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

Area of Science:

• Immunology
• Cell Biology
• Oncology

Background:

• Leukemia relapse is a significant concern after hematopoietic stem cell transplantation.
• T-cell receptor (TCR) engineered T cells show promise for leukemia immunotherapy.
• Controlling TCR expression is crucial to prevent negative selection and autoimmunity.

Purpose of the Study:

• To investigate the use of inducible TCR expression in engineered precursor T cells (preTs) for leukemia immunotherapy.
• To assess the anti-leukemia efficacy and safety of TCR-engineered preTs.
• To determine the optimal timing of transgene induction for T-cell development and function.

Main Methods:

• Engineering precursor T cells (preTs) with leukemia-reactive TCRs under an inducible promoter.
• Administering engineered preTs to mice and inducing transgene expression at different time points.
• Evaluating anti-leukemia effects, T-cell memory formation, and graft-versus-host disease (GVHD).
• Analyzing the impact of transgene induction timing on T-cell differentiation and selection.

Main Results:

• Engineered preTs demonstrated potent anti-leukemia effects and provided protection against leukemia challenges.
• Adoptive transfer of allogeneic TCR-transduced preTs mediated anti-leukemia activity without causing GVHD.
• Early transgene induction promoted CD8(+) T-cell development, efficient positive selection, and abrogated the endogenous T-cell repertoire.
• Late induction favored CD4(+) T-cell differentiation and failed to generate a leukemia-reactive population.

Conclusions:

• Inducible TCR expression in preTs offers a controllable immunotherapeutic strategy against leukemia.
• TCR-engineered preTs can elicit potent anti-leukemia responses and generate memory cells.
• The timing of transgene induction critically influences T-cell development, selection, and therapeutic efficacy.