Health
Programming cells to target brain tumors
Glioblastoma is the most common and aggressive primary brain tumor, with an average survival time of less than 2 years after diagnosis, and current treatments remain ineffective. In recent years, immunotherapy has offered new hope to patients, albeit with relatively modest success. A team from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG) has succeeded in generating immune cells with antibodies that identify specific markers on the surface of tumor cells and destroy them. Additionally, these cells, called CAR-T cells, appear to be able to target diseased cells within tumors that do not have this antigen, while sparing healthy cells. These results were published in the journal Cancer immunology researchis the first step toward developing clinical trials in human patients.
Glioblastoma has biological features that make it particularly difficult to treat. It can induce a microenvironment that limits immune system attack, thus evading standard treatments and relapsing rapidly.
Dennis Migliorini, Assistant Professor, Department of Medicine, UNIGE School of Medicine, holder of the ISREC Foundation Chair in Brain Tumor Immunology, member of the Center for Translational Research in Tumor-Hematology (CRTOH), and Principal Investigator in charge of HUG Neuro-Oncology, CAR-T cells ( He is an expert in chimeric antigen receptor T cells. This immunotherapy involves collecting immune T cells from patients, genetically modifying them in the laboratory to express antibodies that can detect elements specific to tumor cells, and then reinjecting them to specifically target tumors. It is something to do.
“For several years we have been trying to identify protein markers expressed by glioblastoma cells,” explains Dennis Migliorini. “One of these markers, PTPRZ1, turned out to be particularly important. We were able to generate CAR-T cells that carried antibodies that targeted PTPRZ1.” This is the first step toward CAR-T cells that are effective against glioma. ”
mRNA for creating customized cells
Most CAR-T cells are generated using viral vectors. While this technique has proven its value in certain diseases, it is less suited for the brain. “Certainly, in the context of blood cancers, they persist for very long periods of time. The brain is a fragile organ, and this persistence can create a risk of toxicity,” says Dennis Migliorini, from the lab of Dennis Migliorini. explains Darrell Martinez-Bedoya, a postdoctoral researcher and lead author of the study. So the scientists introduced messenger RNA encoding the antibody of interest into T cells. The cellular machinery is then responsible for producing the appropriate proteins to build the receptors that occur on the T cell surface and recognize the tumor target. “This technology has many advantages. CAR-T provides a flexible platform, allowing multiple adaptations depending on tumor specificity and progression,” explains Darel Martinez Bedoya.
Efficacy and safety
To confirm that CAR-T only attacks tumor cells, the Geneva team first tested CAR-T in vitro on healthy and tumor cells. “Surprisingly, not only did CAR-T not attack healthy cells, but through a bystander effect it was able to identify and fight tumor cells that did not express the PTPRZ1 marker.” Dennis・Mr. Migliorini was happy to report. “In this context, CAR-T is probably able to secrete pro-inflammatory molecules involved in tumor cell clearance when co-cultured with target-positive tumor cells, even in the absence of the original marker. Masu.”
The second step involved testing the in vivo treatment in a mouse model of human glioblastoma. Tumor growth was controlled and the lifespan of the mice was significantly extended without any signs of toxicity. “By delivering CAR-T intratumorally in the CNS, we can reduce the number of cells used and significantly reduce the risk of peripheral toxicity. “All lights are green to envisage the first clinical trials in the United States,” the scientists concluded.
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