CYAD-101

Overview

CYAD-101 is an investigational, non–gene-edited, allogeneic CAR T-cell therapy that co-expresses an NKG2D-based CAR and a TCR Inhibitory Molecule (TIM) peptide to suppress endogenous TCR signaling and reduce graft-versus-host disease (GvHD) risk. Development focused on microsatellite-stable (MSS) metastatic colorectal cancer (mCRC). As of October 2022, the sponsor discontinued clinical development after earlier FDA clinical hold–related delays; no new safety signal was cited by the company. (ascopubs.org)

Mechanism of action

• Targeting: The CAR uses the human NKG2D receptor, which recognizes eight stress‑induced ligands frequently upregulated on tumor cells: MICA, MICB, and ULBP1–6. (journals.aai.org)
• Allogeneic platform: TIM is a truncated CD3ζ peptide that incorporates into the TCR complex to blunt TCR signaling, enabling use of donor-derived cells with reduced alloreactivity; preclinical work showed preserved NKG2D CAR‑mediated antitumor activity without GvHD in mice. (ascopubs.org)
• Manufacturing: Clinical-grade CYAD‑101 lots (predominantly CD4+ phenotype) were generated from a single donor for the first‑in‑human program. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Phase 1 (alloSHRINK; NCT03692429) in unresectable mCRC evaluated three CYAD‑101 infusions given after each FOLFOX cycle (dose-escalation, n=15):
- Objective responses: 2 confirmed partial responses (including one in a KRAS‑mutant tumor).
- Disease control: 9 stable diseases (7 lasting ≥3 months); disease control rate 73% (11/15).
- Time-to-event: Median PFS 3.9 months; median OS 10.6 months (dose‑escalation cohort).
These data were reported in ASCO abstracts and company scientific updates. (ascopubs.org)

No efficacy readout from the subsequent Phase 1b KEYNOTE‑B79 (CYAD‑101 + FOLFOX followed by pembrolizumab) has been reported. (globenewswire.com)

Safety

• alloSHRINK (n=15): No dose‑limiting toxicities, no grade ≥3 treatment‑related adverse events, and no GvHD reported. (ascopubs.org)
• KEYNOTE‑B79 (Phase 1b): Dosing/enrollment were voluntarily paused on February 28, 2022 after two fatalities with similar pulmonary findings; the FDA placed a clinical hold on March 1, 2022 and lifted it on August 1, 2022 after eligibility changes. Later, the sponsor discontinued CYAD‑101 development for strategic/financial/medical reasons and stated there were no new safety concerns leading to the decision. (celyad.com)

Further reading

• ASCO GI 2021 abstract: Updated alloSHRINK results and methodology. (ascopubs.org)
• ASCO 2020 abstract: First clinical experience and product characteristics. (ascopubs.org)
• Preclinical/early clinical rationale for TIM-based NKG2D CAR T (JCO abstract). (ascopubs.org)
• Clinical‑grade manufacture and preclinical validation (Cytotherapy, 2022). (pubmed.ncbi.nlm.nih.gov)
• KEYNOTE‑B79 first‑patient‑in and trial design. (globenewswire.com)
• FDA clinical hold and subsequent lift; program discontinuation (company updates). (celyad.com)

Notes: Program status reflects public updates through October 12, 2022; no later human efficacy data were identified. (celyad.com)

Last updated: Oct 2025