Researchers developed lab-grown organoids derived from glioblastoma (GBM) tumors to effectively simulate a patient’s reaction to CAR T cell therapy in real time. The response of these organoids to the treatment closely matched that of the actual tumor within the patient’s brain. Specifically, if the tumor-derived organoid shrank following treatment, the patient’s real tumor did as well.
In a groundbreaking study, scientists utilized lab-grown organoids derived from glioblastoma (GBM) tumors to successfully model how a patient responds to CAR T cell therapy in real time. The treatment’s effect on the organoid reflected the actual tumor’s response in the patient’s brain. If the organoid shrank post-treatment, the patient’s tumor shrank as well. This research was conducted by the Perelman School of Medicine at the University of Pennsylvania and published in Cell Stem Cell.
Hongjun Song, PhD, who is the Perelman Professor of Neuroscience and a co-senior author of the study, stated, “Tracking how a GBM patient responds to treatment is challenging since we cannot frequently perform brain biopsies. Also, distinguishing between tumor growth and inflammation caused by treatment on MRI scans can be difficult. These organoids replicate the events in a patient’s brain extremely well, and we hope they will enable us to understand each patient’s unique tumor and quickly identify the most effective treatments, paving the way for personalized medicine.”
GBM is recognized as the most prevalent and aggressive type of brain tumor in adults. Typically, individuals diagnosed with GBM may only have a life expectancy of 12-18 months post-diagnosis. Despite extensive research efforts over the years, a definitive cure for GBM remains elusive, and current treatments—including surgery, radiation, and chemotherapy—have shown only limited efficacy in extending life.
CAR T cell therapy is a treatment that modifies a patient’s T cells to locate and eradicate specific cancer cells in the body. Although this treatment has FDA approval for certain blood cancers, there has been difficulty in adapting it to target solid tumors, like GBM. Recent findings indicate that utilizing CAR T cell therapy that targets two proteins associated with brain tumors, instead of just one, may prove to be a viable technique for reducing solid tumor growth in patients experiencing recurrent glioblastoma.
Guo-li Ming, MD, PhD, a co-senior author and Perelman Professor of Neuroscience, explained, “GBM’s treatment complexity stems from the tumors being extraordinarily intricate, consisting of multiple cancer cell types, immune cells, blood vessels, and various tissues. By cultivating organoids from small samples of an individual patient’s tumor rather than a single type of cancer cell, we can accurately replicate the tumor’s conditions in the patient and the unique environmental context of its growth, which is a significant limitation of other GBM models.”
The initial approach to treating GBM involves surgical removal of as much of the tumor as possible. In this study, researchers produced organoids from the tumors of six patients with recurrent glioblastoma who were part of a Phase I clinical trial for a dual-target CAR T cell therapy. While producing enough cancer cells in the lab typically takes months, organoids can be developed in just 2-3 weeks, allowing patients to recover from surgery before initiating CAR T cell therapy.
Two to four weeks post-surgery, CAR T cell therapy was administered to both the organoids and the patients simultaneously. The researchers discovered that the organoids’ treatment responses were aligned with those of the patient’s tumors. When the organoid exhibited destruction of cancer cells by T cells, the patient also showed a decrease in tumor size through MRI imaging and an increased presence of CAR-positive T cells in their cerebrospinal fluid, indicating successful targeting by the therapy.
A prevalent concern regarding CAR T cell therapy for GBM is neurotoxicity, which occurs when harmful substances affect the nervous system, potentially damaging or killing brain cells. The researchers noted comparable levels of immune cytokines indicating toxicity in both the organoids and the patients’ cerebrospinal fluid. Both levels dropped a week after treatment concluded, suggesting that organoids can also reliably model a patient’s risk of neurotoxicity, assisting clinicians in determining the appropriate CAR T dosage.
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, remarked, “Our research demonstrates that the GBM organoids are an effective and precise method for understanding the impact of CAR T cell therapy on brain tumors. We aspire not only to introduce these organoids into clinical practice to tailor treatments for patients but also to utilize them to enhance our understanding of how to combat this complex and lethal cancer.”
This research was supported by the National Institutes of Health (grants R35NS116843 and R35NS097370), along with assistance from the Institute for Regenerative Medicine and the GBM Translational Center of Excellence at Abramson Cancer Center.
