The following is a summary of “CYAD-01, an autologous NKG2D-based CAR T-cell therapy, in relapsed or refractory acute myeloid leukaemia and myelodysplastic syndromes or multiple myeloma (THINK): haematological cohorts of the dose escalation segment of a phase 1 trial,” published in the March 2023 issue of Lancet Haematology by Sallman et al.
CYAD-01 is a natural killer (NK) group 2D (NKG2D) receptor-based autologous chimeric antigen receptor (CAR) T-cell product that binds eight ligands that are overexpressed in a variety of haematological malignancies but are largely absent on non-neoplastic cells. A single low-dose infusion of CYAD-01 was evaluated clinically in patients with relapsed or refractory acute myeloid leukemia, myelodysplastic syndromes, and multiple myeloma, providing evidence for the approach’s viability and prompting further investigation of CYAD-01. The purpose of this research was to establish the feasibility of administering CYAD-01 in phase 2 without preconditioning or bridging chemotherapy, and to establish the recommended dose range for this setting. Patients with at least one prior line of therapy and relapsed or refractory acute myeloid leukemia, myelodysplastic syndromes, or multiple myeloma were eligible to participate in the open-label, dose-escalation, phase 1 THINK study. Patients were gathered from five different healthcare facilities in the US and Belgium.
The dose-escalation phase used a 3 + 3 Fibonacci study design, with three infusions at 2-week intervals followed by potential consolidation treatment consisting of three additional infusions, to evaluate three dose levels: 3 × 108 (dose level one), 1 × 109 (dose level two), and 3 × 109 (dose level three) cells per infusion. The primary endpoint was the incidence of dose-limiting toxicities following CYAD-01 infusion across the entire treated population. ClinicalTrials.gov identifier: NCT03018405; EudraCT identifier: 2016-003312-12; completed trial registration. Twenty-five patients were enrolled in the haematological dose-escalation segment between February 6, 2017, and October 9, 2018. Manufacturing failed for seven patients due to low yield, and screening failed for two others. The CYAD-01 treatment group included 16 people (three with multiple myeloma and three with acute myeloid leukaemia at dose level one; three with acute myeloid leukaemia at dose level two; and six with acute myeloid leukaemia and one with myelodysplastic syndromes at dose level three). After a median of 118 days (IQR 46–180).
There were 7 patients (44%), who experienced treatment-related adverse events of grade 3 or 4. Five patients, or 31%, across all doses experienced cytokine release syndrome of grade 3 or 4. The third-level toxicity due to cytokine release syndrome was reported once. There were no treatment-related fatalities, and MTD was not reached. Of of 12 individuals with relapsed or refractory acute myeloid leukemia or myelodysplastic syndromes, 3 (25%). Two patients with acute myeloid leukemia who responded to CYAD-01 went on to receive allogeneic haematopoietic stem-cell transplantation (HSCT), and both are currently in long-term remission (5 and 61 months). Without preconditioning, a multiple-infusion regimen of CYAD-01 is well tolerated and displays anti-leukemic efficacy, although it does not last long. The results of this phase 1 study provide credence to the feasibility of using CAR T-cell therapy to target NKG2D ligands. In order to enhance anti-tumor activity, more clinical trials utilizing NKG2D-based CAR T-cells are necessary, maybe through the use of combinatorial antigen targeting methods.