Abstract CT129: The THINK clinical trial: Preliminary evidence of clinical activity of NKG2D chimeric antigen receptor T cell therapy (CYAD-01) in acute myeloid leukemia

NKG2D is a receptor with specificity for a broad range of stress ligands expressed on the majority of tumors (MICA, MICB and ULBP1-6). In vivo preclinical studies in acute myeloid leukemia (AML), ovarian, multiple myeloma (MM) and pancreatic cancer models all showed potent efficacy of T cells engrafted with a NKG2D Chimeric Antigen Receptor (CAR) indicating the possible effectiveness of CYAD-01 (a.k.a NKR-2) in the clinic. To evaluate the susceptibility of several malignancies to NKG2D ligand targeting in a clinical setting, and the safety of CYAD-01, an open-label phase I THINK (THerapeutic Immunotherapy with NKR-2, NCT03018405) trial was initiated. CYAD-01 was administered three successive times with 2-week intervals, and without prior lymphodepletive conditioning, in refractory or relapsed patients with different metastatic solid tumors and hematological malignancies (AML/MDS and MM), which failed from standard treatments. The study was designed to have two segments. The first dose escalation segment (3+3 design) includes three dose levels: 3x10 8 , 1x10 9 and 3x10 9 CYAD-01 per injection, in both solid and hematological arms. The second, open-label phase I expansion segment of the study will evaluate the recommended dose in each tumor type. By December 2017, within the solid tumor arm, 4 patients had received three CYAD-01 administrations at dose-level 1 and three patients had received three CYAD-01 administrations at dose-level 2 and completed the safety period with no DLT occurrence. Within the hematologic arm, two AML patients and 1 MM patient have received the three CYAD-01 administrations at dose-level 1 and completed the safety period with no dose-limiting toxicity (DLT) occurrence. One relapsed AML patient to salvage CLAG-M chemotherapy reached a morphologic leukemia-free state (MLFS) after the CYAD-01 treatment, and resolution of symptoms with improved hematopoiesis at 3 months follow up at which time he started conditioning therapy for allo-HSCT. At 3 months post allo-HSCT, the patient is in complete remission with 100% donor chimerism. Interestingly, even at this early stage of the evaluation, there is variation in the phenotype of the CYAD-01 cells ( e.g. CD4/CD8 ratio) and an early observation of a relative increase in the systemic levels of SDF-1 and RANTES in the patient who achieved MLFS. In summary, we report the first objective response to CAR-T in r/r AML using CYAD-01 without preconditioning chemotherapy and with no significant toxicities, highlighting the potential of targeting NKG2D ligands in AML. Citation Format: David A. Sallman, Jason B. Brayer, Xavier Poire, Tessa Kerre, Philippe Lewalle, Eunice S. Wang, Bikash Verma, Eytan Breman, Marco Davila, Nathalie Braun, Caroline Lonez, David E. Gilham, Frederic F. Lehmann. The THINK clinical trial: Preliminary evidence of clinical activity of NKG2D chimeric antigen receptor T cell therapy (CYAD-01) in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT129.