Up to now, fungal infections of the lungs have been difficult to treat. Find out here how a secret weapon from cancer therapy might help.
Genetically modified T cells with a chimeric antigen receptor (CAR) – so-called CAR-T cells – are already being used to treat cancer, particularly in the case of leukemia or Lymphomen. The T cells of the immune system are reprogrammed in such a way that they specifically recognize and destroy cancer cells. A research team at the University Hospital of Würzburg has now developed a chimeric antigen receptor in T cells that mimics the structures of a mold – Aspergillus fumigatus – specifically recognizes and can effectively support the immune response once morest the fungus.
Mushroom on a trip around the world
The spores of the fungus are distributed worldwide and can get into the lungs when you breathe. They are harmless in a healthy immune system, but can lead to severe, often fatal infections in people with a severely weakened immune system, for example following chemotherapy. Also in combination with a Covid infection or Flu can Aspergillus fumigatus significantly impair lung function. The new treatment approach might make it possible in the future to treat fungal infections of the lungs effectively and possibly with few side effects. the Results are now in the journal Science Translational Medicine appeared.
“To date, CAR-T cell therapy is already being used in numerous centers around the world for oncology and hematology purposes. It is a large area of application that has developed very quickly in recent years,” says Prof. Jürgen Löffler. Together with Prof. Michael Hudecek, he is the last author of the study and head of the Löffler group, which has been researching invasive fungal infections for over 20 years. “However, the method has so far hardly been used for infectious diseases. There are a few studies on viruses and hardly any research on fungal infections.”
However, it is a major clinical problem that Aspergillus infections of the lungs have not been well managed so far. “Current therapies have many side effects and can lead to liver damage, for example,” reports Löffler. “In addition, it can be used during therapy Azol-Antimykotika how Voriconazol develop resistance. Therefore, there is a great clinical need to develop new treatment approaches. That was also the motivation for our study.”
T-cells recognize fungus – and initiate attack
For the first time, the research team genetically modified T cells in such a way that they carry a chimeric antigen receptor on their surface, which has a specific target – a molecule segment of an antigen – in the cell wall of Aspergillus fumigatus recognizes. To do this, they first had to find a specific target that would activate the T cells and produce significant effects on them. “The method for generating T cells with a chimeric antigen receptor is already well established,” reports Dr. Michelle Seif, postdoc in the Löffler group and the Hudecek group and first author of the study. “But finding a good, precise target was a lot of work and took regarding a year.”
In laboratory studies and in vivo in two different mouse models, the researchers found that the T cells with the Aspergillus-smoked-specific CARs (Af-CARs) migrate to the site of the fungal infection and are found there in large numbers. It was also shown that they recognize certain structures of the mold very well and take effective action once morest them by releasing endogenous messenger substances, so that the burden of the fungus on the lungs is significantly reduced. “In addition to this direct antifungal effect of the T cells, we also observed an indirect effect,” explains Seif. “In the preclinical laboratory models, we found that the Aspergillus-smoked-specific CAR-T cells Cytokine produce, which activate other cells of the immune system – in particular macrophageswhich enhance the immune system’s action once morest the mold.”
This coordinated reaction of the immune cells is important because the fungus can be fought more effectively in this way, emphasizes Löffler. “Our study illustrates the great potential of genetically modified T cells. It forms the basis for a future T-cell therapy for the treatment of fungal infections and many other infectious diseases that are difficult to control with conventional therapies,” says the researcher.
What regarding side effects?
In further steps, the scientists want to prepare the newly developed CAR-T cell therapy for clinical use and evaluate its effectiveness in the first clinical studies. “We are aware that the production of the genetically modified cells is complex and expensive and that various approvals are required for clinical use,” says Löffler. “But we are convinced that this can be a better and more effective therapy than previous treatment approaches for severe fungal infections.”
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But might such a therapy also have side effects? CAR-T cell therapies can lead to overactivation of the immune system and a dangerous Cytokine Release Syndrome or to one Graft-versus-host disease come, in which the immune cells attack the organism of the recipient. “One advantage of the approach we developed, however, is that the CAR-T cells are very specific to Aspergillus fumigatus react and presumably not attack human or other cells,” reports Seif. “In fact, we have not observed any undesirable side effects in animal models and have not been able to determine any binding of our CAR structure to human tissue in vitro.” Löffler emphasizes getting a grip. “Of course, these should also be used in newly developed therapies, for example once morest fungal infections,” says the scientist.
mission allow for further fungi and infections
Further steps in their research might be the effectiveness of other immune cells, such as natural killer cells, once morest Aspergillus fumigatus and to apply the principle of CAR-T cell therapy to other fungi or infectious diseases. “That might be mushrooms of order, for example Mucorales which are very aggressive and difficult to treat in patients with compromised immune systems. They call one Mukormykose emerged, which, among other things, occurred as a complication of corona infections in India,” explains Löffler.
Image source: Guido Blokker, unsplash.
