Updated results from Phase I trials assessing a NKG2D CAR T-cell approach in relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome patients CYAD-01 BACKGROUND David A. Sallman 1 , Marco Davila 1 , Jason B. Brayer 1 , Tessa Kerre 2 , Xavier Poiré 3 , Violaine Havelange 3 , Philippe Lewalle 4 , Samer Al-Homsi 5 , Enkhtsetseg Purev 6 , Eunice S. Wang 7 , Panagiota A. Sotiropoulou 8 , Nathalie Braun 8 , Caroline Lonez 8 , Anne Flament 8 1. Moffitt Cancer Center, Tampa, FL; 2. Gent University Hospital, Ghent, Belgium; 3. Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; 4. Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; 5. New York University School of Medicine, New York, NY; 6. UCHealth University of Colorado Hospital, Denver, CO ; 7. Roswell Park Comprehensive Cancer Center, Buffalo, NY; 8. Celyad, Mont-Saint-Guibert, Belgium ● 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. ● Ligand binding to CYAD-01 triggers a primary signal via CD3ζ and a secondary signal via the adaptor molecule DAP-10. ● CYAD-01 binds to 8 ligands (MHC class I chain related proteins A [MICA] and B [MICB] and Unique long 16 binding proteins [ULBP] 1–6 ligands) expressed by a large variety of malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) [1,2]. ● Preclinically, CYAD-01 has anti-tumor effects beyond direct cancer cell killing by targeting also cells from the tumor microenvironment and neo-vasculature cells expressing NKG2D ligands, and boosting an adaptive anti-tumor immune response. CYAD-01 IN AML/MDS ● CYAD-01 is currently evaluated in relapse/refractory (r/r) AML/MDS patients in a clinical development plan with the objective to define the optimal CYAD-01 treatment with or without prior preconditioning chemotherapy. ● The THINK (NCT03018405) open-label Phase I study evaluates the safety and clinical activity of CYAD-01 administered as a standalone therapy with a multiple infusion schedule in patients with different indications including r/r AML and MDS: o No non-myeloablative preconditioning chemotherapy. o No bridging therapy. o 3+3 design dose escalation: - 3 dose-levels (DL) of CYAD-01 (3×10 8 , 1×10 9 and 3×10 9 cells/infusion) for the 1 st cycle of 3 CYAD-01 infusions Q2W. - 2 DL of CYAD-01 (1×10 9 and 3×10 9 cells/infusion) for the 1 st cycle of 3 CYAD-01 infusions Q1W (dense schedule). o Potential 2 nd cycle of 3 CYAD-01 infusions Q2W in absence of progressive disease (PD) at the end of the 1 st cycle. o Recruitment at 3×10 9 cells/infusion DL of the dense schedule is ongoing. ● The DEPLETHINK (NCT03466320) open-label Phase I/II study evaluates the safety and clinical activity of CYAD-01 administered after a preconditioning regimen in r/r AML and MDS patients: o 3+3 design to evaluate 3 DL (1×10 8 , 3×10 8 and 1×10 9 cells). o Preconditioning regimen (300 mg/m² cyclophosphamide and 30 mg/m² fludarabine daily for 3 days) prior to a single CYAD-01 infusion. o First DL at a safety low dose of CYAD-01 (1×10 8 cells/infusion i.e. ~1.5×10 6 cells/kg) and evaluated at 2 intervals between preconditioning and CYAD-01 infusion (T7: 7 days interval, T3: 3 days interval) for safety precaution to mitigate for any potential increased toxicity due to the administration of the preconditioning chemotherapy. o Potential 2 nd cycle of 3 CYAD-01 infusions Q2W without preconditioning in case of no PD after 