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

Leukemia. 2015 Jul;29(7):1530-42. doi: 10.1038/leu.2015.20. Epub 2015 Feb 5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Flow Cytometry
  • Genetic Engineering
  • Graft vs Host Disease / mortality
  • Graft vs Host Disease / prevention & control*
  • Graft vs Leukemia Effect / immunology*
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Leukemia, Myeloid / immunology*
  • Leukemia, Myeloid / mortality
  • Leukemia, Myeloid / therapy
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Ovalbumin / genetics
  • Precursor Cells, T-Lymphoid / immunology*
  • Promoter Regions, Genetic / genetics
  • Receptors, Antigen, T-Cell / genetics*
  • Receptors, Antigen, T-Cell / immunology
  • Transplantation, Homologous


  • Receptors, Antigen, T-Cell
  • Ovalbumin