Health Technologies

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

For the first time, researchers have used lab-grown organoids created from tumours 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 tumour in the patient’s brain.

That is, if the tumour-derived organoid shrunk after treatment, so did the patient’s actual tumour.

“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 tumour growth from treatment-related inflammation on MRI imaging,” said Hongjun Song, 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 tumour 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 tumour in adults.

Individuals with GBM usually can expect to live just 12 to 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 tumours, like in GBM.

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

“One of the reasons why GBM is so difficult to treat is because the tumours 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, associate d of Institute for Regenerative Medicine

“By growing the organoid from tiny pieces of a patient’s actual tumour rather than one type of cancer cell, we can mirror how the tumour 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 tumour as possible. For this study, researchers created organoids from the tumours 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 two to three weeks, while the individuals recover from surgery and before they can begin 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.

They found that the treatment response in the organoids correlated with the response of the tumours in the patient. When a patient’s organoid demonstrated cancer cell destruction by T cells, the patient also exhibited a reduced tumour 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 tumour with CAR T cell therapy,” said study co-senior author, Donald O’Rourke at the Abramson Cancer Center.

“Our hope is that not only to bring these to clinic to personalise patient treatment, but also to use the organoids to deepen our understanding of how to outsmart and destroy this complex and deadly cancer.”

Image Caption: Patient-derived glioblastoma organoid treated with dual-target CAR-T cells. T cells (magenta) infiltrate the tumour organoid and kill tumour cells (blue) (yellow indicates dying cells).

Credit: Image by Yusha Sun and Xin Wang from the laboratories of Guo-li Ming and Hongjun Song.

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