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Genome editing of donor-derived T-cells to generate allogenic chimeric antigen receptor-modified T cells: Optimizing aß T cell-depleted haploidentical hematopoietic stem cell transplantation.
Genome editing of donor-derived T-cells to generate allogenic chimeric antigen receptor-modified T cells: Optimizing aß T cell-depleted haploidentical hematopoietic stem cell transplantation. Haematologica Wiebking, V. n., Lee, C. M., Mostrel, N. n., Lahiri, P. n., Bak, R. n., Bao, G. n., Roncarolo, M. G., Bertaina, A. n., Porteus, M. H. 2020Abstract
Allogeneic hematopoietic stem cell transplantation is an effective therapy for high-risk leukemias. In children, graft manipulation based on the selective removal of aß T cells and B cells has been shown to reduce the risk of acute and chronic graft-versus-host disease, thus allowing the use of haploidentical donors which expands the population that allogeneic hematopoietic stem cell transplantation can be used in. Leukemic relapse, however, remains a problem. T cells expressing chimeric antigen receptors can potently eliminate leukemia, including in the central nervous system. We hypothesized that by modifying donor aß T cells to simultaneously express a CD19-specific chimeric antigen receptors and inactivating the T cell receptor by genome editing, we could create a therapy that enhances the anti-leukemic efficacy of the stem cell transplant without increasing the risk of graft-versus-host disease. Using genome editing with Cas9 ribonucleoprotein and adeno-associated virus serotype 6, we integrate a CD19-specific chimeric antigen receptor in-frame into the TRAC locus. Greater than 90% of cells lost TCR expression, while >75% expressed the CAR. The product was further purified to ultimately have less than 0.05% residual TCR+ cells. In vitro, the CAR T cells efficiently eliminated target cells and produced high cytokine levels when challenged with CD19+ leukemia cells. In vivo, the gene modified T cells eliminated leukemia without causing xenogeneic graft-versus-host disease in a xenograft model. Gene editing was highly specific with no evidence of off-target effects. These data support the concept that the addition of aß T cell-derived, genome edited T cells expressing CD19-specific chimeric antigen receptors could enhance the anti-leukemic efficacy of aß T cell-depleted haploidentical hematopoietic stem cell transplantation without increasing the risk of graft-versus-host disease.
View details for DOI 10.3324/haematol.2019.233882
View details for PubMedID 32241852