The TAC Advantage
Normal T Cell Activation
The TCR complex, illustrated above, is a structure consisting of the TCR heterodimer in complex with the four chains of the CD3 and a co-receptor (CD4 or CD8). Together the TCR and co-receptor bind to peptides presented on the cell surface by major histocompatibility complex (MHC) proteins. The co-receptor brings the protein kinase LCK in proximity to the TCR and CD3, where it can phosphorylate immunoreceptor tyrosine-based activation motifs (ITAMs) on the TCR complex as one of the initial steps in T cell activation. The TCR evolved to be able to provide a nuanced and regulated activation of T cells, acting more as a rheostat or dimmer than a simple on-off switch.
Activation of CAR-T Cells
Although the CAR construct incorporates activation motifs found on pieces of the TCR, it presents these stimulatory domains to the cells in a synthetic and artificial manner, stripped from the normal context of the TCR. Indeed, the CAR completely bypasses the TCR in activating T cells. The robustness of T cell activation provided by the second generation CARs (featuring the CD3ζ activating domain plus a second co-stimulatory domain, either CD28 or 4-1BB) has generated very impressive efficacy in clinical trials of several different CD19-targeted CARs, but this efficacy has been accompanied by toxicities related to exuberant secretion of cytokines and “on-target, off-tumor” reactivity of CAR-T cells with normal tissues.
The TAC Advantage
As illustrated in this schematic, the TAC receptor is designed to interact with the TCR complex in a way that redirects the TCR from an MHC-bound peptide to a cell-surface antigen recognized by the TAC. In this manner, the integrative function of the TCR complex is preserved, and T cell activation can be regulated in the rheostat-like manner normally dictated by the TCR.
Using TAC Technology to Attack Cancer Cells
At Triumvira Immunologics, we are reprogramming the immune system to attack cancer cells. In order to do this, we use genetic engineering to redirect T cells, an important component of the immune system, to recognize proteins found on the surface of cancer cells. We use T cells taken from a patient, engineer them to express our T cell-Antigen Coupler (TAC), then expand them and then administer the modified cells back to patients, where they will find the cancer cells and kill them. Triumvira’s TACs are a completely novel and innovative approach to reprogramming T cells, which we believe offer important advantages over the approach taken by other companies.