Celyad’s off-the-shelf CAR could bypass Crispr
After something of a lull, developing allogeneic – off-the-shelf – cell therapies is popular again, and the US IND granted to Celyad’s non-gene-edited CAR-T approach shows that the FDA is on board, too. Celyad will start a trial of an off-the-shelf version of its lead project, CYAD-01, in colorectal cancer. Rival allogeneic approaches typically use Crispr or Talen to edit out donor cells’ endogenous T cell receptors (TCRs) to prevent graft-versus-host disease; Celyad, on the other hand, aims to achieve this using a TCR-inhibitory molecule co-expressed with the CAR construct – thus avoiding the complication of genome editing. The co-expressed molecule comprises a truncated CD3zeta chain that when incorporated into the endogenous TCR deprives the complex of signalling ability; of course, it not known whether TCR signalling can be sufficiently inhibited in humans this way. The approach is separate from that described in Celyad’s US patents covering more typical TCR-deficient T cells, hotly opposed by Cellectis and licensed to Novartis for use presumably with Crispr. Recent allogeneic tie-ups include Allogene taking over Pfizer’s Cellectis deal and Gilead working with Sangamo on zinc finger-edited CARs, not to mention a flurry of interest in gamma-delta T cells.