Improved RNA-based engineering of T lymphocytes with leukemia-specific T cell receptors to redirect their effector functions: towards a clinically safe platform to evaluate efficacy and potential off-target toxicity.

The extraordinary specificity of T lymphocytes for their antigen turns them into highly attractive and targeted immunotherapeutics. However, the scarcity of tumor-reactive T cells in cancer patients and the difficulty of their expansion in sufficient numbers for adoptive immunotherapy are substantial hurdles to broaden their clinical application. Transient introduction of a T cell receptor (TCR) specific for a pre-defined tumor-associated antigen by means of RNA-engineering into unselected bulk T cells would instantaneously confer redirected anti-tumor specificity to a large number of effector T cells for adoptive immune therapy with a built-in safety switch. This research project aims to investigate the generation, in vitro validation and preclinical testing of a set of Wilms' tumor 1 (WT1)-specific TCRs derived from leukemia patients that responded successfully to a therapeutic WT1 vaccine. On the short term, we are confident that this research project will provide a sound basis for exploratory and translational phase I trials using WT1-specific TCR mRNA-engineered T cells to study the safety (on- & off-target off-tumor effects) and feasibility of adoptive T cell therapy in patients with WT1-positive hematological malignancies. On the long term, adoptive T cell therapy using redirected T cells is poised to become a new treatment paradigm for both hematological and solid cancer patients at risk of relapse, if needed in combination with other antitumor therapies.

Keywords:LEUKEMIA

Disciplines:Systems biology, Hematology, Laboratory medicine