Gracell Biotechnologies : ASH 2023 Oral Presentation - Updated Results of a Phase I Open-Label Single-Arm Study of Dual Targeting BCMA and CD19 Fastcar-T Cells (GC012F) As First-Line Therapy for Transplant-Eligible Newly Diagnosed High-Risk Multiple Myeloma

Updated results of a phase I open-labelsingle-arm study of dual targeting

BCMA and CD19 FasTCAR-T cells (GC012F) as first-line therapy for transplant-eligible newly diagnosed high-risk multiple myeloma

Juan Du*1, Wanting Qiang1, Jing Lu1, Yanchun Jia1, Haiyan He1, Jin Liu1, Pei Guo1, Ying Yang1, Zhongyuan Feng1, Lina Jin1, Xiaoqiang

Fan1, Jia Liu2, Qi Zhang2, Lianjun Shen2, Lihong Weng2, Wenling, Li2, Wei Cao2

1. Department of Hematology, Myeloma & Lymphoma Center, Shanghai Changzheng Hospital, Shanghai, China
2. Gracell Biotechnologies Ltd, Shanghai, China

Introduction

GC012F: Targeting BCMA/CD19 is designed to drive fast, deep and durable responses in multiple myeloma (MM) patients

	BCMA-CD19
	Dual CAR-T
	anti-CD19 scFv
	anti-BCMA scFv
CD19	CD19
(Low expression)	BCMA
MM cell	MM
Progenitor

• BCMA is universally expressed on malignant plasma cells1
• CD19 is expressed on both multiple myeloma cells and their progenitors2, making it a valid therapeutic target to treat multiple myeloma

1. Tai YT, Anderson KC. Immunotherapy. 2015;7(11):1187-1199.
2. Boucher K, Parquet N, Widen R, et al. Clin Cancer Res. 2012;18(22):6155-6168.

2

GC012F: FasTCAR Cuts Manufacturing Time to Next-Day

Combines Activation & Transduction Steps, and Eliminates Need for ex vivo Expansion

Concurrent

Activation-Transduction

Next-Day

	Purification
Apheresis Isolation	Filling	Releasing Tests
Freezing

Release

&

Infusion

Designed to address major challenges faced by conventional autologous CAR-T

Key advantages:

• Faster to patient
• Enhanced CAR-T cell quality and materially higher concentration of young phenotype T cells

	Purification
Apheresis Isolation	Filling	Releasing Tests
Freezing
Conventional	Release
Manufacturing		&
	Infusion

Activation Transduction	ex vivo Expansion
1 to 3 days 1 to 2 days	5 days to 5 weeks

1 to 6

WEEKS

3

GC012F: Study Design

Single-center, open label, single-arm IIT1 study (N=22)

FPI August 2021

Patients continue to be assessed for response

Data cut-offOct 1st 2023

Endpoints

• Primary: Adverse Events
• Secondary: ORR, BOR, DOR, MRD; PK/PD

Key eligibility criteria

• High-risk2, transplant eligible, newly-diagnosed multiple myeloma (NDMM)
• Measurable disease
• 18-70years old
• ECOG 0-2
• Expected survival ≥3 months

				Consent and Screening
		Apheresis			VRD induction therapy 2
					cycles 3
			GCO12F Next Day Manufacturing
				QC Release
				Lymphodepletion	D-5 to -3
				GC012F Single infusion			D0
Dose		Level 1		Dose		Level 2	Dose		Level 3
1x105 cells/kg		2x105 cells/kg	3x105 cells/kg

Post-infusion treatment based on PI's evaluation

Follow-up assessment visits

1. IIT - Investigator Initiated Study
2. High-riskis defined as meeting at least one of the following: a) R-ISS stage II or III; b) High-risk cytogenetics: del17p, t(4;14), t(14;16), or 1q21 ≥4 copies; c) Extramedullary disease; d) IgD or IgE subtype; e) High-risk definition according to mSMART3.0; f) LDH > the upper limit of normal.
3. 2 cycles of induction therapy VRD (PAD cycle in one case) are given before or after apheresis.

4

GC012F: Baseline Characteristics

Baseline Characteristics (N=22)

Median age, years (range)	59 (43-69)
Male, n (%)	14	(64)
Type of myeloma, n (%)
IgG	9	(41)
IgA	7	(32)
IgD	2 (9)
Light chain	4	(18)
Induction therapy, n (%)
2 cycles RVd 1	21	(95)

1. except one cycle of PAD (bortezomib, doxorubicin, and dexamethasone)

1. pts evaluable for cytogenetics high risk.

