CRISPR Therapeutics : ASH 2022 (Carbon) 627 KB

CTX110 Allogeneic CRISPR-Cas9-Engineered CAR T Cells in Patients (Pts) with Relapsed or

Poster 4629

Refractory (R/R) Large B-Cell Lymphoma (LBCL): Results From the Phase 1 Dose Escalation CARBON Study

Joseph P. McGuirk1, Constantine S. Tam2, Nicolaus Kröger3, Peter Riedell4, Hemant S. Murthy5, P. Joy Ho6, Joseph Maakaron7, Edmund K. Waller8, Farrukh T. Awan9, Paul J. Shaughnessy10, Armin Ghobadi11, Michael Bishop4, Ana Alfonso Piérola12, Michael Dickinson2, Praveen Ramakrishnan Geethakumari9, Ainsley Ross13, William Stevens13, Huansheng Xu13, Anna Ma13, Sarah Beaussant Cohen13, Richard T. Maziarz14, Carlos Bachier10

1Department of Blood and Bone Marrow Transplant, The University of Kansas Medical Center, Kansas City, KS; 2Peter MacCallum Cancer Centre, Royal Melbourne Hospital and The University of Melbourne, Melbourne, VIC, Australia; 3Department of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Hamburg, Germany; 4Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL; 5Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL; 6Royal Prince Alfred Hospital and University of Sydney, Camperdown, Australia; 7Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN; 8Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA; 9Division of Hematology/Oncology, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX; 10Sarah Cannon Transplant and Cellular Therapy Program at Methodist Hospital, San Antonio, TX; 11Washington University School of Medicine, St Louis, MO; 12Department of Hematology, Clínica Universidad de Navarra, IdiSNA, Pamplona, Spain; 13CRISPR Therapeutics, Boston, MA; 14Knight Cancer Institute, Oregon Health and Science University, Portland, OR

Introduction

• Outcomes for patients with R/R B-cell malignancies are historically poor. However, the use of auto CAR T-cell therapy has produced complete and durable responses1-5
• Owing to the aggressive nature of R/R LBCL, some patients experience disease progression while waiting for auto CAR T-cell manufacture and infusion and may be ineligible to receive cells once available6-9
• • Among patients who are eligible for auto CAR T cell therapy, less than 30% go on to receive CAR T-celltherapy10-13
• Allo CAR T-cell therapies that produce durable remissions in patients with R/R LBCL may offer advantages over auto CAR T products such as the potential for immediate "off-the-shelf" availability, no required leukapheresis, potential for an improved safety profile, and the option for additional infusions6,14
• We designed a phase 1 study to evaluate the safety and efficacy of CTX110, an allogeneic CD19-directed CAR T cell therapy in patients with R/R LBCL and report here results from the dose-escalation phase of the study

Figure 1: CTX110™ Construct

•			Anti-CD19
Investigational allogeneic anti-CD19		CAR
	CAR T cell therapy
•	Modified using CRISPR/Cas9 editing		TCR
	designed to disrupt the endogenous TRAC
	locus to remove TCR expression and	MHC I	disruption
	disrupt β2M	disruption

