The graft-versus-host reaction can be prevented
Researchers at Baylor College of Medicine, together with colleagues from the Houston Methodist Clinic and the Texas Children's Clinic, found that a single application of a drug harmless to the body makes it possible to neutralize the severe and often fatal side effect of haploidentical (from a semi–compatible donor - for example, one of the parents) hematopoietic stem cell transplantation.
During haploidentical transplantation of hematopoietic stem cells, the donor and recipient cells coincide only by 50% in the genes of the major histocompatibility complex (MHC, Major Histocompatibility Complex). Therefore, such patients are at high risk of developing a potentially fatal complication known as the "graft versus host reaction" (GVHD), in which the T-lymphocytes contained in the transplant attack the recipient's tissues, whose immune system was destroyed during pre-transplant preparation. At the same time, the removal of all T-lymphocytes from the transplant significantly increases the risk of developing other serious side effects: transplant rejection, relapse of the disease and severe viral infections.
The authors proposed a fundamentally new approach to solving this problem, which consists in introducing not "natural", but genetically modified donor T-lymphocytes to the patient. These cells are carriers of the "molecular switch" represented by the gene of the induced caspase-9 activated by a single application of the biologically inert compound AP1903. This procedure makes it possible to cope with GVHD in the shortest possible time due to self-destruction (apoptosis) of donor T-lymphocytes that are out of control and attacking the recipient's tissues. At the same time, T-lymphocytes remain in the recipient's body, providing protection from viral infections.
A total of 12 patients aged 2 to 50 years who underwent haploidentical hematopoietic stem cell transplantation participated in the clinical study conducted by the authors. During the period from 30 to 90 days after transplantation, all patients were injected with genetically modified donor T-lymphocytes with the gene of induced caspase-9.
Four patients developed GVHD, the symptoms of which disappeared 6-48 hours after a single administration of AP1903. During the next 90 days of follow-up, the symptoms of GVHD did not resume, while the T-lymphocytes preserved in the body provided effective protection of patients from viruses.
Unexpectedly for themselves, the authors found that the technique they developed ensured the destruction of uncontrolled T-lymphocytes not only in peripheral blood, but also in the central nervous system. They came to this conclusion based on the fact that meningitis, which developed in one of the patients against the background of acute GVHD, also resolved quickly after administration of the drug AP1903.
Currently, commercial forms of AP1903 and the "switch gene" of induced caspase-9 activated by it are being developed by Bellicum Pharmaceuticals.
The results of the work were presented at the annual congress of the American Society for Gene and Cell Therapy held on May 13-16 in New Orleans.
Article by Xiaoou Zhou et al. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation is published in the journal Blood.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Baylor College of Medicine:
Safety switch preserves beneficial effects of cell therapy.
18.05.2015