Customised immune cells used to fight brain cancer

Glioblastoma is one of the most aggressive types of brain cancer, with a five-year survival rate of less than 5% and all available treatments proving disappointing. Now, a team from the University of Geneva (UNIGE) and the Geneva University Hospital (HUG) has developed CAR-T cells — ie, genetically modified immune cells manufactured in the laboratory — that are capable of destroying glioblastoma cells, as detailed in the Journal for ImmunoTherapy of Cancer.

Glioblastoma presents as a mass in the brain, consisting of tumour cells but also other types of cells, as is the case in most cancers. “However, glioblastoma is unique in that it contains very few T cells — the immune cells that are able to recognise cancer cells and destroy them,” said Valérie Dutoit, a researcher at the UNIGE Faculty of Medicine.

“This is why glioblastoma, unlike melanoma or certain lung cancers, for example, does not respond to standard immunotherapies. Our approach is therefore to provide the patient with the missing T cells by generating them in the laboratory.”

The production of CAR-T cells involves taking T cells from the blood of the patient, modifying them in the laboratory to enable them to identify and destroy tumour cells, and then re-injecting them. As explained by Denis Migliorini, a professor in the UNIGE Faculty of Medicine and Head of the Neuro-oncology Unit at the HUG, “This approach is based on identifying tumour-specific proteins that T cells can target without affecting healthy cells — a task that is particularly complex in the case of glioblastoma, which is characterised by a high cellular heterogeneity.”

Migliorini continued: “In a previous study, we identified an important target, the PTPRZ1 marker, which is present on the surface of certain tumour cells. However, attacking glioblastoma on a single target is not enough to avoid the risk of relapse.”

The team is now strengthening its arsenal with a new target associated with glioblastoma: the Tenascin-C (TNC) protein, produced and released into the tumour environment. It constitutes the extracellular matrix — a kind of jelly in which tumour cells are immersed. By targeting Tenascin-C, CAR-T cells trigger a series of pro-inflammatory reactions that induce the death of the cells that produce it.

“Furthermore, we have been able to demonstrate that CAR-T cells are capable of locally destroying cancer cells that do not produce Tenascin-C, which amplifies their activity without any risk of deleterious effects on healthy cells,” Migliorini said.

One of the problems encountered by scientists is the emergence of resistance mechanisms, which lead to the rapid exhaustion of CAR-T cells. Dutoit noted, “By identifying three markers of cell exhaustion and counteracting their activity, we were able to significantly prolong the efficacy of CAR-T cells in mice with glioblastoma used as models of the human disease” — with the positive results of this study making it possible to consider a clinical trial.

“Our goal is to generate genetically modified immune cells against several targets at once in the hope of reaching as many cancer cells as possible,” Migliorini said. “It will also involve adjusting CAR-T cells to each patient in order to eradicate as many cells as possible, even when facing tumour heterogeneity.”

Image credit: iStock.com/Rasi Bhadramani