Researchers have developed a method to “remove” a blood system affected by leukemia and at the same time build a new, healthy system with donor blood stem cells. writing in the diary NatureThe team reports promising results obtained in experiments with animals and with human cells in the laboratory.
In aggressive cases of leukemia, the only chance for a cure is to replace the diseased blood system with a healthy one. Although donor blood stem cell transplantation is a well-established form of treatment, it is an onerous process for patients. First, chemotherapy is used to eliminate the body’s own blood stem cells, as well as most blood cells. Only then do the treating doctors administer stem cells from a suitable donor to the patient intravenously. This procedure is associated with side effects and possible complications.
The team led by Professor Lukas Jeker from the Department of Biomedicine at the University of Basel has taken a different approach. writing in the diary NatureThe team describes how all of a leukemia patient’s blood cells can be selectively removed while building a new blood system. The results represent the successful completion of a project funded by the European Research Council with a consolidation grant of €2.4 million.
Mixing console for blood systems
The system developed by researchers on Jeker’s team can be imagined as a mixing console, where a DJ gradually lowers the level of the first song while increasing the volume of the second until the first track is completely turned off and only the second.
The attenuation process works as follows: specific antibodies coupled to a cytotoxic drug recognize all blood cells in the patient’s body based on a surface structure. This marker is common to all different types of blood cells (both healthy and diseased), but does not appear in other cells in the body. In this way, the antibody-drug conjugate recognizes and gradually destroys all the cells of the diseased blood system.
While this is happening, the second song also begins: the patient receives a transplant of new, healthy blood cells from a suitable donor. To prevent antibody-drug conjugates from also attacking new blood stem cells, or the blood cells they produce, researchers use genetic engineering techniques to specifically modify the donor stem cells. Specifically, they introduce a small change to the surface molecule so that the antibodies do not recognize the new blood cells. Researchers refer to this targeted modification of donor stem cells as “shielding,” because it acts as a protective shield against cancer treatment.
Elaborate search for suitable regulators
The first two authors of the study, Simon Garaudé and Dr. Romina Matter-Marone, worked with an interdisciplinary team of bioinformaticians, biochemists, genetic engineering specialists, and clinicians from academia and industry to select the most suitable target structure and the The best protective modification for the fading process, coming from the multitude of surface molecules on blood cells. The chosen molecule, called CD45, showed great promise in laboratory tests with mice and human cells.
“We needed a surface molecule that appeared with approximately the same frequency on all blood cells, if possible, including leukemic cells, but was not present on other cells in the body,” explains Jeker. CD45 fulfilled this requirement and at the same time was also suitable for “protection”, that is, it could be modified in the donor’s blood stem cells in such a way that these cells were protected from cancer treatment, but the function of CD45 was remained completely normal.
Applications beyond cancer
“The new approach could pave the way for new treatment options for patients whose health status is incompatible with the chemotherapy necessary for stem cell transplant,” says joint first author Romina Matter-Marone. Although more testing and optimization is needed, the goal is for the first clinical trials to begin within a few years.
The “mixing console for blood systems” also opens up new possibilities, as joint first author Simon Garaudé explains: “We show how cells that are ‘invisible’ to a blood cell extractor can be used to change the entire blood system.” This, he says, is an important step toward a programmable blood system that could also take on functions on demand, for example to correct a serious genetic defect or impart resistance to specific viruses such as HIV.