Phase I studies assessing the safety and clinical activity of multiple doses of a NKG2D-based CAR-T therapy, CYAD-01, in metastatic colorectal cancer
Bibliographic record
Abstract
Background: Chimeric antigen receptor T-cell (CAR-Ts) therapies have yet to demonstrate positive results in the context of solid tumors likely because of the inability of classical CAR-Ts to infiltrate into the tumor and overcome the hostile immune suppressive tumor microenvironment (TME). CYAD-01, a NKG2D receptor-based CAR-T, is currently evaluated in the ongoing THINK study (NCT03018405) without preconditioning therapy in both hematologic and solid indications, and demonstrated encouraging signs of clinical stabilization in refractory metastatic colorectal (mCRC) and ovarian cancer patients. These preliminary results prompted us to design a clinical development plan evaluating CYAD-01 in multiple settings. Trial design: To improve the likeliness to observe clinical activity of CYAD-01 in metastatic solid tumors, the SHRINK (NCT03310008) and the LINK (NCT03370198) trials have been designed to address, respectively, the challenge related to the immunosuppressive TME and difficulty of CAR-T cells to access the site of metastases. The SHRINK trial is evaluating the multiple infusion CYAD-01 treatment i.v. administered concurrently to a standard-of-care FOLFOX neoadjuvant treatment for the treatment of mCRC disease with potentially resectable liver metastases, with the aim to (i) favor infiltration into the immunosuppressive TME but also (ii) provide an opportunity for the CYAD-01 cells to better engraft due to the lymphodepletion induced by the FOLFOX, and likely (iii) increase the NKG2D ligand expression in tumor tissues targeted by CYAD-01. The LINK trial is evaluating multiple hepatic transarterial administrations of CYAD-01 in mCRC patients with unresectable liver metastases with the potential advantage of a lower systemic toxicity and higher and more persistent concentration of the infused cells on the TME compared to systemic administration and difference in blood supply between uninvolved liver parenchyma and metastases. Finally, the boosting of the adaptive immune response by CYAD-01 might control distant lesions due to a possible abscopal effect. Both studies were initiated in 2018 and the first patients were successfully enrolled. Clinical trial identification: NCT03310008, EudraCT: 2017-000616-41; NCT03370198, EudraCT 2017-000959-11. Legal entity responsible for the study: Celyad SA. Funding: Celyad SA. Disclosure: A. Flament, F.F. Lehmann, C. Lonez: Employee: Celyad SA. All other authors have declared no conflicts of interest.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".