26 May 2020

Hematopoietic and leukaemic stem cells could be selectively eliminated using immunotherapy instead of chemotherapy, a new Swiss study has suggested.

Researchers from the University of Zurich have developed CAR-T cells which, when implanted into mice, accurately targeted both acute myeloid leukaemia (AML) initiating cells and healthy haematopoietic stem cells from humans. They now want to test the new immunotherapy in human trials as soon as possible, as a potential replacement for chemotherapy conditioning regimes ahead of stem cell transplants.

Acute myeloid leukaemia patients are usually treated with intensive chemotherapy and sometimes radiotherapy, after which they require a transplant of hematopoietic stem cells from a healthy donor. However, there are serious side effects associated with the treatment, making it unsuitable for many patients.

Writing in the journal Leukaemia, the team of scientists and physicians from the University of Zurich, the University Hospital Zurich and ETH Zurich reveal they have used CAR-T therapy to eliminate the leukaemic and hematopoietic stem cells more selectively.

The CAR-T cells recognise the CD117 antigen, which is highly expressed on AML cells and healthy haematopoietic stem cells. After the therapy has eliminated these cells, the CAR-T cells are then terminated using a combination therapy of rituximab and ATG, an antibody treatment which neutralises T cells. The patient can then receive a donor stem cell transplant to restore haematopoiesis.

Study leader Professor Markus Manz, professor of medicine at UZH and director of the Department of Medical Oncology and Haematology at USZ, said: “Compared to normal strategies, our method works very selectively, meaning that mature blood cells and other tissues are spared.”

The results were achieved using cell cultures in the lab and in mice with human blood and cancer cells, but Professor Manz is confident that the treatment could also be effective in humans.

“The principle works: It is possible to eliminate, with high precision, the leukaemic and hematopoietic stem cells in a living organism,” he said.

Researchers are now testing to see if the method is only possible with CAR-T cells or also with simpler constructs, such as T cell-activating antibodies.

Prof Manz said if the method also works with humans, it could eventually replace chemotherapy and reduce the side effects associated with it.


 

Source: Myburgh R, Kiefer JD, Russkamp NF, Magnani CF, Nuñez N, Simonis A, Pfister S, Wilk CM, McHugh D, Friemel J, Müller AM, Becher B, Münz C, van den Broek M, Neri D, Manz MG (2020) “Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells”, Leukemia, doi: 10.1038/s41375-020-0818-9.

 

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