For the first time, researchers used lab-grown organoids created from tumors of individuals with glioblastoma (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, according to new research from the Perelman School of Medicine at the University of Pennsylvania, published in Cell Stem Cell.

“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,” said Hongjun Song, PhD, the Perelman Professor of Neuroscience and co-senior author of the research. “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 medicine.”

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.

A treatment called 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. Recent research suggests that CAR T cell therapy that targets two brain tumor-associated proteins — rather than one — may be a promising strategy for reducing solid tumor growth in patients with recurrent glioblastoma.

“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,” said study co-senior author, Guo-li Ming, MD, PhD, the Perelman Professor of Neuroscience and Associate Director of 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. It can take months to grow enough cancer cells in the lab to test treatments on, but an organoid can be generated in 2-3 weeks, while the individuals recover from surgery and before they can begin CAR T cell therapy.

2-4 weeks following surgery, the CAR T cell therapy was administered to the organoids and the patients at the same time. They found that the treatment response in the organoids correlated with the response of the tumors in the patient. When a patient’s organoid demonstrated cancer cell destruction by T cells, the patient also exhibited a reduced tumor size via MRI imaging and increased presence of CAR-positive T cells in their cerebrospinal fluid, indicating that the therapy met its targets.

A common concern with CAR T cell therapy for GBM is neurotoxicity, which occurs when a toxic substance alters the activity of the nervous system and can disrupt or kill brain cells. The researchers found that there were similar levels of immune cytokines, which indicate toxicity, in both the organoids and the patients’ cerebrospinal fluid. Both levels decreased a week after treatment ended, suggesting that the organoid can also accurately model a patient’s risk of neurotoxicity, and help clinicians determine what size dose of CAR T to use.

“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,” said study co-senior author, Donald M. O’Rourke, MD, the John Templeton, Jr., MD Professor in Neurosurgery and director of the Glioblastoma Translational Center of Excellence at the Abramson Cancer Center. “Our hope is that 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.”

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



Source link

Leave a Reply

Your email address will not be published. Required fields are marked *

Before you post, please prove you are sentient.

what is 7 in addition to 6?

Explore More

Both high, low levels of magnesium in blood linked to risk of dementia

People with both high and low levels of magnesium in their blood may have a greater risk of developing dementia, according to a study published in the September 20, 2017,

Epigenetics blood markers can help explain dementia risk

New research suggests that epigenetic markers in the blood could be useful for understanding dementia risk. Two linked papers from the University of Exeter and Maastricht University have together progressed

Common degenerative brain disease may begin to develop in middle age

Lewy body disease is the second most common brain degenerative disease after Alzheimer’s disease. Lewy bodies, deposits of alpha-synuclein protein, are found in the brainstem, limbic system and cerebral cortex.