Novel CAR-T cells effectively target glioblastoma with reduced toxicity

Glioblastoma is the most common and most aggressive primary brain tumor, with a median survival after diagnosis of less than two years and against which current treatments remain ineffective. In recent years, immunotherapies have given patients renewed 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 system cells that carry an antibody to destroy them. In addition, these cells, called CAR-T cells, appear to be able to target diseased cells in the tumor that do not carry this antigen, while sparing healthy cells. These results were published in the journal Cancer Immunology Researchthey are a first step towards the development of clinical trials with human patients.

Glioblastomas have biological characteristics that make them particularly difficult to treat. Able to induce a microenvironment that limits the immune system’s attack, they escape standard treatments and recur rapidly.

Denis Migliorini, assistant professor at the Department of Medicine of the UNIGE School of Medicine, holder of the ISREC Foundation Chair in Brain tumor Immunology, member of the Translational Research Center in Onco-Aematology (CRTOH) and attending physician responsible for the HUG Neuro-Oncology Unit, is an expert in CAR-T cells (for chimeric antigen receptor T-cells). This immunotherapy involves harvesting immune T cells from patients, genetically modifying them in the lab to make them express antibodies capable of detecting elements specific to cancer cells, before re-injecting them to specifically target the tumor.

For several years we have been trying to identify protein markers expressed by glioblastoma cells. One of these markers, PTPRZ1, turned out to be particularly important: we were able to generate CAR-T cells bearing antibodies targeting PTPRZ1. This is a first step towards CAR-T cells effective against malignant gliomas.”

Denis Migliorini, Assistant Professor in the Department of Medicine at UNIGE School of Medicine

mRNA to create a custom cell

Most CAR-T cells are produced using viral vectors, a technique that has proven its value in some diseases but is not well-suited for the brain. “Indeed, they persist for a very long time in blood cancers. The brain is a fragile organ, and this persistence can create a risk of toxicity,” explains Darel Martinez Bedoya, a postdoctoral fellow in Denis Migliorini’s lab and first author of this research. Therefore, the scientists introduced the messenger RNA encoding the desired antibody into the T-cells. The cellular machinery is then responsible for producing the correct protein to make the receptor that will take place on the surface of the T-cell and recognize the tumor target. “This technique has many advantages: CAR-Ts offer a flexible platform, allowing multiple adaptations according to the specificities and evolution of the tumor,” explains Darel Martinez Bedoya.

Efficiency and safety

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

The second stage involved testing the treatment in vivo in mouse models of human glioblastoma. Tumor growth was controlled, extending the lives of the mice remarkably well without signs of toxicity. ”By delivering CAR-Ts intratumorally into the CNS, we can use fewer cells and significantly reduce the risk of peripheral toxicity. With these data and others yet to be published, all the lights are green to now envisage a first clinical trial in humans,” the scientists conclude.