A research team has discovered a way to increase the effectiveness of CAR-T cell immunotherapy by inhibiting metabolic mechanisms, thereby prolonging the cells' ability to fight cancer. The study found that blocking this mechanism of CAR-T cells helps them convert into memory T lymphocytes, thereby providing longer-lasting anti-tumor immune protection.
Researchers in western Switzerland have discovered how to enhance the anti-tumor ability of CAR-T cells, an artificial immune "super cell" that could be used to fight blood cancers.
Among existing immunotherapies, the use of "CAR-T" cells to treat certain blood cancers has shown significant efficacy, but only half of patients receive this treatment. One of the main reasons is the premature dysfunction of these immune cells that have been engineered in vitro.
A collaborative research team from the University of Geneva (UNIGE), the University of Lausanne (UNIL), the University Hospital of Geneva (HUG) and the University Hospital of Canton Vaud (CHUV), all part of the Swiss Cancer Center Lehmann (SCCL), has found a way to prolong the function of CAR-T cells. By inhibiting a very specific metabolic mechanism, the research team successfully created CAR-T cells with enhanced immune memory that could fight tumor cells for longer.
These very promising results were recently published in the journal Nature.
CAR-T cell immunotherapy refers to extracting immune cells (usually T lymphocytes) from cancer patients, modifying them in the laboratory to enhance their ability to recognize and fight tumor cells, and then reinjecting them into the patient. However, as with other types of immunotherapy, many patients do not respond to treatment or relapse.
CAR-T cells must be propagated on a large scale before they can be administered, explains Mathias Wenes, the researcher who coordinated the study. The combination of the patient's medical history and the expansion process exhausts the cells: they reach a state of terminal differentiation, prompting the end of their life cycle without giving them time to act. He works in the laboratory of Professor Denis Migliorini, Department of Medicine, Faculty of Medicine, University of Iquique, and Department of Oncology, Harbin Institute of Technology.
Common mechanisms of cancer cells and immune cells
In the absence of oxygen, cancer cells adopt a very specific survival mechanism: they metabolize the amino acid glutamine as an alternative energy source through a chemical reaction called 'reductive carboxylation'. ''The metabolisms of immune cells and cancer cells are quite similar, which allows them to proliferate rapidly. Here we indeed found that T cells also use this mechanism," explains Alison Jaccard, first author of the study and a doctoral student in the laboratory of Professor Ping-Chih Ho at the Department of Oncology at UNIL-CHUV.
To study the role of reductive carboxylation, the scientists inhibited this mechanism in CAR-T cells in mouse models of two blood cancers, leukemia and multiple myeloma. "Our modified CAR-T cells reproduced normally and did not lose their ability to attack, suggesting that reductive carboxylation is not important for them," Mathias-Venes concluded.
Curing mice with these CAR-T cells
What's more, mice treated with this method were nearly cured of their cancer, a result that far exceeded the team's expectations. Without reductive carboxylation, cells no longer differentiate as well as before and can maintain anti-tumor function longer. "Even more, and this is central to our discovery, they tend to convert into memory T lymphocytes, immune cells that retain the memory of tumor elements that need to be attacked."
Memory T lymphocytes play a key role in secondary immune responses. They retain the memory of previously encountered pathogens and can be reactivated when the pathogen reappears—as a virus, but also as a tumor pathogen—to provide longer-lasting immune protection. The same principle applies to CAR-T cells: the greater the number of memory cells, the more effective the anti-tumor response and the better the clinical effect. Therefore, the differentiation status of CAR-T cells is a key factor in the success of treatment.
The DNA in each of our cells is about two meters long when unfolded. To fit into the tiny cell nucleus, DNA is packed around proteins called histones. For gene transcription to occur, specific regions of DNA need to unfold, and this is accomplished by changing histone proteins.
When T cells are activated, histones change. On the one hand, they condense the DNA and prevent gene transcription, ensuring longevity. On the other hand, they open the DNA, allowing gene transcription to drive their inflammatory and killing functions. Reductive carboxylation directly acts on the generation of metabolites, that is, changes the small chemical elements of histones, thereby affecting the packaging of DNA and preventing the entry of longevity genes. Inhibiting reductive carboxylation keeps these genes open and promotes their conversion into long-lived memory CAR-T.
Is clinical application just around the corner?
"The inhibitor that the scientists used to block reductive carboxylation is a drug already approved for the treatment of certain cancers. Therefore, we propose to repurpose it to expand its use and to grow more powerful CART cells in vitro. Of course, their efficacy and safety will need to be tested in clinical trials, but we have high hopes," the authors concluded.
Without the network established by the Lehmann Cancer Center in Switzerland, this potentially translatable work would never have been possible. In fact, no less than four Lehmann Institute laboratories have joined forces for this influential project: they are: the UNESCO Institute for Lifelong Learning (UNIL), the French Center for Advanced Study (CHUV), the French Université de Supérieure des Engineering Supérieures (UNIGE) and the German Institute of Higher Education (HUG). Alliances between these institutions facilitate collaboration among research groups, resulting in synergies in complementary areas (tumor metabolism, tumor immunology, immune cell engineering).