2023-09-27 04:00:07
A team in French-speaking Switzerland has discovered how to improve the anti-tumor power of CAR-T cells, artificial immune “super-cells” used to fight blood cancers.
Immunotherapy treatment involves helping the immune system to fight tumors or strengthen it. But many patients do not respond to current treatments or relapse.
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In immunotherapy, the use of so-called “CAR-T” cells has proven extremely effective once morest certain blood cancers, but in only half of patients. The cause in particular is the rapid dysfunction of these immune cells artificially modified in the laboratory.
A team from the universities of Geneva (UNIGE), Lausanne (UNIL), the University Hospitals of Geneva (HUG) and the Vaud University Hospital Center (CHUV), under the aegis of the Swiss Cancer Center Léman (SCCL), discovered how extend their functionality. By inhibiting a very specific metabolic mechanism, it created CAR-T cells with reinforced immune memory, capable of fight once morest tumor cells much longer. Very promising results, read in the journal Nature.
“CAR-T” cell immunotherapy involves taking immune cells – usually T lymphocytes – from a person suffering from cancer, modifying them in the laboratory to increase their ability to recognize and fight tumor cells, then to reinject them. However, as with other types of immunotherapies, many patients do not respond to treatment or relapse.
“CAR-T cells must be massively multiplied before being administered,” explains Mathias Wenes, assistant professor in the laboratory of Professor Denis Migliorini in the Department of Medicine of the UNIGE Faculty of Medicine, who led this work . “But the medical history of the patients combined with this amplification process exhausts the cells: they reach a state of terminal differentiation which precipitates the end of their life cycle without giving them time to act on the length (The length of an object is the distance between its two most extremities…).”
A mechanism common to cancer and immune cells
In lack of oxygen, cancer cells resort to a very particular survival mechanism: they metabolize glutamine, an amino acid (Glutamine is one of the 20 amino acids in the genetic code. Its chain…), an amino acid ( An amino acid is an organic molecule with a carbon skeleton and…), as an alternative source of energy to a chemical reaction called “reductive carboxylation”. “However, immune cells and cancer cells have a fairly similar metabolism (Metabolism is the set of molecular and energetic transformations…) which allows them to proliferate very quickly. We have discovered that T lymphocytes also use this mechanism”, indicates Alison Jaccard, doctoral student in the laboratory of Professor Ping-Chih Ho in the UNIL-CHUV Department of Oncology, first author of this study.
To decipher the role of this mechanism, scientists inhibited it in CAR-T cells in mice, in models of leukemia and multiple myeloma (Multiple myeloma of bones (better known as Kahler’s disease , or, simply,…), two blood cancers. “Our modified CAR-T cells multiplied normally and did not lose their attack capacity, indicating that reductive carboxylation is not essential for them,” summarizes Mathias Wenes .
Mice cured thanks to these CAR-T
In addition, the mice treated in this way were almost cured of their cancer, a result well beyond the expectations of the research team. “Without reductive carboxylation, the cells no longer differentiate as much and retain their anti-tumor function for longer. And even – and this is the heart of our discovery – they tend to transform into memory T lymphocytes, a type of cell immune system which preserves the memory of the tumor elements to be fought.”
Memory T cells play a key role in the secondary immune response. Indeed, they retain the memory of previously encountered pathogens and can reactivate when they reappear – as in the case of a virus, but also when it comes to tumor pathogens – ensuring much more lasting immune protection. “This same principle is found in CAR-T cells: the higher the number of memory cells, the more effective the anti-tumor response and the more favorable the clinical outcome. The state of differentiation of CAR-T cells therefore constitutes a key element of the success of the treatment.”
Dialogue between metabolism and gene expression
Unfolded, the DNA contained in each of our cells would measure approximately two meters long. To fit into the tiny cell nucleus, it is condensed around proteins called histones. For gene transcription to occur, specific regions of DNA must unfold, which occurs by modifying histones.
When T cells are activated, histones undergo modifications which, on the one hand, condense the DNA and prevent the transcription of genes ensuring longevity and, on the other hand, open and allow the transcription of genes ensuring their longevity. inflammatory and destructive function.
Reductive carboxylation acts directly on the generation of metabolites, small chemicals that modify histones, to influence DNA packaging and prevent accessibility to longevity genes. Its inhibition keeps these genes open and promotes their transformation into long-lived CAR-T.
Soon a clinical application?
The inhibitor used by scientists to inhibit reductive carboxylation is a drug already approved in the treatment of certain cancers. “We therefore propose to reposition it to broaden its use and produce more powerful CART cells in vitro. Of course, their effectiveness and safety must be tested in clinical trials, but we have very good hopes!”, conclude authors.
An example of what the Swiss Cancer Center Léman can achieve
This work with significant application potential would never have been possible without the network set up by the SCCL. In fact, laboratories from no less than four Lake Geneva institutes have joined forces to carry out this impactful project: UNIL, CHUV, UNIGE and HUG. The alliance between these institutions promotes collaborations between groups which allow synergies in complementary fields (tumor metabolism, onco-immunology, engineering (Engineering designates all functions ranging from design and studies to… ) immune cells).
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