Prevent recurrence of leukemia
The adjustment of donor T cells prevented the return of acute myeloid leukemia
Svetlana Yastrebova, N+1
American oncologists have tested a way to significantly reduce the frequency of relapses of acute myeloid leukemia after its treatment with donor hematopoietic cells. To do this, after transplantation of such cells, patients still need to inject donor T-lymphocytes, on the surface of which there are receptors for the WT1 protein. Article by Chapuis et al. T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant published in Nature Medicine.
Acute myeloid leukemia (AML) is a malignant tumor of a part of the hematopoietic tissue from which white blood cells, such as lymphocytes, are formed. AML is amenable to chemotherapy, but very often returns. In case of relapse, patients undergo transplantation of donor blood cells, however, this does not always prevent future exacerbations of the disease.
Over time, T-lymphocytes can develop from the donor's hematopoietic cells in the host body, which in theory can give an immune response to the tumor. However, no one checks them for the ability to attack malignantly degenerated cells or the inability to kill healthy tissues around the tumor. It turns out that the frequency of AML relapses and transplant complications can be reduced if the donor's T-lymphocytes are selected for the ability to find cell tags characteristic of this disease and neutralize their owners. Such "selected" cells could be injected after hematopoietic cell transplantation.
One of the characteristic markers of acute myeloid leukemia is the WT1 protein (Wilms tumor antigen) encoded by the gene of the same name. It promotes the division and growth of tumor cells in AML and some similar diseases. Like any other protein, you can "incite" T cells on WT1, then it will be neutralized. To do this, the T cells must have receptors for WT1.
Philip D. Greenberg and his colleagues from the Cancer Research Center named after Fred Hutchinson was selected from the donor cells of those T-lymphocytes on which there were receptors for the antigens characteristic of AML. A group of CD8+ T cells reacting to the Epstein–Barr virus was isolated from them. This very common virus reproduces especially well in leukemia-affected cells, which means that T-lymphocytes tuned against it will mainly affect tumors, and not the tissues around. Receptors for the WT1 protein were injected into these selected cells, after which 12 patients with a high risk of relapse of acute myeloid leukemia who had recently received donor hematopoietic cells were transplanted.
At least 44 months after the introduction of modified T cells, none of this group of subjects with AML had a return of the disease. During the same period, in a control group of 88 people with a similar risk of relapse, who were not injected with hematopoietic T-lymphocyte cells after transplantation, leukemia reappeared in 54 percent of cases. The researchers periodically assessed the number of living donor T cells in the subjects, and it remained at a high level for a long time, which indicates their good survival. Additional selection for sensitivity to the Epstein–Barr virus, according to the authors, will help to combat viral diseases in patients.
The authors of the study will test its results on a larger number of patients, moreover, this time they will be divided into groups randomly, and in the described series the division was not randomized. Scientists note: it is necessary to assess whether the effect of preventive administration of T-lymphocytes against WT1 is reproduced, whether this procedure has side effects, and so on. According to the plan, clinical trials of the method will be completed in 2030.
The introduction of T-cells with a modified set of receptors to fight various tumors has been actively studied and improved over the past few years. In this case, both donor lymphocytes and the cells of the patients themselves are used. It was modified T-lymphocytes that became the first approved means of gene therapy in the United States.
Portal "Eternal youth" http://vechnayamolodost.ru