T cell receptor Inhibitory Molecule (TIM) is a small peptide that interferes with the ability of the T cell receptor to signal and eventually drive GvH responses
TIM is a truncated form of the CD3ζ component of the TCR complex which lacks important signaling domains of the wild-type CD3ζ. In our CYAD-100 series of CAR T candidates, TIM is co-expressed in our constructs to reduce the potential of the TCR to induce Graft-versus-Host Disease (GvHD). Following the expression of TIM, the peptide acts as a competitive inhibitor to wild-type CD3ζ and is incorporated into the TCR complex. Preclinical data to date have demonstrated that inclusion of TIM into the TCR complex interferes with the signaling potential of the TCR.
The expression of TIM results in the competitive inhibition of CD3ζ and reduces signaling of the TCR complex
Proof-of-concept using TIM technology
TIM has been optimized to function with our NKG2D CAR T candidates, including CYAD-101. Preliminary results from the Phase 1 alloSHRINK trial evaluating CYAD-101 in advanced colorectal cancer patients has demonstrated proof-of-concept that the non-gene edited TIM technology has the potential to knockdown signaling of the TCR complex, with no clinical GvHD observed in the first fifteen patients treated with CYAD-101 in the alloSHRINK trial.