Summary: Glioblastoma organoids, lab-grown replicas of a patient’s tumor, accurately predict how the tumor responds to CAR T cell therapy. This breakthrough allows real-time testing of therapies, showing that responses in the organoid closely mirror those in the patient. These organoids also help clinicians gauge risks of neurotoxicity and personalize treatment doses.
By modeling the complexity of glioblastoma, this technology offers a promising step toward individualized treatments for this aggressive brain cancer. The approach could accelerate understanding of glioblastoma and enhance survival outcomes. This innovation combines cutting-edge neuroscience and immunotherapy to tackle one of the deadliest cancers.
Key Facts:
- Organoid Accuracy: Glioblastoma organoids precisely mirrored patient tumor responses to CAR T cell therapy, aiding in personalized treatment.
- Treatment Prediction: Organoids helped predict both tumor shrinkage and neurotoxicity risks, enabling dose optimization.
- Rapid Modeling: Organoids can be generated within weeks, providing actionable insights before treatment begins.
Source: University of Pennsylvania
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 today 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.”
Funding: 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.
About this brain cancer research news
Author: Kelsey Geesler
Source: University of Pennsylvania
Contact: Kelsey Geesler – University of Pennsylvania
Image: The image is credited to Yusha Sun and Xin Wang from the laboratories of Guo-li Ming and Hongjun Song
Original Research: Open access.
“Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy” by Hongjun Song et al. Cell Stem Cell
Abstract
Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy
Patient-derived tumor organoids have been leveraged for disease modeling and preclinical studies but rarely applied in real time to aid with interpretation of patient treatment responses in clinics.
We recently demonstrated early efficacy signals in a first-in-human, phase 1 study of dual-targeting chimeric antigen receptor (CAR)-T cells (EGFR-IL13Rα2 CAR-T cells) in patients with recurrent glioblastoma.
Here, we analyzed six sets of patient-derived glioblastoma organoids (GBOs) treated concurrently with the same autologous CAR-T cell products as patients in our phase 1 study.
We found that CAR-T cell treatment led to target antigen reduction and cytolysis of tumor cells in GBOs, the degree of which correlated with CAR-T cell engraftment detected in patients’ cerebrospinal fluid (CSF).
Furthermore, cytokine release patterns in GBOs mirrored those in patient CSF samples over time.
Our findings highlight a unique trial design and GBOs as a valuable platform for real-time assessment of CAR-T cell bioactivity and insights into immunotherapy efficacy.
