De presentatie:
CYAD-101: an allogeneic NKG2D CAR T cell therapy using a TCR inhibitory molecule
Sophie AGAUGUE, PhD1, Alexandre Michaux, PhD1, Eytan Breman, MSc1, Sebastien Mauen, PhD1, David Gilham, PhD1
1Celyad SA, Mont Saint Guibert, Belgium
362
Background Chimeric antigen receptor (CAR) T cells have demonstrated impressive clinical results in B cell malignancies. Most CAR T cell therapies rely on autologous peripheral blood cells that present some challenges including manufacturing time and product variability. Allogeneic T cells derived from a healthy donor may circumvent these issues. However, allogeneic T cells can induce graft versus host disease (GvHD), a response triggered by the recognition of non-self Human Leukocyte Antigen molecules expressed on recipient cells by the T Cell Receptor (TCR) of donor cells. To avoid GvHD, we targeted the TCR signalling by using a TCR inhibitory molecule (TIM) peptide consisting of a truncated form of CD3zeta. Our mechanistic studies suggest that TIM is acting as a dominant negative form of CD3zeta reducing downstream TCR signaling pathway activity. To assess TIM in the context of a CAR therapy, an allogeneic CAR T cell was developed by co-expressing TIM and a NKG2D-based CAR (referred as CYAD-101).
Methods CYAD-101 CAR T cells were produced from five different healthy donors. In vitro and in vivo experiments have been performed to evaluate the culture parameters, phenotype, alloreactivity and potency against NKG2D ligand-expressing tumor targets.
Results In vitro experiments confirmed the suppression of TCR alloreactivity of the TIM-combined CAR as compared to control cells. However, the CYAD-101 T cells showed variability between donors in terms of CD4/CD8 ratio and percentage of central and effector memory populations potentially relating to the variability of the starting material to produce CAR T cells. In addition, harvested CYAD-101 cells were mainly composed of a non-activated and nonexhausted population (i.e. CD25-/CD69- and PD1/LAG3-). A concomitant reduction in the level of phospho-ZAP-70 was observed in cells expressing the
TIM. Importantly, in vitro cytotoxicity and cytokine production of CYAD-101 cells upon co-culture with NKG2D ligand-expressing tumor cell lines was not affected by the insertion of TIM. Finally, compared to control T cells, CYAD-101 cells efficiently delayed in vivo tumor progression and increased survival of NSG mice bearing orthotopic colorectal tumors while avoiding the induction of GvHD.
Conclusions Following these promising preclinical results showing the combination of effective anti-cancer activity and inhibition of alloreactivity of CYAD-101 CAR T cells, a phase I clinical trial will be shortly initiated to assess the safety, cell kinetics and clinical activity of CYAD101 CAR T cells in patients with unresectable metastatic colorectal cancer.