Interim Results from the Phase I Deplethink Trial Evaluating the Infusion of a NKG2D CAR T-Cell Therapy Post a Non-Myeloablative Conditioning in Relapse or Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients
Authors: Al-Homsi A. Samer , Purev Enkhtsetseg , Lewalle Philippe , Abdul-Hay Maher , Pollyea Daniel A , Salaroli Adriano , Lequertier Thomas , Alcantar-Orozco Erik , Borghese Fabian , Lonez Caroline , Braun Nathalie , Renard Florence , Flament Anne , Moors Ine , Kerre Tessa 
Published: November 2019

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 binds to 8 ligands (MICA, MICAB, and ULBP1-6) over-expressed by a large variety of malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
Phase I DEPLETHINK study (NCT03466320) evaluates the safety and preliminary efficacy of a single CYAD-01 infusion (inf.) after lymphodepletion with cyclophosphamide and fludarabine in patients with relapsed or refractory (r/r) AML and MDS. A second cycle of 3 CYAD-01 infusions without preconditioning could be administered in absence of progressive disease (PD) following the 1st infusion. Three dose-levels (DLs; 1x108, 3x108 and 1x109 cells/inf.) are evaluated in the dose escalation segment. The first DL is also evaluated at two different intervals between preconditioning and CYAD-01 infusion (T7: seven days interval; T3: three days interval) in order to mitigate for any potential increased toxicity due to the administration of lymphodepletion.
As of end of July 2019, 6 patients (4 AML and 2 MDS) were enrolled in the first 2 cohorts which evaluated DL1 (1x108 cells/inf. at T3 or T7) and 3 patients (3 AML) were enrolled in the cohort 3 evaluating DL2 (3x108 cells/inf. at T3). The blasts in the bone marrow of 8 out of 9 patients ranged between 3% and 48% at baseline. Of the 6 patients treated at DL1 (with lymphodepletion administered up to 7 or 3 days before first CYAD-01 infusion), 3 patients experienced grade (G) 1 toxicity (cytokine release syndrome or CRS and diarrhea), or G2 CRS (uncleaned database). The patient with G2 CRS following the first infusion also experienced G4 CRS and G3 CAR T-cell-related encephalopathy syndrome (CRES) during the second inf. at 3x109 cells/inf. One other patient experienced G1 CRS during the second cycle. At DL2, only 1 patient experienced G1 related AEs (diarrhea and CRS) after the first CYAD-01 infusion. Another patient experienced G3 CRS during the second cycle. All patients recovered with treatment including tocilizumab and, when indicated, steroids.
At DL1, two out of 5 evaluable patients reached a stable disease (SD) at day (d) 36, allowing the initiation of the 2nd cycle. At DL2, one patient out of 3 reached SD. The DEPLETHINK study is currently enrolling at DL3 (T3).
Preliminary correlative studies show that the area under the curve at d36 (AUC D1-D36) after a single infusion of CYAD-01 with prior lymphodepletion is better than without preconditioning. Furthermore, the T3 interval between the preconditioning and CYAD-01 provides better engraftment than the T7 interval.
In conclusion, to date, the results demonstrate the safety and tolerability for CYAD-01 doses 1x108 and 3x108 cells/infusion with a prior lymphodepletion in patients with r/r AML and MDS. The T3 interval was therefore chosen for further CYAD-01 evaluations. The improved persistence of CYAD-01 with lymphodepletion, in particular 3 days before infusion, could lead to improved clinical responses. The study is ongoing and further data will be provided at the meeting.

Disclosures
Al-Homsi: Celyad: Membership on an entity's Board of Directors or advisory committees. Abdul-Hay:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pollyea:Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lequertier:Celyad: Employment. Alcantar-Orozco:Celyad: Employment. Borghese:Celyad: Employment. Lonez:Celyad: Employment. Braun:Celyad: Employment. Renard:Celyad: Employment. Flament:Celyad: Employment.