Glioblastoma is the most common and aggressive primary brain tumor — the average survival after diagnosis is less than two years — and current treatments remain ineffective. In recent years, immunotherapies have revived hope for patients, although with relatively modest success.
© Denis Migliorini – UNIGE/HUG
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 to generate immune cells carrying an antibody to destroy them. In addition, these cells, called “CAR-T”, seem capable of targeting, in the tumor, diseased cells not carrying this antigen while sparing healthy cells. These results, to read in the journal Cancer Immunology Researchconstitute a first step towards the development of clinical trials on humans.
Glioblastomas have biological characteristics that make them particularly difficult to treat. Capable of inducing a micro-environment limiting the attack of the immune system, they escape standard treatments and quickly recur.
Denis Migliorini, assistant professor in the Department of Medicine of the Faculty of Medicine of UNIGE, holder of the ISREC Foundation Chair in the immunology of brain tumors, member of the Center for research translational onco-hematology (CRTOH) and associate physician, head of the Neuro-oncology Unit at HUG, is a specialist in “CAR-T cells“, or chimeric antigen receptor T cells.
This immunotherapy consists of taking T lymphocytes – immune cells – from the sick person, then genetically modifying them in the laboratory in order to provide them with antibodies capable of detecting elements specific to tumor cells before reinjecting them so that they can attack the tumor in a targeted manner.
“We have been seeking for several years to identify the protein markers expressed by the cells making up these malignant gliomas,” 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 was a first step towards effective CAR-T against these tumors.”
mRNA to make a tailor-made cell
Most CAR-T cells are generated using viral vectors, a technique which has proven itself in certain diseases but is poorly suited for brain. “They persist for a very long time in blood cell cancers. However, the brain is a fragile organ and this persistence may generate a risk of toxicity“, explains Darel Martinez Bedoya, post-doctoral student in Denis Migliorini’s laboratory and first author of this work. The scientists then introduced, into the T lymphocytes, the messenger RNA specific to the desired antibody. The cellular machinery takes charge then to produce the right protein to make the receptor which will be placed on the surface of the lymphocyte and will recognize the tumor target.
“This technique has many advantages. CAR-T offers a flexible platform: they allow multiple adaptations depending on the specificities and evolution of the tumor,” explains Darel Martinez Bedoya.
Efficacy and safety
To verify that CAR-T only attacks tumor cells, the Geneva team first tested them in vitroon healthy and diseased cells.
“We were pleasantly surprised to note that not only did the CAR-T not attack healthy cells, but that they were also capable, through proximity effect, of identifying and fighting diseased cells not carrying the PTPRZ1 marker”, rejoices Denis Migliorini. “In this context, CAR-Ts are likely capable of secreting pro-inflammatory molecules that mediate the elimination of tumor cells, even in the absence of the original marker.”
The second step consisted of testing the treatment in vivo with mouse models of glioblastoma. Tumor growth was controlled, effectively extending the life of the mice remarkably without signs of toxicity. “We administered the CAR-T directly into the tumor. This allows us to use fewer cells and greatly reduces the risk of peripheral toxicity.
All the signals are green to now consider a first clinical trial on humans,” conclude the scientists.
