Brain tumor organoids accurately model patient response to CAR T cell therapy

“It’s difficult to measure the response to treatment in patients with GBM because we can’t regularly biopsie the brain, and it’s difficult to discern tumor growth and treatment-related inflammation through MRI imaging,” said Hongjun Song, Ph.D., professor of neuroscience at the Perelman Hospital. and co-senior author of the study. “These organoids reflect what is happening in an individual’s brain with great accuracy, and we hope that they can be used in the future to ‘get to know’ each patient’s distinctly complicated tumor and quickly determine which therapies would be most effective for them for personalized drug.”

GBM is the most common and aggressive type of cancerous brain tumor in adults. People with GBM typically live only 12-18 months after diagnosis. Despite decades of research, there is still no known cure for GBM, and approved treatments (such as surgery, radiation, and chemotherapy) have limited effectiveness in extending life expectancy.

A type of treatment called CAR T-cell therapy reprograms a patient’s T cells to find and destroy specific types of cancer cells in the body. While this therapy is FDA-approved to fight germline blood cancers, researchers have been working to engineer cells to successfully seek out and kill solid tumors, such as GBM. Recent research suggests that CAR T-cell therapy that targets two brain tumor-associated proteins instead of one may be a promising strategy for reducing solid tumor growth in patients with recurrent glioblastoma.

“One of the reasons GBM is so difficult to treat is because the tumors are very complex, composed of several different types of cancer cells, immune cells, blood vessels and other tissues,” said Guo, co-senior author of the study. Dr. Ming Li, who is also deputy director of the Institute of Regenerative Medicine, said: “By growing organoids from tiny fragments of a patient’s actual tumor rather than from one type of cancer cell, we can reflect the way the tumor exists in the body. The patient and their growing ‘ Microenvironment’ is a major limitation of other GBM models.

The first line of treatment for GBM is surgical removal of as much of the tumor as possible. In the study, researchers created organoids from the tumors of six patients with recurrent glioblastoma who were participating in a phase I clinical trial of dual-target CAR T-cell therapy. Growing enough cancer cells in the lab to test a treatment can take months, but organoids can be generated in 2-3 weeks while the individual recovers from surgery before CAR T-cell therapy can begin.

Two to four weeks after surgery, CAR T-cell therapy was administered to both the organoids and the patient. They found that the treatment response of the organoids correlated with the response of the patients’ tumors. While the patient’s organoids showed T cells destroying cancer cells, the patient also showed a decrease in tumor size via MRI imaging and an increased presence of CAR-positive T cells in his cerebrospinal fluid, suggesting the therapy was achieving its goal. .

A common problem with CAR T cell therapy for GBM is neurotoxicity, which occurs when toxic substances alter the activity of the nervous system and may damage or kill brain cells. The researchers found similar levels of immune cytokines in the cerebrospinal fluid of the organoids and patients, suggesting they were toxic. Both levels dropped a week after treatment ended, showing that organoids can also accurately model a patient’s risk for neurotoxicity and help clinicians determine what dose of CAR T to use.

“This study shows that our GBM organoids are a powerful and accurate tool to help us understand what exactly happens when we use CAR T-cell therapy to treat brain tumors,” said John Hog, co-senior author of the study. Donald M. O’Rourke, MD, of Princeton University. “Our hope is not only to bring these into the clinic to provide personalized treatments for patients, but also to use these organoids to deepen our understanding of how to outsmart and eliminate this complex and deadly cancer.”

This research was funded by the National Institutes of Health (R35NS116843 and R35NS097370) and was supported by the Institute for Regenerative Medicine and the GBM Translational Center of Excellence at the Abramson Cancer Center.