Hi-TIDe : T cell engineering

Our research focuses on the development of gene-engineered T cells, tailored to treat specific tumors, that enable or promote:

1. tumor-targeting
2. productive T-cell signaling and metabolic activity under suppressive conditions
3. tumor microenvironment (TME) re-programming to foster immunity
4. safety

We have developed a variety of novel chimeric antigen receptors (CARs ; hybrid receptors that activate T cells upon tumor antigen binding), as well as T-cell receptors (TCRs), for T-cell engineering purposes, having strong clinical potential in terms of specificity, functionality and safety. We have also identified several promising molecules, both natural and rationally modified (and either expressed intracellularly or secreted) for improved in vivo tumor control and survival following the adoptive transfer of co-engineered TCR/CAR T cells (Figure 1). These molecules either directly promote T-cell activity and/or other protective immune infiltrate, and/or block/counteract various inhibitory mechanisms (low pH, cAMP, check-point ligands, etc.) in specific TMEs.

Moreover, important advances have been made by our group in vector design and T-cell transduction methodologies for improved gene-expression.

We have also developed a robust pre-clinical protocol for low-dose irradiation, rationally and optimally combined with immunotherapeutic drugs and antibodies based on TME characterization (gene-upregulation identified by Nanostring, qPCR, flow cytometry, immunohistochemistry etc.), for the treatment of advanced ovarian cancer which has been used as the rationale for a proposed clinical trial at the CHUV. Thanks to the Human-Tumor Immunology Discovery Engine (H-TIDE) platform, and close synergy between the CHUV-UNIL-SIB-EPFL, we have an unprecented opportunity to link patient bedside to benchwork & computer modeling in order to develop cutting-edge and powerful combinatorial immunotherapies to help cure patients. 

• Irving M, et.al.,. 2017. Engineering CAR T-Cells for Racing in Solid Tumors; Don't Forget the Fuel. Front Immunol 8;267

• Lanitis, E, et. al., 2017. Mechanisms regulating T-cell infiltration and activity in solid tumors. Ann Oncol.; in press

• Santoro SP, et.al., 2014. T Cells Bearing a Chimeric Antigen Receptor against Prostate-Specific Membrane Antigen Mediate Vascular Disruption and Result in Tumor Regression. Cancer Immunol 3(1); 68-84

• Irving M, et. al., 2012. Interplay between T cell receptor binding kinetics and the level of cognate peptide presented by major histocompatibility complexes governs CD8+ T cell responsiveness. J Biol Chem 287(27);23068-78

• Irving M, et. al., 2010. Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function. J Immunol 184; 4936-4946