Gentle transplantation
For leukemias, lymphomas and other oncological diseases of the blood, stem cell transplantation is the gold standard of medical care. The procedure involves replacing the patient's own hematopoietic stem cells with donor stem cells. Before transplantation, the patient is subjected to intensive chemotherapy or radiation therapy to completely destroy his stem cells. This so-called conditioning regime frees up space for incoming donor stem cells, helps to remove atypical cells remaining in the body, and weakens the patient's immune system so that it cannot attack donor stem cells. However, the high toxicity and suppression of the immune system caused by the conditioning regime expose patients to a high risk of infections, organ damage and other life-threatening undesirable effects.
Researchers from Washington University School of Medicine in St. Louis have developed and successfully tested on mice a method of stem cell transplantation that does not require radiation or chemotherapy. Instead, an immunotherapeutic approach is used, combining the targeted destruction of hematopoietic stem cells in the bone marrow with immunomodulatory drugs that prevent the rejection of donor stem cells by the immune system. Using the new technique, mice successfully underwent stem cell transplantation from unrelated mice without signs of dangerously low blood cell count, bleeding, organ damage and secondary infections, which are a hallmark of the traditional procedure. The potential benefits of the new strategy are of particular importance for bone marrow transplantation or gene therapy in patients with non-oncological diseases, for example, sickle cell anemia, when it is important to avoid the toxicity of chemotherapy or radiation associated with conditioning.
As an alternative to high-dose chemotherapy and radiation therapy, the group used cytotoxic drugs, attaching them to antibodies targeting specific surface proteins that are expressed mainly on bone marrow stem cells. The resulting conjugates bind to these specific proteins, then are absorbed by stem cells, only then the drug is released and, ultimately, cell death occurs. Using a derivative of the vegetable poison ricin saporin as an active ingredient, the researchers created two different drugs to target two specific proteins found on the surface of blood stem cells. This minimizes the risk of unintentional destruction of other cell types.
On the right is the bone marrow of a mouse after exposure to radiation therapy followed by infusion of donor T cells that attack the bone marrow. On the left is the bone marrow of a mouse after transplantation using a new method. In this case, the donor T cells do not damage the recipient's bone marrow.
To prevent a rejection reaction from the recipient's immune system of donor cells, the researchers injected mice with an immunosuppressive component, the janus kinase inhibitor (IAC) baricitinib, which is approved by the FDA for the treatment of rheumatoid arthritis. They found that baricitinib stops the recipient's immune cells, including T-lymphocytes and natural killer cells, from attacking donor stem cells.
By combining IAC with antibody and drug conjugates, the researchers achieved successful stem cell transplantation between two completely unrelated mouse lines. They also showed that the new technique made it possible to achieve the "graft against leukemia" effect, when the immune cells of donors attack cancer cells and ignore healthy tissues, and avoid the "graft against the host" reaction. According to the researchers, immunological rejection did not develop in mice, because the IACS suppressing immunity prevented it, which is another unique and significant advantage of this approach.
The group found that it is possible to gradually reduce the effect of IAC and, as soon as the donor stem cells replace the original cells, completely turn them off.
To understand whether this relatively simple and minimally toxic regime is suitable for humans, additional studies need to be conducted, including on other animal models of leukemia. The authors have applied for a patent for a combination of drug antibody conjugates with janus kinase inhibitors for graft conditioning.
The article by S.P.Persaud et al. Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation is published in the Journal of Clinical Investigation.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Washington University School of Medicine: New technique may lead to safer stem cell transplants.