A research team at the University of Geneva (UNIGE) and Geneva University Hospitals (HUG) has developed CAR-T cells that specifically target malignant glioma cells while preserving healthy tissue. The study offers a promising direction for the treatment of glioblastoma, one of the most aggressive and challenging primary brain tumors to treat, as current therapies often fall short. These findings are published in the journal Cancer Immunology Research.
Background: Challenges of Treating Glioblastoma
Glioblastoma is characterized by its aggressive nature, with patients surviving an average of less than two years post-diagnosis. The tumor exhibits a microenvironment that limits immune response, allowing it to evade standard treatments and rapidly recur.
CAR-T therapy represents a promising immunotherapy, wherein a patient's T cells are modified to express chimeric antigen receptors (CARs) targeting specific tumor antigens. This technique has seen success in certain cancers but has remained a challenge for brain tumors like glioblastoma.
| Glioblastoma Characteristics | Description |
|---|---|
| Aggressiveness | Most aggressive primary brain tumor |
| Survival | Average post-diagnosis survival < 2 years |
| Treatment Challenges | Rapid recurrence, microenvironment evades immune response |
| Current Treatments | Standard treatments largely ineffective |
Study Overview: Development of CAR-T Cells for Glioblastoma
The research team, led by Denis Migliorini, identified a tumor-specific surface marker, PTPRZ1, present on glioblastoma cells. They generated CAR-T cells that target PTPRZ1 to destroy glioblastoma cells while leaving healthy brain cells intact. This approach opens up the potential for a more precise and safe immunotherapy.
"One of these markers, PTPRZ1, proved particularly important: we were able to generate CAR-T cells carrying antibodies targeting PTPRZ1. This is a first step towards CAR-T cells effective against malignant gliomas," said Migliorini.
| CAR-T Development | Description |
|---|---|
| Target Identification | PTPRZ1 identified as a specific marker on glioblastoma cells |
| CAR-T Function | Targets glioblastoma cells expressing PTPRZ1 |
| Therapeutic Potential | Offers precise targeting of tumor cells with minimal effect on healthy tissue |
mRNA-Engineered CAR-T Cells
Instead of using viral vectors for CAR-T cell development, which may not be suitable for brain tumors, the researchers introduced mRNA encoding the antibody against PTPRZ1. The cellular machinery then produces the necessary receptor on the T-cell surface, which is capable of recognizing the tumor target.
| mRNA CAR-T Advantages | Description |
|---|---|
| Non-Viral Delivery | Uses mRNA instead of viral vectors for safer application in the brain |
| Flexible Platform | Allows for multiple adaptations as tumor evolves |
| Reduced Toxicity | Less risk of long-term toxicity due to non-persistent T-cells |
"By administering CAR-Ts intratumorally in the CNS, we can use fewer cells and greatly reduce the risk of peripheral toxicity," said Darel Martinez Bedoya, lead author of the study.
Efficacy and Safety Testing
In Vitro Testing
The CAR-T cells were initially tested in vitro on both healthy and tumor cells. These cells specifically targeted tumor cells while sparing healthy cells. Interestingly, CAR-T cells also induced a bystander effect, attacking tumor cells that did not express the PTPRZ1 marker when co-cultured with target-positive tumor cells.
"CAR-Ts are probably capable of secreting pro-inflammatory molecules responsible for eliminating tumor cells even in the absence of the original marker," said Migliorini.
| Efficacy Results | Description |
|---|---|
| Targeting | CAR-T cells selectively target PTPRZ1-expressing glioblastoma cells |
| Bystander Effect | CAR-T cells eliminate nearby tumor cells lacking the PTPRZ1 marker |
| Healthy Cell Sparing | CAR-T cells did not attack healthy brain cells |
In Vivo Testing
Subsequent in vivo tests in mouse models of human glioblastoma demonstrated that the CAR-T cells controlled tumor growth and prolonged survival without signs of toxicity.
| In Vivo Efficacy | Description |
|---|---|
| Tumor Growth | Controlled in mice implanted with human glioblastoma |
| Survival Prolongation | Increased survival rates in treated mice |
| No Toxicity | No observed toxicity in central nervous system (CNS) |
Implications and Future Directions
The positive preclinical results support advancing to clinical trials with human patients. The team’s focus on target specificity and safety highlights the potential for CAR-T cell therapy to effectively treat glioblastoma while minimizing side effects.
| Future Steps | Description |
|---|---|
| Clinical Trials | Plans to initiate human trials based on preclinical efficacy and safety data |
| CAR-T Delivery | Administering CAR-Ts intratumorally to reduce peripheral toxicity |
| Therapeutic Promise | CAR-T therapy as a precision medicine for glioblastoma treatment |
"With this data, all lights are green to now envisage a first clinical trial in humans," the scientists concluded.
More Information:
- Title: PTPRZ1-targeting RNA CAR T cells exert antigen-specific and bystander antitumor activity in glioblastoma
- Published By: Cancer Immunology Research (2024)
- Authors: Darel MartÃnez Bedoya et al.
- DOI: 10.1158/2326-6066.CIR-23-1094
References
- Migliorini, D., et al. (2024). PTPRZ1-targeting RNA CAR T cells exert antigen-specific and bystander antitumor activity in glioblastoma. Cancer Immunology Research. DOI: 10.1158/2326-6066.CIR-23-1094
Provided by: University of Geneva, MedicalXPress
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