Results from the Completed Dose-Escalation of the Hematological Arm of the Phase I Think Study Evaluating Multiple Infusions of NKG2D-Based CAR T-Cells As Standalone Therapy in Relapse/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients

CYAD-01 cells are engineered T-cells expressing a chimeric antigen receptor (CAR) based on the natural full-length human natural killer group 2D (NKG2D) receptor fused to the intracellular domain of CD3ζ. NKG2D receptor binds to 8 ligands (MICA/B, ULBP1-6) expressed by a large variety of malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

The hematological arm of the Phase I THINK study (NCT03018405) evaluates the safety and clinical activity of multiple CYAD-01 infusions (inf) without any prior preconditioning chemotherapy in r/r AML, MDS and multiple myeloma (MM) patients (pts). Three dose levels (DL) were evaluated: 3x10⁸, 1x10⁹ and 3x10⁹ T-cells/inf. The first cycle of the treatment consists of 3 CYAD-01 infusions every 2 weeks and a potential 2^nd cycle of 3 CYAD-01 infusions every 2 weeks if the patient is not in progressive disease (PD) at the end of the 1^st cycle. Additional cohorts evaluate DL2 and DL3 following a denser treatment schedule for the 1^st cycle of treatment, with the first 3 CYAD-01 infusions administered every week.

As of end of July 2019, 16 pts were enrolled in the dose-escalation segment of the hematological cohort with the initial schedule (CYAD-01 infusions every 2 weeks) for 1^st cycle, now completed. In total (uncleaned database), 7 pts experienced grade (G) 3/4 treatment-related adverse events (AEs). Cytokine release syndrome (CRS) occurred in 7 pts with only 2 pts at DL2 who experienced G3 CRS and 1 pt who experienced G4 CRS at DL3 reported as a dose-limiting toxicity (DLT). All CRS AEs resolved with early tocilizumab treatment. No treatment-related neurotoxicity AEs have been observed. Out of the 10 AML/MDS pts who received at least 3 CYAD-01 infusions and were assessed for clinical activity, 4 showed overall response (OR) at Day 29 of which 1 complete remission (CR) with partial hematologic recovery (CR_h) for > 21 months in a r/r AML pt at DL1, 2 CR with incomplete hematologic recovery (CR_i) for 1 month in AML pt at DL1 and DL3, and 1 marrow CR (mCR) for 1 month in an MDS pt at DL3. 2 AML pts at DL2 had stable disease (SD) for ≥ 3 months with bone marrow (BM) blast percentage decrease. Two other AML pts in DL3 achieved SD for at least 2 months. 2 AML pts did not have evidence of clinical response. The 2 evaluable MM pts did not show evidence of clinical response.

As of end of July 2019, 8 pts were enrolled in cohorts with the dense schedule (4 in DL2 and 4 in DL3). Recruitment at 3x10⁹ T-cells/inf. is still ongoing and is expected to be completed by the time of presentation. At DL2 (uncleaned database), only 1 pt out of 4 experienced a study treatment-related G4 AE (infusion related reaction). The 3 other pts experienced G1 or 2 study treatment-related AEs, with 3 pts who experienced G1/2 CRS. One AML pt reached a stable disease at the Day 32 tumor evaluation. At DL3, 2 out of 4 currently enrolled pts experienced study treatment related G3 AE (CRS) after their first CYAD-01 infusion. One of these G3 CRS was reported as a dose-limiting toxicity.

Altogether, results obtained to date demonstrate an encouraging safety and tolerability profile of CYAD-01 without preconditioning chemotherapy in pts with r/r hematological malignancies. Encouraging anti-leukemic activity was observed in 6 out of 13 (46%) evaluable r/r AML/MDS pts in the THINK study, presenting relevant decrease in BM blasts. Four objective responses (1 CR_h, 2 CR_i, 1 mCR) were observed with the initial schedule. At DL2, the denser schedule did not modify the safety profile while increasing the area under the curve of CYAD-01 peripheral blood levels, which could suggest a possible impact on clinical activity at DL3, results expected by the time of presentation.