‒ Disruption of the TCR minimizes risk of

GvHD

‒ Disruption of β2M eliminates MHC class

I expression to mitigate host T-cell-

mediated clearance of CTX110

• Anti-CD19 CAR transgene construct is

precisely inserted into the TRAC locus

Table 1: Patient Demographics and Baseline Characteristics

	DL1	DL2	DL3	DL3.5	DL4		Total
	N=3	N=3*	N=6	N=6	N=14		N=32
Median age, y (range)	52 (50-61)	64 (58-74)	69 (62-74)	67.5 (25-74)	64 (35-75)		64 (25-75)
Female, n (%)	1 (33.3)	1 (33.3)	4 (66.7)	2 (33.3)	2 (14.3)		10 (31.3)
ECOG PS at screening, n (%)
0	2 (66.7)	1 (33.3)	2 (33.3)	4 (66.7)	4 (28.6)		13	(40.6)
1	1 (33.3)	2 (66.7)	4 (66.7)	2 (33.3)	10 (71.4)		19	(59.4)
Refractory disease, n (%)	3 (100)	3 (100)	2 (33.3)	1 (16.7)	8 (57.1)		17	(53.1)
Prior anticancer therapies
Median prior therapies, n (range)	2 (2-8)	3 (2-3)	2 (2-4)	2.5 (2-10)	2.5 (2-10)		2 (2-10)
≥3 prior therapies, n (%)	1 (33.3)	2 (66.7)	2 (33.3)	3 (50)	7 (50)		15	(46.9)
Prior stem cell transplant, n (%)	0	0	3 (50)	4 (66.7)	4 (28.6)		11	(34.4)
NHL subtype, n (%)
DLBCL, NOS	1 (33.3)	2 (66.7)	2 (33.3)	4 (66.7)	8 (57.1)		17	(53.1)
HGLBCL w MYC/BCL2 and/or BCL6 rearr.	0	1 (33.3)	1 (16.7)	1 (16.7)	2 (14.3)		5 (15.6)
Transformed FL	1 (33.3)	0	2 (33.3)	1 (16.7)	3 (21.4)		7 (21.9)
Grade 3b FL	0	0	0	0	1 (7.1)		1	(3.1)
Other†	1 (33.3)	0	1 (16.7)	0	0		2	(6.2)
Baseline SPD >50 cm2, n (%)	1 (33.3)	1 (33.3)	2 (33.3)	1 (16.7)	6 (42.9)		11	(34.4)
Baseline LDH > ULN, n (%)	1 (33.3)	2 (66.7)	2 (33.3)	5 (83.3)	7 (50)		17 (53.1)

*1 patient received two CTX110 infusions with the first infusion at DL2 and the second at DL3.

† 1 patient enrolled in DL1 had Richter's transformation of CLL, and 1 patient in DL3 had both grade 3b FL and germinal center B-cell-like DLBCL.

• As of Oct 6, 2022, 34 patients with LBCL were enrolled for dose escalation and 32 received CTX110. Only 2 enrolled patients did not receive CTX110 due to intercurrent infections (COVID-19 and pneumonia)
• Median time from enrollment to the beginning of lymphodepleting chemotherapy (LDC) was 2 days

Figure 3: Durable Responses Occurred at Clinically Active Doses

DL3

*

**

**

DL3

DL3.5

DL2/DL3

DL4

DL3.5/DL4

DL4

DL3

*

DL3.5

DL4

*

DL4

DL4

DL4

DL3.5

*

DL3

*

DL4

DL4

DL4

*

DL3

*

DL4

*

DL4

*

DL3

*

DL4

*

DL3.5

*

DL4

*

Pre-evaluation

CR

PR

SD

PD

NE

DL3.5

*

Re-infusion

* Death

DL4

*

0

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25

26

27

28

Time since First CTX110 Infusion (Months)

*PET CT identified a single new small FDG-avid node located in the left upper arm. The lesion was completely excised. The patient remained clinically well and required no subsequent anti cancer therapy including no steroids, no radiotherapy and no chemotherapy.

• On the Month 9 scan, the PET CT identified unspecific localized small FDG uptake in the right upper arm. The patient did not have subsequent surgery nor anti cancer therapy, and the lesion spontaneously resolved.

Figure 4: Case Study

Baseline	Month 24 (CR)

Patient characteristics

• 62-year-oldfemale diagnosed with DLBCL
• Relapsed following 2 prior lines of therapy, including autologous SCT
• Treated with single infusion of CTX110 at DL3 (300x106 CAR+ T cells)

Safety and efficacy data

• CR at Day 28 after a single dose with no tumor visible
• No CRS, ICANS, or infections
• CR ongoing at 24+ months

using an AAV vector

Figure 2: CARBON™ (NCT04035434) Clinical Trial Design

			Dose Level, CAR+ T cells
Informed	CTX110	DL1	DL2	DL3	DL3.5	DL4
consent form	infusion:	30×106	100×106	300×106	450×106	600×106

Screening Lymphodepletion

D28 Assessment and Follow-up

Table 2: CTX110 Demonstrated Encouraging Efficacy at Dose Level ≥3

Cell dose	DL1	DL2	DL3	DL3.5	DL4		≥1 Infusion at DL≥3
(CAR+ T cells)	N=3	N=3*	N=6	N=6	N=14		N=27
ORR, n (%)	0	1 (33.3)	4 (66.7)	4 (66.7)	9 (64.3)		18 (66.7)
CR	0	1 (33.3)	2 (33.3)	4 (66.7)	4 (28.6)		11 (40.7)
PR	0	0	2 (33.3)	0	5 (35.7)		7 (25.9)

*1 patient received two CTX110 infusions with the first infusion at DL2 and the second at DL3.