1 st infusion. o Recruitment in DL-2 ongoing (3×10 8 cells/infusion). THINK without preconditioning DEPLETHINK with prior preconditioning DEMOGRAPHICS DL-1: 3×10 8 DL-2: 1×10 9 DL-3: 3×10 9 DL-2: 1×10 9 (dense) TOTAL DL1: 1×10 8 (T3 & T7) N=6 N=3 N=7 N=4 N = 20 N = 6 Age (years): Mean (range) 64.8 (52-79) 74.0 (60-83) 60.1 (29-80) 61.3 (29-80) 63.9 (29-83) 61.7 (50-73) Gender: Male/Female 5 / 1 2 / 1 6 / 1 1 / 3 14 / 6 4 / 2 ECOG performance score: Grade 0 / 1 2 / 4 2 / 1 2 / 5 2 / 2 8 / 12 0 / 6 LVEF (%): Mean (range) 58.8 (48-66) 64.7 (55-79) 61.3 (55-67) 58.8 (52-65) 60.6 (48-79) 56.5 (45-65) Tumor type r/r Acute Myelogenous Leukemia 3 3 6 3 15 4 De novo 2 2 5 3 12 4 AML-MRC (secondary AML) 1 1 1 0 3 0 r/r Myelodysplastic Syndrome 0 0 1 1 2 2 r/r Multiple Myeloma 3 0 0 0 3 - ELN 2017/R-IPSS risk stratification for AML/MDS Favorable (AML) / Intermediate (MDS) 1 / 0 1 / 0 0 / 1 0 / 0 2 / 1 0 / 0 Intermediate (AML) / High-Risk (MDS) 1 / 0 0 / 0 1 / 0 2 / 0 4 / 0 1 / 0 Adverse (AML) / Very High-Risk (MDS) 1 / 0 2 / 0 5 / 0 1 / 1 9 / 1 3 / 2 Bone marrow blasts (%) mean (range) 9.5 (6-21) 27.3 (9.8-48.2) 12.2 (4-20) 41.5 (15-82) 19.5 (4-82) 27.9 (5.5-48.0) Platelets (10 3 /μL) mean (range) 127.7 (22-261) 101.3 (63-144) 53.6 (6-157) 72 (39-159) 86.7 (6-261) 80.2 (45-156) ANC (10 3 /μL) mean (range) 2.13 (0-8.1) 1.28 (0.14-3.46) 1.27 (0.09-2.59) 0.66 (0.12-2.08) 1.4 (0-8.1) 2.67 (0.0-8.7) GRADE 3/4 RELATED AEs 15 infusions over 6 patients 12 infusions over 3 patients 24 infusions over 7 patients 15 infusions over 4 patients 66 infusions over 20 patients 6 infusions over 6 patients All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 Adverse Event (AE) Preferred Term Total pts with at least ≥ 1 related AE (%) 6 (100) - 1 (16.7) 3 (100) 2 (66.7) - 6 (85.7) 2 (28.6) 3 (42.9) 4 (100) - 1 (25.0) 19 (95) 4 (20.0) 5 (25.0) 3 (50.0) - - Cytokine release syndrome (CRS) 1 (16.7) - - 2 (66.7) 2 (66.7) - 4 (57.1) - 1 (14.3) 3 (75.0) - - 10 (50.0) 2 (10.0) 1 (5.0) 3 (50.0) - - Hypoxia 1 (16.7) - 1 (16.7) 2 (66.7) - - - - - 1 (25.0) - - 4 (20.0) - 1 (5.0) - - - Pneumonitis 1 (16.7) - 1 (16.7) - - - - - - - - - 1 (5.0) - 1 (5.0) - - - Fatigue 2 (33.3) - - - - - 1 (14.3) 1 (14.3) - - - - 3 (15.0) 1 (5.0) - - - - Headache - - - - - - 1 (14.3) 1 (14.3) - - - - 1 (5.0) 1 (5.0) - - - - Infusion related reaction 1 (16.7) - - - - - - - - 1 (25.0) - 1 (25.0) 2 (10.0) - 1 (5.0) - - - Lymphopenia 1 (16.7) - 1 (16.7) 1 (33.3) - - 1 (14.3) - 1 (14.3) - - - 3 (15.0) - 2 (10.0) - - - Thrombocytopenia - - - 1 (33.3) 1 (33.3) - 1 (14.3) - 1 (14.3) - - - 2 (10.0) 1 (5.0) 1 (5.0) - - - AML/MDS BEST OVERALL CLINICAL RESPONSES Non evaluable patients * 1 0 2 1 4 1 Evaluable patients 2 3 5 3 13 5 Objective responses 1 CR h , 1 CR i - 1 CR i , 1 mCR - 1 CR h , 2 CR i , 1 mCR - Stable disease - 2 2 1 5 2 SD 3 months with BM blast % decrease - 2 - - 2 - SD < 3 months - - 2 1 3 2 Progressive disease - 1 1 2 4 3 * Patients were considered evaluable if they received at least 3 infusions in the THINK study or at least 1 infusion and reached Day 21 in the DEPLETHINK study BM: bone marrow; CR: complete remission; CR h : CR with partial hematologic recovery; CR i : CR with incomplete hematologic recovery; mCR: marrow CR; MRC: myelodysplasia-related changes; SD: stable disease (As of May 23, 2019 - uncleaned database) CYAD-01 PHARMACOKINETICS