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New Technology Recreates Tumors to Anticipate Responses to Brain Cancer Treatment


This study represents a major breakthrough because, for the first time, a clinical trial has used real-time patient tumor organoids to monitor an experimental treatment. This model opens up new possibilities for predicting the effectiveness of innovative therapies before they are even administered to patients, allowing for personalized adjustments and potentially improving clinical outcomes.


In recent years, scientists have been exploring ways to create more accurate models to study cancer and develop new therapies. One such strategy involves the use of tumor organoids, which are small, three-dimensional structures grown in the laboratory from cells from real patient tumors.


These organoids have proven to be valuable tools because they preserve the original characteristics of tumors better than traditional models, such as cell cultures or xenografts (implants of human tumor cells into laboratory animals).


As a result, they offer a more realistic view of how tumors grow, interact with their environment, and respond to different treatments.


Although tumor organoids have already been used to study the mechanisms of cancer and create biobanks (collections of tumor samples stored for research), a recent advance has attracted attention: their ability to predict how a specific patient will respond to treatment in real time. 


a) From human cancer tissue, tumor cells can be isolated and cultured to produce spheroids. b) Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are two common types of stem cells used as cell sources for organoid production. Both ESCs and iPSCs can form a variety of organoid models when given the right signaling cues and specific extracellular matrix (ECM). Image: Vanessa Velasco, S. Ali Shariati & Rahim Esfandyarpour


This approach has already been explored in some cancers, such as breast, skin (melanoma), lung and gastrointestinal tract. However, this strategy has not yet been applied to central nervous system (CNS) tumors, such as glioblastoma, in an immediate clinical context.


Until now, tumor organoids have been used primarily for retrospective analyses, i.e. studies conducted after patients have already been treated. The big question was: could tumor organoids be generated quickly enough to track a patient’s treatment and help predict their response?


Glioblastoma (GBM) is the most common malignant brain tumor in adults and, unfortunately, one of the most aggressive. Even with standard treatment, which involves surgery to remove as much of the tumor as possible, followed by radiotherapy and chemotherapy with temozolomide, the average survival rate for patients is less than two years.


In the case of recurrent glioblastoma (rGBM), which grows back after initial treatment, the situation is even more challenging: patients often survive less than a year. This reality highlights the urgent need for new, more effective therapies.


One of the main obstacles in treating glioblastoma is its enormous heterogeneity, i.e., tumors vary greatly from one patient to another and even within the same individual, making it difficult for drugs to work.

Furthermore, traditional methods for studying glioblastoma, such as cell lines and xenografts, take a long time to develop, making them of little use for rapid decision-making in clinical treatment.


To overcome these limitations, researchers have developed an innovative protocol to create glioblastoma organoids (GBOs) from patient tumors shortly after surgery. Unlike other methods, this approach maintains the original structure of the tumor, including different cell types, genetic patterns, and even interactions with the tumor microenvironment.


The great advantage of this protocol is its speed: GBOs can be generated in just 2 to 3 weeks after surgery, which allows them to be tested at the same time as the patient receives their treatment.


These organoids can not only be used for research, but can also be stored in biobanks or implanted in the brains of mice for more detailed experiments.


One of the most promising therapeutic approaches in the fight against cancer is immunotherapy with CAR-T cells, which has already shown great efficacy in blood cancers, such as leukemia.


However, this strategy faces major challenges in solid tumors such as glioblastoma, due to the complexity of the tumor microenvironment and the variability of tumor antigens (the molecules that the immune system recognizes to attack the cancer).

Image: UNC Medical Center


To address this challenge, researchers have developed a unique CAR-T cell that attacks two targets simultaneously: the epidermal growth factor receptor (EGFR) and the interleukin-13 receptor alpha 2 (IL13Rα2). This innovative treatment is currently being tested in a phase 1 clinical trial in patients with recurrent glioblastoma.


In the study, patients undergo surgery to shrink the tumor and receive a small device called an Ommaya reservoir, which allows direct administration of CAR-T cells into the cerebrospinal fluid (CSF).


Early results indicate that the treatment was safe and well tolerated, with patients experiencing significant expansion of CAR-T cells in the CSF and release of inflammatory cytokines, suggesting activation of the immune system against the tumor.


In addition, all six patients in the study showed some degree of tumor regression within the first month after treatment, according to MRI scans.


However, responses were not long-lasting for all patients, and some experienced a phenomenon known as pseudoprogression, in which the tumor appears to grow temporarily before shrinking.

A unique trial design with parallel treatments of patients and patient-derived glioblastomas


The big problem with glioblastoma therapies, especially with CAR-T cells, is that it can take months to determine whether a patient is actually responding to treatment. Given that recurrent glioblastoma has a very short survival time, this wait can be fatal for some patients.


This is where organoids come in as a revolutionary tool. At the same time that CAR-T cells were being prepared for patients in the clinical trial, the researchers also grew tumor organoids from these same patients.


This way, they were able to test the CAR-T cells in the organoids at the same time that the patients were receiving the actual treatment, allowing an early assessment of the efficacy of the therapy.


The results were promising: in organoids treated with the patient's own CAR-T cells, researchers observed a reduction in tumor targets and significant destruction of cancer cells, an effect that was directly related to the amount of CAR-T cells detected in the patients' cerebrospinal fluid.

Patient-derived glioblastoma organoid treated with dual-targeted CAR-T cells. T cells (magenta) infiltrate the tumor organoid and kill tumor cells (blue; yellow indicates dying cells). (Image: Yusha Sun and Xin Wang from the labs of Guo-li Ming and Hongjun Song)


In addition, cytokine release patterns in the organoids mirrored those seen in patients over time, indicating that the organoids can accurately reflect a patient’s response to treatment.


This study represents a major breakthrough because, for the first time, a clinical trial has used patient tumor organoids in real time to monitor an experimental treatment.


This model opens up new possibilities for predicting the efficacy of innovative therapies before they are even administered to patients, enabling personalized adjustments and potentially improving clinical outcomes.


Furthermore, the data obtained from organoids may help to better understand the biological mechanisms behind responses (or lack of response) to treatments, aiding in the development of new therapeutic strategies.


In short, the combination of tumor organoids and CAR-T cells could revolutionize the way we treat glioblastoma.


This approach not only enables rapid testing of new personalized treatments, but also helps fill a critical gap in oncology: the need for effective tools to predict patient response to therapies, especially for highly aggressive tumors such as glioblastoma.


Although more studies are needed, this research points to a promising future, in which personalized treatments based on organoids may increase the chances of success of therapies and improve the quality of life of patients with brain cancer.



READ MORE:


Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy

Meghan Logun, Xin Wang, Yusha Sun, Stephen J. Bagley, Nannan Li, Arati Desai, Daniel Y. Zhang, MacLean P. Nasrallah, Emily Ling-Lin Pai, Bike Su Oner, Gabriela Plesa, Donald Siegel, Zev A. Binder, Guo-li Ming, Hongjun Song, and Donald M. O’Rourke

Cell Stem Cell


Abstract:


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.

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