title: Inducible T-cell receptor expression in precursor T cells for leukemia control.
abstract: Co-transplantation of hematopoietic stem cells with those engineered to express leukemia-reactive T-cell receptors (TCRs) and differentiated ex vivo into precursor T cells (preTs) may reduce the risk of leukemia relapse. As expression of potentially self-(leukemia-) reactive TCRs will lead to negative selection or provoke autoimmunity upon thymic maturation, we investigated a novel concept whereby TCR expression set under the control of an inducible promoter would allow timely controlled TCR expression. After in vivo maturation and gene induction, preTs developed potent anti-leukemia effects. Engineered preTs provided protection even after repeated leukemia challenges by giving rise to effector and central memory cells. Importantly, adoptive transfer of TCR-transduced allogeneic preTs mediated anti-leukemia effect without evoking graft-versus-host disease (GVHD). Earlier transgene induction forced CD8(+) T-cell development was required to obtain a mature T-cell subset of targeted specificity, allowed engineered T cells to efficiently pass positive selection and abrogated the endogenous T-cell repertoire. Later induction favored CD4 differentiation and failed to produce a leukemia-reactive population emphasizing the dominant role of positive selection. Taken together, we provide new functional insights for the employment of TCR-engineered precursor cells as a controllable immunotherapeutic modality with significant anti-leukemia activity.
authors: Department of Pediatric Hematology/Oncology and Blood Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: S S
authors: SS
authors: Hoseini
authors: Department of Pediatric Hematology/Oncology and Blood Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: M
authors: M
authors: Hapke
authors: Department of Pediatric Hematology/Oncology and Blood Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: J
authors: J
authors: Herbst
authors: Department of Central Animal Laboratory, Hannover Medical School, Hannover, Germany.
authors: D
authors: D
authors: Wedekind
authors: Clinic for Radiation Oncology, Hannover, Germany.
authors: R
authors: R
authors: Baumann
authors: LOEWE Research Group for Gene Modification in Stem Cells, Paul-Ehrlich-Institute, Langen, Germany.
authors: N
authors: N
authors: Heinz
authors: Department of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors: B
authors: B
authors: Schiedlmeier
authors: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: D A A
authors: DA
authors: Vignali
authors: Department of Immunology and Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: M R M
authors: MR
authors: van den Brink
authors: Department of Experimental Hematology, Hannover Medical School, Hannover, Germany.
authors: A
authors: A
authors: Schambach
authors: University of Minnesota Cancer Center and Department of Pediatrics, Division of Blood & Marrow Transplantation, Minneapolis, MN, USA.
authors: B R
authors: BR
authors: Blazar
authors: Department of Pediatric Hematology/Oncology and Blood Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors: M G
authors: MG
authors: Sauer
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D005434:Flow Cytometry; D005818:Genetic Engineering; D006086:Graft vs Host Disease / Q000401:mortality / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007951:Leukemia, Myeloid / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin
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