• Among patients who received ≥1 infusion of CTX110 at doses of ≥300 x 106 CAR T cells (DL ≥3; N=27):

- Best ORR and CR rates were 66.7% (18/27) and 40.7% (11/27), respectively

- 6-mo CR rate was 19% (5/27)

- Three patients have achieved and maintained ongoing CR for more than 24 months**

- For the 13 patients who received a second infusion of ≥300 x 106 CAR T cells, CAR T cell expansion was observed in all

Figure 5: Pharmacokinetics

1. Observed peak expansion CTX110 levels following 1st Infusion by dose

	1000000
copies/µg)	100000
10000
(CAR	1000
Expansion
100
Peak	10

B. Peak expansion of CTX110 in subjects following 1st and 2nd infusions

	10000
(CAR copies/µg)	1000
100
Expansion
10
Peak

• Dose-dependentincrease in observed peak expansion (CAR T copies/μg) among patients receiving CTX110 at DL≥3 (Figure 5A)
• Expansion observed after second infusion (Figure 5B)

Fludarabine 30 mg/m2 + Cyclophosphamide 500 mg/m2 for 3 days

Patients could receive an additional infusion of CTX110 if they achieved initial benefit and subsequently progressed. Additionally, a subset of patients were eligible for a second planned

patients, with no change in the overall safety profile

** 2 patients were in CR for more than 24 months at the time of the data cutoff; 3 patients were in CR for over 24 months at the date of the presentation.

1

DL3 DL3.5 DL4 (N=5) (N=6) (N=14)

1

1st Infusion (N=7) 2nd Infusion (N=7)

This is an open-label, multicenter, Phase 1 study evaluating the safety and efficacy of CTX110 in subjects with relapsed or refractory B-cell malignancies (NCT04035434)

Key eligibility criteria

• Age ≥18 years
• R/R DLBCL NOS, double- or triple-hit DLBCL, or transformed or grade 3b FL, as evidenced by ≥2 lines of prior therapy
• No prior allogeneic SCT or treatment with CAR-T therapy
• No history of CNS lymphoma involvement
• No minimum CBC requirements

infusion on Day 35

Primary endpoint

• Incidence AEs, defined as DLTs
• ORR (per Lugano 2014 criteria)

Secondary endpoints

• CR rate
• DOR
• OS

Allogeneic	• Short	• No bridging
screening	chemotherapy
CAR T enables
timeframe	• On-site availability
simplified trial
• No	of CAR-T cell
design:
apheresis	product

Table 3: Adverse Events of Interest, N (%)

	DL1	DL2		DL3	DL3.5		DL4
					Total
	30x106	100x106	300x106	450x106		600x106
	N=3	N=3		N=6	N=6			N=14			N=32
	Gr 1-2	Gr ≥3	Gr 1-2	Gr ≥3	Gr 1-2	Gr ≥3	Gr 1-2	Gr ≥3	Gr 1-2	Gr ≥3		Gr 1-2	Gr ≥3
CRS	1 (33.3)	0	2 (66.7)	0	2 (33.3)	0	3 (50)	0	10	(71.4)	0		18	(56.3)	0
ICANS	0	0	1 (33.3)	0	0	0	0	0		0	2 (14.3)		1	(3.1)	2 (6.2)
GvHD	0	0	0	0	0	0	0	0		0	0			0	0
Infections	0	1 (33.3)	0	0	1 (16.7)	1 (16.7)	2 (33.3)	0	1	(7.1)	2 (14.3)		4 (12.5)	4 (12.5)

All events listed in table are treatment-emergent adverse events.

