Inducible T-cell receptor expression in precursor T cells for leukemia control

被引:7
作者
Hoseini, S. S. [1 ]
Hapke, M. [1 ]
Herbst, J. [1 ]
Wedekind, D. [2 ]
Baumann, R. [3 ]
Heinz, N. [4 ]
Schiedlmeier, B. [5 ]
Vignali, D. A. A. [6 ]
van den Brink, M. R. M. [7 ]
Schambach, A. [5 ]
Blazar, B. R. [8 ]
Sauer, M. G. [1 ]
机构
[1] Hannover Med Sch, Dept Pediat Hematol Oncol & Blood Stem Cell Trans, Hannover, Germany
[2] Hannover Med Sch, Dept Cent Anim Lab, Hannover, Germany
[3] Clin Radiat Oncol, Hannover, Germany
[4] Paul Ehrlich Inst, LOEWE Res Grp Gene Modificat Stem Cells, Langen, Germany
[5] Hannover Med Sch, Dept Expt Hematol, Hannover, Germany
[6] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA USA
[7] Mem Sloan Kettering Canc Ctr, Dept Immunol & Med, New York, NY 10021 USA
[8] Univ Minnesota, Ctr Canc, Minneapolis, MN USA
基金
美国国家卫生研究院;
关键词
STEM-CELLS; MHC BARRIERS; ANTIGEN; CANCER; IMMUNOTHERAPY; TRANSPLANTATION; RECONSTITUTION; IMMUNITY; THYMUS; MOUSE;
D O I
10.1038/leu.2015.20
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:1530 / 1542
页数:13
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