Glioblastoma is the most common and aggressive primary brain tumor, with an average survival after diagnosis of less than two years, and against which current treatments remain ineffective. In recent years, immunotherapies have given patients new hope, albeit with relatively modest success. A team from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG) managed to identify a specific marker on the surface of tumor cells and generate immune cells carrying an antibody to destroy them. Furthermore, these cells, called CAR-T cells, appear to be able to attack diseased tumor cells that do not carry this antigen, without affecting healthy cells. These results, published in the journal Research in cancer immunologyThey are a first step towards the development of clinical trials with human patients.
Glioblastomas have biological characteristics that make them particularly difficult to treat. Capable of inducing a microenvironment that limits the attack of the immune system, they escape standard treatments and quickly reappear.
Denis Migliorini, assistant professor of the Department of Medicine at the UNIGE Faculty of Medicine, holder of the ISREC Foundation Chair in Brain Tumor Immunology, member of the Center for Translational Research in Oncohematology (CRTOH) and treating physician in charge of HUG Neuro -Oncology Unit, is an expert in CAR-T cells (for T cells with chimeric antigen receptors). This immunotherapy involves collecting immune T cells from patients, genetically modifying them in the laboratory to make them express antibodies capable of detecting specific elements of tumor cells, before reinjecting them so that they can specifically attack the tumor.
“For several years we have been trying to identify the protein markers expressed by glioblastoma cells,” explains Denis Migliorini. ”One of these markers, PTPRZ1, turned out to be particularly important: we were able to generate CAR-T cells carrying antibodies targeting PTPRZ1. “This is a first step toward effective CAR-T cells against malignant gliomas.”
mRNA to create a custom cell
Most CAR-T cells are generated using viral vectors, a technique that has proven effective in certain diseases but is not very suitable in the brain. ”In fact, they persist for a long time in the context of blood cancers. The brain is a fragile organ and this persistence can generate a risk of toxicity,” explains Darel Martínez Bedoya, postdoctoral fellow in Denis Migliorini’s laboratory and first author of this research. Therefore, the scientists introduced the messenger RNA that encodes the desired antibody into the T cells. The cellular machinery is then responsible for producing the appropriate protein to build the receptor that will sit on the surface of the T cells and recognize the tumor target. “This technique has a series of advantages: CAR-Ts offer a flexible platform that allows multiple adaptations according to the specificities and evolution of the tumor,” explains Darel Martínez Bedoya.
Efficiency and safety
To verify that CAR-T attacks only tumor cells, the Geneva team first tested them in vitro on healthy and tumor cells. “To our surprise, the CAR-T not only did not attack healthy cells, but they were also able, by bystander effect, to identify and combat tumor cells that do not express the PTPRZ1 marker,” Denis Migliorini is delighted. “In this context, CAR-Ts are likely capable of secreting pro-inflammatory molecules that are responsible for killing tumor cells even in the absence of the original marker when co-cultured with positive target tumor cells.”
The second stage involved testing the treatment in vivo in murine models of human glioblastoma. Tumor growth was controlled, notably prolonging the life of the mice without signs of toxicity. ”By delivering CAR-T intratumorally into the CNS, we can use fewer cells and greatly reduce the risk of peripheral toxicity. With these data and other unpublished data, all the lights are green to now foresee a first clinical trial in humans,” the scientists conclude.