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 chimericantigen receptor (CAR) based on the natural full-length humannatural killer group 2D (NKG2D) receptor fused to theintracellular domain of CD3ζ.

● Ligand binding to CYAD-01 triggers a primary signal via CD3ζand 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 myelodysplasticsyndrome (MDS) [1,2].

● Preclinically, CYAD-01 has anti-tumor effects beyond directcancer cell killing by targeting also cells from the tumormicroenvironment and neo-vasculature cells expressing NKG2Dligands, 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 theobjective to define the optimal CYAD-01 treatment with orwithout prior preconditioning chemotherapy.

● The THINK (NCT03018405) open-label Phase I study evaluatesthe safety and clinical activity of CYAD-01 administered as astandalone therapy with a multiple infusion schedule in patientswith 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 (3×108, 1×109 and 3×109

cells/infusion) for the 1st cycle of 3 CYAD-01 infusionsQ2W.

- 2 DL of CYAD-01 (1×109 and 3×109 cells/infusion) for the1st cycle of 3 CYAD-01 infusions Q1W (dense schedule).

o Potential 2nd cycle of 3 CYAD-01 infusions Q2W in absenceof progressive disease (PD) at the end of the 1st cycle.

o Recruitment at 3×109 cells/infusion DL of the denseschedule is ongoing.

● The DEPLETHINK (NCT03466320) open-label Phase I/II studyevaluates the safety and clinical activity of CYAD-01administered after a preconditioning regimen in r/r AML andMDS patients:

o 3+3 design to evaluate 3 DL (1×108, 3×108 and 1×109 cells).

o Preconditioning regimen (300 mg/m² cyclophosphamideand 30 mg/m² fludarabine daily for 3 days) prior to a singleCYAD-01 infusion.

o First DL at a safety low dose of CYAD-01 (1×108

cells/infusion i.e. ~1.5×106 cells/kg) and evaluated at 2intervals between preconditioning and CYAD-01 infusion(T7: 7 days interval, T3: 3 days interval) for safety precautionto mitigate for any potential increased toxicity due to theadministration of the preconditioning chemotherapy.

o Potential 2nd cycle of 3 CYAD-01 infusions Q2W withoutpreconditioning in case of no PD after 1st infusion.

o Recruitment in DL-2 ongoing (3×108 cells/infusion).

THINKwithout preconditioning

DEPLETHINKwith prior preconditioning

DEMOGRAPHICS DL-1: 3×108 DL-2: 1×109 DL-3: 3×109 DL-2: 1×109 (dense) TOTAL DL1: 1×108 (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 / 2ECOG performance score: Grade 0 / 1 2 / 4 2 / 1 2 / 5 2 / 2 8 / 12 0 / 6LVEF (%): 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 typer/r Acute Myelogenous Leukemia 3 3 6 3 15 4

De novo 2 2 5 3 12 4AML-MRC (secondary AML) 1 1 1 0 3 0

r/r Myelodysplastic Syndrome 0 0 1 1 2 2r/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 / 0Intermediate (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 / 2Bone 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 (103/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 (103/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 patientsAll 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 TermTotal 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 RESPONSESNon evaluable patients * 1 0 2 1 4 1Evaluable patients 2 3 5 3 13 5Objective responses 1 CRh, 1 CRi - 1 CRi, 1 mCR - 1 CRh, 2 CRi, 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 studyBM: bone marrow; CR: complete remission; CRh: CR with partial hematologic recovery; CRi: 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 anyprior preconditioning chemotherapy showed:

o An encouraging safety and tolerability profile withonly 8 pts with grade (G) 3/4 treatment-relatedadverse events (AEs).

o CRS occurred in 10 pts with only 2 G3 CRS and 1G4 CRS, which resolved with tocilizumabtreatment. No treatment-related neurotoxicityAEs.

o Encouraging preliminary anti-leukemic activitywith 6/13 pts (46%) presenting relevant BMblasts decrease in r/r AML/MDS pts evaluable perprotocol with 4 objective responses(CRh/CRi/mCR).

o Most responses were of short durability.

o The dense schedule at 1x109 cells/infusion did notmodify the overall well tolerated safety profile.

● DEPLETHINK single infusion of a safety low dose ofCYAD-01 ( 1.5×106 cells) post preconditioningchemotherapy 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 atsubtherapeutic DL were eligible for aconsolidation cycle of 3 CYAD-01 infusions w/opreconditioning,

o Evaluation of higher dose-levels similar to thosefrom the THINK study are ongoing.

● CYAD-01 pharmacokinetics data:

o CYAD-01 is detected in peripheral blood aftereach infusion at all dose levels.

o Persistence of cells after each infusion with noprior preconditioning was not durable, inagreement with preclinical data.

o Better time-averaged engraftment (area underthe curve) was observed with the denser scheduleof infusions.

o Better time-averaged engraftment was observedafter a single infusion of a low dose of CYAD-01with a prior preconditioning, especially if theinterval between the preconditioning regimen andCYAD-01 was short (3 days (T3) better than 7days (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 3×109 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. Oncogene2008;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-01CYAD-01

THINK 3×10 8 cells/inf. w/o preconditioning

THINK1×10 9 cells/inf. w/o preconditioning

THINK3×10 9 cells/inf. w/o preconditioning

DEPLETHINK1×10 8 cells/inf. with preconditioning

THINK dense schedule1×10 9 cells/inf. w/o preconditioning

T7 scheduleT3 schedule