Customised cells to fight brain cancer

Visualisation of cell death induced by CAR-T cells. A real-time imaging experiment (images taken at 0, 5 and 10 minutes) shows a CAR-T cell in contact with a glioblastoma cell (artificially marked in green). This contact causes the CAR-T cell to concentrate granules (lytic granules, shown in pink) containing the proteins necessary for the death of the target cell. These proteins penetrate the cancer cell and induce its death. After 10 minutes, the cancer cell begins to die, as indicated by the loss of its structure (evidenced by the appearance of "bubbles").
Image Credit: © Denis Migliorini

With a five-year survival rate of less than 5%, glioblastoma is one of the most aggressive types of brain cancer. Until now, all available treatments, including immunotherapy — which involves strengthening the immune system to fight cancer— have proved disappointing. CAR-T cells are genetically modified immune cells manufactured in the laboratory and designed to identify and destroy cancer cells. By targeting a protein present in the tumor environment, a team from the University of Geneva (UNIGE) and the Geneva University Hospital (HUG) has developed CAR-T cells capable of destroying glioblastoma cells. Their efficacy in an animal model of the disease paves the way for clinical trials in humans. These results are published in the Journal for ImmunoTherapy of Cancer. 

Valérie Dutoit, Privat-Docent, Department of Medicine, Translational Research Centre in Onco-Haematology (CRTOH), Faculty of Medicine, UNIGE. 
Photo Credit: Courtesy of UNIGE

Glioblastoma is present as a mass in the brain, consisting of tumor 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 recognize cancer cells and destroy them,’’ says Valérie Dutoit, a researcher in the Department of Medicine and the Translational Research Centre in Onco-Hematology (CRTOH) 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.’’ 

This approach is based on identifying tumor-specific proteins that T cells can target without affecting healthy cells. 

High-precision cells 

The production of CAR-T cells (for chimeric antigen receptor T cells) involves taking T cells from the blood of the patient, modifying them in the laboratory to enable them to identify and destroy tumor cells, and then re-injecting them. ‘‘This approach is based on identifying tumor-specific proteins that T cells can target without affecting healthy cells, a task that is particularly complex in the case of glioblastoma, which is characterized by a high cellular heterogeneity,’’ explains Denis Migliorini, professor in the Department of Medicine and at the CRTOH of the UNIGE Faculty of Medicine and head of the neuro-oncology unit at the HUG. ‘‘In a previous study, we identified an important target, the PTPRZ1 marker, which is present on the surface of certain tumor cells. However, attacking glioblastoma on a single target is not enough to avoid the risk of relapse.’’ 

Denis Migliorini, Assistant Professor, ISREC Foundation Chair in Brain, Tumour Immunology, Department of Medicine, Translational Research Centre in Onco-haematology (CRTOH). © UNIGE UNIGE Faculty of Medicine Attending physician Head, Neuro-oncology Unit, HUG Department of Oncology
Photo Credit: Courtesy of UNIGE

The team is now strengthening its arsenal with a new target associated with glioblastoma: the Tenascin-C (TNC) protein, produced and released into the tumor environment. It constitutes the extracellular matrix – a kind of jelly in which tumor 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,’’ says Denis Migliorini. 

 Overcoming tumor resistance 

One of the problems encountered by scientists is the emergence of resistance mechanisms, which lead to the rapid exhaustion of CAR-T cells. ‘‘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,’’ enthuses Valérie Dutoit. 

 The very positive results of this study now make 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,” says Denis Migliorini. This clinical study is expected to begin in about a year and will take place in Geneva and Lausanne. ‘‘It will also involve adjusting CAR-T cells to each patient to eradicate as many cells as possible, even when facing tumor heterogeneity.’’ 

Published in journal: Journal for ImmunoTherapy of Cancer

Title: Targeting the extracellular matrix with Tenascin-C-specific CAR T cells extends survival in preclinical models of glioblastoma

Authors: Jana de Sostoa, Eliana Marinari, Martin Pedard, Valérie Widmer, Suzel Davanture, Karl Schaller, Stephanie Tissot, Michele De Palma, Benita Wolf, Gertraud Orend, Valérie Dutoit, Denis Migliorini

Source/Credit: Université de Genève

Reference Number: imgy112025_01

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