OVERALL CONCLUSIONS ● THINK multiple infusions of CYAD-01 without any prior preconditioning chemotherapy showed: o An encouraging safety and tolerability profile with only 8 pts with grade (G) 3/4 treatment-related adverse events (AEs). o CRS occurred in 10 pts with only 2 G3 CRS and 1 G4 CRS, which resolved with tocilizumab treatment. No treatment-related neurotoxicity AEs. o Encouraging preliminary anti-leukemic activity with 6/13 pts (46%) presenting relevant BM blasts decrease in r/r AML/MDS pts evaluable per protocol with 4 objective responses (CR h /CR i /mCR). o Most responses were of short durability. o The dense schedule at 1x10 9 cells/infusion did not modify the overall well tolerated safety profile. ● DEPLETHINK single infusion of a safety low dose of CYAD-01 ( 1.5×10 6 cells) post preconditioning chemotherapy showed: o No G3/4 treatment-related AE. o CRS G2 occurred in 3 pts (two G1 and 1 G2). o 2/5 pts with SD post first CYAD-01 infusion at subtherapeutic DL were eligible for a consolidation cycle of 3 CYAD-01 infusions w/o preconditioning, o Evaluation of higher dose-levels similar to those from the THINK study are ongoing. ● CYAD-01 pharmacokinetics data: o CYAD-01 is detected in peripheral blood after each infusion at all dose levels. o Persistence of cells after each infusion with no prior preconditioning was not durable, in agreement with preclinical data. o Better time-averaged engraftment (area under the curve) was observed with the denser schedule of infusions. o Better time-averaged engraftment was observed after a single infusion of a low dose of CYAD-01 with a prior preconditioning, especially if the interval between the preconditioning regimen and CYAD-01 was short (3 days (T3) better than 7 days (T7)). MAIN RESULTS ● Altogether, results obtained to date in both phase I studies demonstrate the safety of CYAD-01 with or without a prior preconditioning chemotherapy in patients with r/r AML and MDS. ● The anti-leukemic activity, although mostly of short durability, observed in 46% of patients after multiple CYAD-01 infusions in the absence of preconditioning chemotherapy is highly promising in such refractory patient population. ● Data on an initial dose-level with a denser schedule of infusions showed a better CYAD-01 cell engraftment . The THINK study is now recruiting at the dense schedule with 3×10 9 cells/infusion. ● Data with a single CYAD-01 infusion following a preconditioning regimen showed a better time-averaged engraftment of the cells even at a low safety CYAD-01 dose. The DEPLETHINK study is now recruiting at dose- levels comparable to the THINK study. ● These initial clinical and persistence data suggest a potential improvement of the clinical response durability could be obtained through an optimized infusion schedule or addition of a preconditioning regimen. REFERENCES [1] Nausch N, Cerwenka A. Oncogene 2008;27:5944-58. [2] Lanier L. Cancer Immunol Res 2015;3(6):575-82. © Celyad SA 2019 CYAD-01 CYAD-01 CYAD-01 CYAD-01 CYAD-01 CYAD-01 CYAD-01 CYAD-01 CYAD-01 CYAD-01 CYAD-01 CYAD-01 CYAD-01 CYAD-01 THINK 3 ×10 8 cells/inf. w/o preconditioning THINK 1 ×10 9 cells/inf. w/o preconditioning THINK 3 ×10 9 cells/inf. w/o preconditioning DEPLETHINK 1 ×10 8 cells/inf. with preconditioning THINK dense schedule 1 ×10 9 cells/inf. w/o preconditioning T7 schedule T3 schedule