Description of the ATTACK Workpackages
Workpackage 1
TCR genes can be derived from T cell clones, and transferred to redirect T cells towards target cells expressing the antigen of interest. Human T cells have been successfully retargeted to various peptide/MHC epitopes present on a variety of tumors and viruses. Despite preclinical successes, clinical TCR gene therapy still awaits serious challenges. The following concerns directly relate to TCR properties and are dealt with in WP1.
- TCR mispairing.
- Compromised expression and/or function.
- Low to intermediate ligand-binding affinity.
Workpackage 2
This Work package focuses on antibody – based chimeric receptors (CR) and the best design and configuration of chimeric receptors.
Accordingly, the main objectives of this WP are to:
- Design and optimise the specificity and functionality of single-chain Fv (scFv) based chimeric receptors.
- Expand the repertoire of scFv-based CR specific to tumour-antigens and generating new, TCR-like scFv.
Workpackage 3
The goal of this WP is to compare the relative efficacy of T cells in vivo. In addition, this workpackage will dissect mechanisms and define strategies that can enhance the in vivo efficacy of redirected T cells.
Wokpackage 4
Planned work in WP4 relates to the following tasks:
- Access homing and persistence and anti-tumour function of retargeted T cells in vivo.
- Enhance the in vivo homing, persistence and anti-tumour function of receptor redirected T cells.
Workpackage 5
The overall aim of this work package is to generate protocols which reproducibly generate specific T cell phenotypes for testing in vivo and potentially for wider ranging pre-clinical and clinical applications.
- T cell activation
- Cytokine impact upon T cell culture
- Transduction of T cells under minimal stimulation
- Development of antigen-specific T cell activation / selection systems
- Regulatory T cell depletion / cytokine secretion studies.
Workpackage 6
The overall aim of Work Package 6 is to identify the risks of receptor-modified T cells and to develop strategies to minimize the risks in clinical applications.
The objectives include:
- Evaluation of immunogenicity of engineered T cells.
- Evaluation of autonomous growth of receptor-modified T cells in vivo upon continuation stimulation with antigen.
- Elimination or receptor-modified T cells by a novel suicide switch and monitoring side effects in vivo.