Two patients have died after receiving Celyad Oncology’s off-the-shelf CAR-T cell therapy CYAD-101. The colorectal cancer patients had similar pulmonary findings, prompting Celyad to voluntarily pause the trial while it investigates the events.
Celyad is studying the allogeneic NKG2D CAR-T in patients with unresectable metastatic colorectal cancer in the phase 1b trial. Participants in the trial, which is aiming to enroll 34 subjects, receive CYAD-101 and a chemotherapy regimen followed by Merck’s checkpoint inhibitor Keytruda. The goal is to generate data on dose-limiting toxicities and the objective response rate.
Having begun the trial late last year, Celyad has now paused work to buy time to review the safety data. Celyad is investigating the two deaths and “evaluating any similar events in additional patients treated on study.” The pause is voluntary, but Celyad is talking to regulators and may need to take further action.
The pause comes months after the now-resolved FDA hold on all Allogene Therapeutics’ off-the-shelf CAR-T trials. Celyad’s safety concerns appear to have a narrower focus. While Celyad has paused the trial of CYAD-101, it doesn’t expect the safety signal to have any impact on other candidates that feature a different allogeneic technology.
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CYAD-101 uses a T-cell receptor inhibitory molecule (TIM) to prevent graft-versus-host disease (GvHD). By engineering cells to co-express TIM, Celyad provides a competitive inhibitor to wild-type CD3ζ and thereby interferes with signaling that drives GvHD. An earlier phase 1 trial provided evidence that Celyad was on the right track, with none of the 25 subjects suffering dose-limiting toxicities.
While the TIM-based candidate cleared its first clinical test, Celyad continued to work on an alternative allogeneic technology. CYAD-211, which is being trialed in multiple myeloma, co-expresses a single short hairpin RNA (shRNA) targeting CD3ζ to interfere with the expression of the T-cell receptor without using gene editing. Work on the shRNA-enabled, BCMA-directed cell therapy is continuing.