Journal
HAEMATOLOGICA
Volume 106, Issue 3, Pages 847-858Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2019.233882
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Funding
- Deutsche Forschungsgemeinschaft (DFG)
- Care-for-Rare Foundation (Germany)
- Amon Carter Foundation
- Sutardja Foundation
- Laurie Kraus Lacob Faculty Scholar Award in Translational Research
- Chan-Zuckerberg Biohub
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This study investigates the enhancement of anti-leukemic efficacy of allogeneic hematopoietic stem cell transplantation through gene editing to engineer donor αβ T cells to express CD19-specific chimeric antigen receptors. The results demonstrate efficient elimination of leukemia cells without causing graft-versus-host disease, supporting the potential for this approach in improving outcomes for high-risk leukemias.
Allogeneic hematopoietic stem cell transplantation is an effective therapy for high-risk leukemias. In children, graft manipulation based on the selective removal of alpha beta 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 of recipients in whom allogeneic hematopoietic stem cell transplantation can be used. Leukemic relapse, however, remains a challenge. T cells expressing chimeric antigen receptors can potently eliminate leukemia, including those in the central nervous system. We hypothesized that by engineering the donor alpha beta T cells that are removed from the graft by genome editing to express a CD19-specific chimeric antigen receptor, while simultaneously inactivating the T-cell receptor, 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 integrated a CD19-specific chimeric antigen receptor inframe into the TRAC locus. More than 90% of cells lost T-cell receptor expression, while >75% expressed the chimeric antigen receptor. The initial product was further purified with less than 0.05% T-cell receptor positive cells remaining. In vitro, the chimeric antigen receptor 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 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 alpha beta T-cell-derived, genome-edited T cells expressing CD19-specific chimeric antigen receptors could enhance the anti-leukemic efficacy of alpha beta T-cell-depleted haploidentical hematopoietic stem cell transplantation without increasing the risk of graft-versus-host disease.
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