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

Glioblastoma (GBM) is the most common—and most aggressive—type of cancerous brain tumor in adults. Individuals with GBM usually can expect to live just 12–18 months following their diagnosis. Despite decades of research, there is no known cure for GBM, and approved treatments—such as surgery, radiation, and chemotherapy—have limited effect in prolonging life expectancy.
 
Now, in a new study published in Cell Stem Cell, researchers from the Perelman School of Medicine have—for the first time—used lab-grown organoids created from tumors of individuals with GBM to accurately model a patient’s response to CAR T cell therapy in real time. The organoid’s response to therapy mirrored the response of the actual tumor in the patient’s brain. That is, if the tumor-derived organoid shrunk after treatment, so did the patient’s actual tumor. 

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“It’s hard to measure how a patient with GBM responds to treatment because we can’t regularly biopsy the brain, and it can be difficult to discern tumor growth from treatment-related inflammation on MRI imaging,” says Hongjun Song, a professor at the School of Medicine and co-senior author of the research. 
 
CAR T cell therapy reprograms a patient’s T cells to find and destroy a specific type of cancer cell in the body. While this therapy is FDA approved to fight several blood cancers, researchers have struggled to engineer cells to successfully seek out and kill solid tumors, like in GBM.
 
“One of the reasons why GBM is so difficult to treat is because the tumors are incredibly complicated, made up of several different types of cancer cells, immune cells, blood vessels, and other tissue,” says study co-senior author, Guo-li Ming, a professor at the School of Medicine and associate director of the Institute for Regenerative Medicine. “By growing the organoid from tiny pieces of a patient’s actual tumor rather than one type of cancer cell, we can mirror how the tumor exists in the patient, as well as the ‘micro-environment’ in which it grows, a major limitation of other models of GBM.”
 
The first line of treatment for GBM is surgery to remove as much of the tumor as possible. For this study, researchers created organoids from the tumors of six patients with recurrent glioblastoma participating in a Phase I clinical trial for a dual-target CAR T cell therapy. 
 
Two to four weeks following surgery, the CAR T cell therapy was administered to the organoids and the patients at the same time. The researchers found that when a patient’s organoid demonstrated cancer cell destruction, the patient also exhibited a reduced tumor size.
 
“This research shows that our GBM organoids are a powerful and accurate tool for understanding what exactly happens when we treat a brain tumor with CAR T cell therapy,” says study co-senior author Donald M. O’Rourke, a professor at the School of Medicine and director of the Glioblastoma Translational Center of Excellence at the Abramson Cancer Center. “Our hope is not only to bring these to clinic to personalize patient treatment but also to use the organoids to deepen our understanding of how to outsmart and destroy this complex and deadly cancer.”
 
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