•	CTX110 demonstrated a tolerable safety profile across all dose levels
•	There were no infusion reactions with CTX110
•	All cases of ICANS were considered related to CTX110 and all CRS events were related or possibly related
•	Gr ≥3 infections occurred in 4/32 patients (12.5%) including 1 patient who died with HHV6 encephalitis. 1 infection was

Conclusions

• In a heavily pre-treated patient population with R/R LBCL (46.9%

with 3 or more prior lines of therapy), CTX110 at DL≥3 or higher

resulted in clinically meaningful ORR, CR rate, and durable

remissions, accompanied by a favorable safety profile during

dose escalation

• Nearly half of all patients who achieved a CR maintained this

response for at least 6 months

• CTX110 offers a potential off-the-shelf and feasible treatment

option for patients and the median time from enrollment to LDC

was just 2 days; median time from enrollment to infusion of

CTX110 was 7 days. Only 2 enrolled patients were unable to

receive CTX110

• Administration of a second CTX110 infusion was well tolerated

Acknowledgments

• Thank you to all the patients, families, caregivers, and investigators involved with the CARBON Study
• This study was sponsored by CRISPR Therapeutics
• Editorial support provided by PRECISIONscientia, funded by CRISPR Therapeutics

CARBON (NCT04035434) Study Sites

References

1.	June CH, et al. Science. 2018;359:1361-1365.2. Maus MV and June CH. Clin Cancer Res. 2016;22:1875-1884.
3.	Neelapu SS, et al. N Engl J Med. 2017;28:2531-2544.4. Schuster SJ, et al. N Engl J Med. 2019;380:45-56.
5.	Schuster SJ, et al. N Engl J Med. 2017;28:2545-2554.6. Depil S, et al. Nat Rev Drug Discov. 2020;19(3):185-199.
7.	Ruella M, et al. BioDrugs. 2017;31:473-481.8. Tully S, et al. JCO Clin Cancer Inform. 2019;3:1-9.

considered possibly related to CTX110

• There were 7 patients who experienced serious adverse events that were attributed to CTX110; these included CRS, ICANS,

and febrile neutropenia

and CAR T cells expanded following the second infusion

• CTX110 will continue to be evaluated in an expansion phase of the

study

9. Zhang J, et al. Adv Ther. 2020;37:3040-3058.10. Pasquini MC, et al. Blood. 2019;134(Supplement_1):764.
11.	Jaglowski S, et al. Blood. 2019;134(Supplement_1):766. 12. Halwani AS, et al. Blood. 2019;134(Supplement_1):1622.
13.	Sermer D, et al. Blood Adv. 2020;4:4669-4678.14. Graham C, et al. Cells. 2018;7(10):155.

Abbreviations: AE, adverse event; allo, allogeneic; auto, autologous; β2M, β2 microglobulin; CAR, chimeric antigen receptor; CBC, complete blood count; CLL, chronic lymphocytic leukemia; CNS, central nervous system; CR, complete response; CRS, cytokine release syndrome; DL, dose level; DLBCL, diffuse large B-cell lymphoma; DLT, dose-limiting toxicity; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; FDG, fluorodeoxyglucose; FL, follicular lymphoma; Gr, grade; GvHD, graft versus host disease; HGLBCL, high-grade large B-cell lymphoma; HHV6, human herpesvirus 6; ICANS, immune effector cell associated neurotoxicity syndrome; LBCL, large B-cell lymphoma; LDC, lymphodepleting chemotherapy; LDH, lactate dehydrogenase;

LLOQ, lower limit of quantification; LOD, limit of detection; MHC, major histocompatibility complex; NHL, non-Hodgkin's lymphoma; NOS, not otherwise specified; ORR, objective response rate; OS, overall survival; PET-CT, positron emission tomography-computed tomography; PD, progressive disease; PR, partial response; PS, performance status; R/R, relapsed/refractory; SCT, stem cell transplant; SD, stable disease; SPD, sum of the perpendicular diameters; TCR, T-cell receptor; TLS, tumor lysis syndrome; ULN, upper limit of normal; y, years.