Pioneering CAR-T cells effectively target glioblastoma multiforme with reduced toxicity

Glioblastoma multiforme is the most common and aggressive primary brain tumor, with an average survival time after diagnosis of less than two years and for which current treatments remain ineffective. In recent years, immunotherapies have given patients 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 cancer cells and generate immune cells carrying an antibody to destroy them. Moreover, these cells, called CAR-T cells, appear to be able to attack diseased cancer cells that do not carry this antigen while sparing well cells. These results were published in the journal Cancer immunology researchare the first step towards the development of clinical trials involving humans.

Gliomas have biological characteristics that make them particularly complex to treat. Capable of creating a microenvironment that limits the immune system’s attack, they escape standard treatment and recur quickly.

Denis Migliorini, assistant professor at the Faculty of Medicine of the UNIGE Faculty of Medicine, head of the ISREC Foundation Chair in the Immunology of Brain Tumors, member of the Center for Translational Research in Onco-Haematology (CRTOH) and attending physician of the HUG Neuro -Department of Oncology, is an expert in the field of CAR-T cells ( for T cells with chimeric antigen receptors). Immunotherapy involves taking immune T cells from patients and genetically modifying them in the laboratory to express antibodies that can detect elements specific to cancer cells, before reinjecting them so they can specifically target the tumor.

For several years, we have been trying to identify protein markers expressed by glioma cells. One of these markers, PTPRZ1, turned out to be particularly vital: we were able to generate CAR-T cells carrying antibodies directed against PTPRZ1. This is the first step towards CAR-T cells effective in the fight against malignant gliomas.”

Denis Migliorini, assistant professor at the Department of Medicine, Faculty of Medicine, UNIGE

mRNA to create a customized cell

Most CAR-T cells are produced using viral vectors. This is a technique that has been effective for some diseases, but is not very suitable for the brain. “They actually persist for a very long time in the context of blood cancers.” The brain is a fine organ and such persistence may pose a risk of toxicity,” explains Darel Martinez Bedoya, a PhD student in Denis Migliorini’s laboratory and first author of this study. Therefore, scientists introduced messenger RNA encoding the desired antibody into T cells. The cellular machinery is then responsible for producing the appropriate protein to build a receptor that will be located on the surface of T cells and recognize the tumor target. “This technique has many advantages: CAR-Ts offer a adaptable platform that allows multiple adaptations depending on the specificity and evolution of the tumor,” explains Darel Martinez Bedoya.

Effectiveness and safety

To check whether CAR-Ts only target cancer cells, the Geneva team first tested them in vitro on well and cancer cells. “To our surprise, CAR-T not only did not attack well cells, but were also able, thanks to the bystander effect, to identify and fight cancer cells that do not express the PTPRZ1 marker,” Denis Migliorini happily reports. “In this context, CAR-Ts are likely capable of secreting pro-inflammatory molecules that are responsible for eliminating tumor cells even in the absence of the original marker when co-cultured with target positive tumor cells.”

The second step involved testing the treatment in vivo in mouse models of human glioblastoma multiforme. tumor growth was controlled, which significantly extended the life of the mice without any signs of toxicity. “By delivering CAR-T to tumors in the CNS, we can exploit fewer cells and significantly reduce the risk of peripheral toxicity. With these data and other yet unpublished data, all lights are green and the first clinical trial in humans can now be considered,” the researchers conclude.