict a patient’s response to treatment and biomarkers that indicate when a patient is likely not to respond to treatment. With this personalized information, oncologists can then make a therapeutic shift or change to the patient’s treatment plan.
Of her research at Stanford, Thomas states, “It’s truly that concept of bench to bedside. We create the individualized CAR-T cell therapy for each patient in our own manufacturing facility, and it’s really incredible bringing this treatment that is uniquely Stanford to our patients. We are grateful to be able to advance this innovative therapy for our patients and remain hopeful that this personalized approach may ultimately achieve a meaningful, long-term therapeutic response for patients with glioblastoma and other solid tumors in the future.”
January 2025
By Katie Shumake
