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.
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
A. Flament, F.F. Lehmann, C. Lonez: Employee: Celyad SA. All other authors have declared no conflicts of interest.