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The idea of genetically modifying a patient's own immune cells and deploying them against infections and tumors has existed since the 1980s. But to date, modified T cells are still not as effective as natural T lymphocytes and have had only a limited clinical value. With the help of the new CRISPR-Cas9 gene editing tool, a team at the Technical University of Munich (TUM) has developed T cells that are very similar to physiological immune cells.
There are two forms of T cell therapy: either a recipient receives donor cells, or his own T cells are removed, genetically reprogrammed in the lab and released against an infection or tumor in the body. Although the first method has been proven in clinical models, reprogramming of T cells still faces problems.
Modification of T cell receptors
The team led by Professor Dirk Busch, Director of the TUM Institute for Medical Microbiology, Immunology and Hygiene, generated for the first time modified T cells that are very similar to their natural counterparts and could resolve some of these problems. To do this, they used the new CRISPR-Cas9 gene scissors, which can be used to cut and replace targeted segments of the genome.
Conventional methods and new methods target both the main T-cell targeting instrument called the T-cell receptor. The cell-surface receptor recognizes specific antigens badociated with pathogens or cells. tumor cells, which T cells can then attack. Each receptor is composed of two linked molecular chains. The genetic information of the chains can be engineered to produce new receptors capable of recognizing any desired antigen. In this way, it is possible to reprogram the T cells.
Targeted exchange using CRISPR-Cas9 gene scissors
The problem with conventional methods is that the genetic information of the new receptors is inserted randomly into the genome. This means that T cells are produced with new and old receivers or with receivers having an old and a new chain. As a result, cells do not function as efficiently as physiological T cells and are also controlled differently. In addition, mixed chains may cause dangerous side effects (graft vs. host disease, GvHD).
"By using the CRISPR method, we were able to completely replace the natural receptors with new ones, because we were able to insert them at the same place in the genome, and we replaced the information from both channels. there are more mixed receivers, "says Kilian Schober, lead author of the new study with his colleague Thomas Müller.
Quasi natural properties
Thomas Müller explains the benefits of modified T cells: "They look much more like physiological T cells, but can be flexibly modified, they are controlled like physiological cells and have the same structure but can be genetically modified." scientists have demonstrated in a cell culture model that T-lymphocytes thus modified behave almost exactly like their natural counterparts.
"Another advantage is that the new method allows the simultaneous modification of several T cells so that they are able to recognize different targets and can be used in combination.This is particularly interesting for the treatment of cancer because the tumors are very heterogeneous, "Dirk Busch adds. In the future, the team plans to study the new cells and their properties in preclinical mouse models, a milestone in the preparation of clinical trials in humans.
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More information:
Profile of Professor Dirk Busch
http: // www.
Institute of Medical Microbiology, Immunology and Hygiene (German only)
http: // www.
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Contact:
Dr. Dirk Busch
Technical University of Munich
Institute of Medical Microbiology, Immunology and Hygiene
T: +49 (0) 89 4140-4120
[email protected]
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