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Advancing Gentler Cell Therapies for Blood Cancer

Cell therapy.
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In aggressive cases of leukemia, the only chance for a cure is to replace the diseased blood system with a healthy one. Although the transplantation of donor blood stem cells is a well-established form of treatment, it is an onerous process for patients. First, chemotherapy is used to remove the body’s own blood stem cells as well as most of the blood cells. Only then do the attending physicians intravenously administer the stem cells from a suitable donor to the patient. This procedure is associated with side effects and potential 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 journal Nature, the team describes how all blood cells can be removed from a leukemia sufferer in a targeted manner while a new blood system is built up at the same time. The results represent the successful completion of a project funded by the European Research Council with a Consolidator Grant of EUR 2.4 million.

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Mixing console for blood systems

The system established by the researchers in Jeker’s team can be imagined as a mixing console, where a DJ gradually fades down the level of the first song while raising the volume of the second until the first track dies away completely and only the second is audible.

The fading-down 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 the different types of blood cell (both healthy and diseased) but does not appear on other cells of the body. Bit by bit, the antibody-drug conjugate therefore recognizes and destroys all cells of the diseased blood system.

While this is taking place, the second song also starts – that is, the patient receives a transplant of new, healthy blood cells from a suitable donor. To prevent the antibody-drug conjugates from also attacking the new blood stem cells, or the blood cells they produce, the researchers use genetic engineering techniques to modify the donor stem cells in a targeted manner. Specifically, they introduce a small change in the surface molecule so that the antibodies don’t recognize the new blood cells. The researchers refer to this targeted modification of the donor stem cells as “shielding,” because it acts like a protective shield against the cancer treatment.

Elaborate search for suitable regulators

The two first 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 best-suited target structure – and the best protective modification for the fading-down process – from the multitude of surface molecules on blood cells. The chosen molecule, known as CD45, proved extremely promising in trials on mice and human cells in the laboratory.