Abstract CT123: A phase I study assessing the safety and clinical activity of multiple doses of a NKG2D-based CAR-T therapy, CYAD-01, administered concurrently with the neoadjuvant FOLFOX treatment in patients with potentially resectable liver metastases from colorectal cancer

We recently developed a novel chimeric antigen receptor (CAR) T-cell therapy, called CYAD-01 (a.k.a. NKR-2), incorporating the full-length human natural killer receptor NKG2D fused with the human CD3 zeta signaling domain, which associates with the adaptor molecule DAP10 to provide co-stimulatory signal upon ligand binding. CYAD-01 is currently evaluated in the ongoing THINK study (NCT03018405) without preconditioning therapy in both hematological and solid indications. Classical CAR-Ts has yet to demonstrate positive results in the context of solid tumors. Underlying reasons for this reduced clinical activity include the need to extravasate from the peripheral circulation, infiltrate into the tumor and overcome the hostile immune suppressive tumor microenvironment (TME) to deliver anti-tumor effector responses. To address the challenge related to the immunosuppressive TME, the SHRINK trial (Standard cHemotherapy Regimen and Immunotherapy with NKR-2) has been developed to assess the safety and clinical activity of multiple infusion CYAD-01 treatment (every 2 weeks x 3 infusions) in patients undergoing standard-of-care FOLFOX (Folinic acid, Fluorouracil (5-FU) and Oxaliplatin) chemotherapy, as neoadjuvant treatment, for the treatment of colorectal metastatic disease with potentially resectable metastases (NCT03310008). The FOLFOX treatment is given every two weeks for six cycles and CYAD-01 cells are infused shortly after chemotherapy on cycles 3, 4 and 5. This concurrent administration of chemotherapy and CYAD-01 treatments would not only (i) favor infiltration into the immunosuppressive TME due to the effect of chemotherapy on TME and cancer cells but also (ii) provide an opportunity for the CYAD-01 cells to better engraft due to the lymphodepletion induced by the standard chemotherapy administration, and likely (iii) increase the NKG2D ligand expression in tumor tissues targeted by CYAD-01, even in patients presenting heterogeneity and/or low ligand expression. The study contains two consecutive segments. The dose escalation segment will enroll 9 patients and will evaluate 3 dose levels of CYAD-01 (1x108, 3x108 and 1x109 CYAD-01 per injection) following a 3+3 design. The expansion segment will then enroll 21 additional patients to further evaluate the safety and potential signs of activity of the CYAD-01 therapy when administered concurrently with chemotherapy. Peripheral blood samples, as well as tumor biopsies from patients at baseline and at resection, will be collected to determine, among others, CYAD-01 persistence, NKG2D ligand expression and systemic cytokine levels in peripheral blood post-infusion.