Phase 1 Studies Assessing the Safety and Clinical Activity of Multiple Doses of a NKG2D-Based CAR-T Therapy, Cyad-01, in Acute Myeloid Leukemia
Authors: Brayer Jason B. , Sallman David A , Kerre Tessa , Poire Xavier , Havelange Violaine , Lewalle Philippe , Wang Eunice S. , Selleslag Dominik , Anguille Sebastien , Beguin Yves , Purev Enkhtsetseg , Al-Homsi Ahmad-Samer , Dekker Doreen , Breman Eytan , Sotiropoulou Panagiota A. , Snykers Sarah , Braun Nathalie , Lonez Caroline , Verma Bikash , Lehmann Frédéric F. , Davila Marco L. 
Published: October 2019

Abstract
Introduction:
CYAD-01 is a chimeric antigen receptor T-cell (CAR-T) product based on the receptor NKG2D which demonstrated anti-tumor efficacy through different mechanisms of action in numerous preclinical models. A comprehensive clinical program was developed with the aim to define the optimal CYAD-01 treatment in acute myeloid leukemia (AML).
Methods:
The ongoing Phase I THINK trial (NCT03018405) evaluates multiple CYAD-01 injections in 2 parallel cohorts: one in patients (pt) with metastatic solid tumors and the other one in relapsing/refractory hematological malignancies. The dose escalation segment of the study evaluates 3 dose levels (DL; 3x108, 1x109 and 3x109 cells per injection) of one cycle of 3 CYAD-01 administration at 2 weeks apart. As of July 30, 2018, 12 pts in the THINK hematological cohort (8 AML, 3 MM and 1 MDS) have been enrolled at the 3 DLs without prior preconditioning. No dose-limiting toxicity occurred. We evidenced promising anti-leukemic activity with 42% ORR in r/r AML with 5/7 pts having clinical benefit. Based on the initial data generated into the THINK study, two additional Phase I clinical trials have been developed to evaluate 3 DLs (1x108, 3x108 and 1x109 cells per injection) post preconditioning regimen or in association with standard of care (SoC).
The DEPLETHINK study (NCT03466320) aims at evaluating the CYAD-01 treatment administered after a cyclophosphamide and fludarabine preconditioning regimen to r/r AML patients. The preconditioning chemotherapy should (i) favor the expansion and engraftment of CYAD-01, (ii) increase NKG2D ligand expression on tumor cells and (iii) help to overcome the strong immunosuppressive microenvironment.
The EPITHINK study (EudraCT 2018-000745-39) aims at assessing the safety of the CYAD-01 treatment administered concurrently with SoC 5-azacytidine treatment in treatment-naïve AML pts ineligible for intensive treatment. Similar to the preconditioning treatment, the epigenetic treatment could contribute to favor engraftment of CYAD-01 cells and increase target antigen expression while better controlling the disease progression of patients early in the treatment.
Results:
Description of the study design and preliminary clinical data from the first cohorts of the EPITHINK and DEPLETHINK studies will be presented. The preliminary data in term of CYAD-01 engraftment kinetics, NKG2D ligand expression (including blasts and soluble ligands), and the kinetics of cytokine induction will be correlated with the concurrent treatment (preconditioning or epigenetic treatment) versus the stand alone therapeutic approach.
Conclusions:
We have demonstrated the feasibility and safety of multiple injections of CYAD-01 without preconditioning chemotherapy (THINK). Preliminary safety, activity and correlative science data will be presented according a prior preconditioning (DEPLETHINK) and concurrent administration with SoC epigenetic treatment (EPITHINK).

Disclosures
Sallman: Celgene: Research Funding, Speakers Bureau. Kerre:BMS: Consultancy; Celgene: Consultancy, Research Funding; Celyad: Consultancy. Wang:Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: 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; Jazz: Speakers Bureau. Selleslag:Kiadis Pharma: Other: Financial support for study-related issues. Beguin:Kiadis Pharma: Consultancy. Al-Homsi:Celyad: Membership on an entity's Board of Directors or advisory committees. Dekker:Celyad: Employment. Breman:Celyad: Employment. Sotiropoulou:Celyad: Employment. Snykers:Celyad: Employment. Braun:Celyad: Employment. Lonez:Celyad: Employment. Verma:Celyad: Employment. Lehmann:Celyad: Employment, Honoraria, Patents & Royalties; GSK: Patents & Royalties. Davila:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees.