Celyad’s non-edited approach not immune to clinical hold

 For a cell company like Celyad, which has shifted towards off-the-shelf therapies, halting a trial of its lead allogeneic project spells a significant setback. This is especially true given that until now Celyad could argue that having a non-gene-edited approach differentiated it from the likes of Allogene, which suffered a damaging hold as a result of the perceived risk, since allayed, of multiple chromosome edits. Today’s voluntary hold concerns Keynote-B79, a Keytruda combo study of CYAD-101 in colorectal cancer, and comes after the deaths of two separate patients who had “presented with similar pulmonary findings”. CYAD-101 is a T-cell therapy with an NKG2D receptor-based Car, and its monotherapy study, presented at last year’s Asco-GI meeting, showed no dose-limiting toxicity and a 13% response rate in 15 colorectal cancer patients. To disable graft-versus-host reactions CYAD-101 uses a TIM (T-cell receptor inhibitory molecule), and it is notable that this might not be Celyad’s favoured approach; instead, the group has tended to play up shRNA, which is what its other clinical-stage allogeneic asset, CYAD-211, uses to avoid GvHD. Still, it is not clear whether the latest problem might extend beyond CYAD-101, or indeed whether it is even related to CYAD-101.

Celyad's allogeneic Car-T assets
Project	CYAD-101	CYAD-211	CYAD-203	CYAD-221
Target	NKG2D ligands	BCMA	NKG2D ligands (uses IL-18)	CD19
TCR silencing tech	TIM	shRNA	shRNA	shRNA
Clinical trials	AlloShrink (monoRx)	NCT04613557	IND planned mid-2022	None
	Keynote-B79 (Keytruda combo)*
Source: company filings; shRNA=short-hairpin RNA; TIM=TCR inhibitory molecule; *on voluntary clinical hold. https://www.evaluate.com/vantage/articles/news/trial-results-snippets/celyads-non-edited-approach-not-immune-clinical-hold