Baseline Characteristics (N=22)

High-risk, n (%)	22	(100)
R-ISS stage II/III	20 (91)
High-risk cytogenetics2	12 (55)
Extramedullary plasmacytoma ≥1	12 (55)
High-risk as mSMART3.0	20 (91)
LDH > upper limit of normal	3	(14)
ECOG performance status, n (%)
0		(23)
5
1	11 (50)
2	6	(27)

5

GC012F: Safety Profile

All CRS were Grade 1 or 2 and resolved within 4 days · No ICANS or any neurotoxicity was observed

	N=22	CRS1, n (%)	ICANS2, n (%)
	Grade 1	5 (23)	0 (0)
	Grade 2	1 (5)	0 (0)
	Grade 3	0 (0)	0 (0)
	Grade 4-5	0 (0)	0 (0)
	All grade	6 (27)	0 (0)
	CRS any grade	Median (days)	Range (days)
	Time to onset	7	6-9
	Duration	1	1-4

*AEs were graded according to CTCAE v5.0; TEAE-treatment emergent adverse event; LDH- Lactase dehydrogenase.

1CRS-Cytokine Release Syndrome, graded by ASTCT Consensus; treated with tocilizumab and/or glucocorticoids.

2ICANS-Immune Effector Cell-Associated Neurotoxicity Syndrome, graded by ASTCT Consensus.

N=22	All Grades, n (%)	Grade ≥3, n (%)
Hematologic TEAEs* (≥20% All Grades)
Leukopenia	19 (86)	10 (45)
Lymphopenia	17 (77)	14 (63)
Neutropenia	17 (77)	9 (41)
Anemia	8 (36)	1 (5)
Thrombocytopenia	6 (27)	0 (0)
Non-Hematologic TEAEs* (≥20% All Grades)
LDH increased	9 (41)	0 (0)
Hypoalbuminemia	9 (41)	0 (0)
Hypocalcemia	7 (32)	0 (0)
Upper respiratory	5 (23)	3 (14)
infection

6

GC012F: Efficacy Assessment - ORR

Patients(%)

100

80

60

40

20

0

ORR at time of data cut off Oct 1st 2023

ORR	ORR	ORR	ORR
100%	100%	100%	100%

95	100	100	94

5			6
All patients	DL1	DL2	DL3
(N=22)	(n=1)	(n=4)	(n=17)

VGPR CR/sCR

• ORR = 100% (22/22) patients
• • Best response achieved to date
  • 95% (21/22) MRD- sCR
  • 100%(12/12) MRD- sCR in the pts with EM
  • 100% (22/22) VGPR or better
• Median duration of response (DOR) and median progression free survival (PFS) were not reached at data cut off
• Median duration of follow up 18.8 months (range:
  6.6 - 28.4 months)
• All patients remained alive at data cutoff

7

GC012F: Efficacy Assessment - MRD Negativity

Data cut-offOct 1st 2023

MRD assessment* at the 1st , 6th and 12th month

	100
Patients(%)		80
	40
		60		100	95			100
		20
			0					5
				Month 1			Month 6	Month 12
					(n = 19)			(n = 19)	(n = 15)
							MRD+		MRD-
					*MRD was tested by Euroflow at a sensitivity of 10-6

• 100% of MRD evaluable patients achieved MRD negativity at Month 1 and Month 12
• 100% of MRD evaluable patients achieved MRD negativity in all dose levels
• All patients achieved MRD negativity before lenalidomide maintenance

8

GC012F: Efficacy Assessment - Swimmer plot

Y 4 Pt 01

Y 3 Pt 02

Y 4 Pt 03

Y 3 Pt 04

Y 4 Pt 05

Y 2 Pt 06

N 3 Pt 07

Y 3 Pt 08

N 2 Pt 09

Y 4 Pt 10

Y 5 Pt 11

N 4 Pt 12

Y 4 Pt 13

N 2 Pt 14

N 3 Pt 15

Y 3 Pt 16

N 3 Pt 17

Y 2 Pt 18

N 3 Pt 19

N 3 Pt 20

N 1 Pt 21

N 3 Pt 22

Not evaluated

PR

VGPR

sCR

PD

0

3

6

9

12

15

18

21

24

27

30

Months after CAR-T infusion

1HR: High-risk factors include: a) R-ISS stage II or III; b) High-risk cytogenetics: del17p, t(4;14), t(14;16), or 1q21 ≥4 copies; c) Extramedullary disease; d) IgD or IgE subtype; e) High-risk definition according to mSMART3.0; f) LDH > the upper limit of normal.

9

GC012F: Pharmacokinetics

Copy Number (copies/μg gDNA)

1×10	6
1×10	5
1×10	4
1×10	3
1×10	2
1×10	1
1×10	0
1×10	-1

Pt01

Pt02

Pt03

Pt04

Pt05

Pt06

Pt07

Pt08

Pt09

Pt10

Pt12

Pt13

Pt14

Pt15

Pt16

Pt17

Pt18

Pt19

Pt20

Pt21

Cmax (copies/μg gDNA) 60652 (8754-331159)

AUC0-28 (copies/μg gDNA*Days) 289685 (80181-3985420)

Tmax (Days) 10 (9-14)

0	0	0	0	0	50	00
	3	6	9	0
			1		4	8
		Days (after infusion)

LLOQ=30 (copies/μg gDNA)

Pt11

Pt22

10