Caribou Biosciences : CB-010 ANTLER Update ASCO 2024

Abstract 7025

A CRISPR-edited allogeneic anti-CD19CAR-T cell therapy with a PD-1 knockout (CB-010) in patients with

relapsed/refractory B cell non-Hodgkin lymphoma (r/r B-NHL): Updated phase 1 results from the ANTLER clinical trial

Boyu Hu1, Loretta Nastoupil2, Houston Holmes3, Ayad Hamdan4, Abraham S. Kanate5, Umar Farooq6, Mohamad Cherry7, Elizabeth Brem8, Lauren Pinter-Brown8, Daniel Ermann1, Muhammad Husnain9,

Kenneth Micklethwaite10, Syed Rizvi11, Ashley Hammad11, Ben Thompson11, Enrique Zudaire11, Socorro Portella11, Mehdi Hamadani12, James Essell13, Susan O'Brien8

1Huntsman Cancer Institute, Salt Lake City, Utah, USA; 2MD Anderson Cancer Institute, Houston, Texas, USA; 3Texas Oncology - Baylor Sammons Cancer Center, Dallas, Texas, USA; 4University of California San Diego Health, San Diego, California, USA; 5HonorHealth, Scottsdale, Arizona, USA; 6University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA; 7Morristown Medical Center, Morristown, New Jersey, USA; 8University

of California Irvine, Irvine, California, USA; 9University of Arizona Cancer Center, Tucson, Arizona, USA; 10New South Wales Health, St Leonards, New South Wales, Australia; 11Caribou Biosciences, Inc., Berkeley, California, USA; 12Medical College of Wisconsin Cancer Center, Milwaukee, Wisconsin, USA; 13Oncology Hematology Care, Cincinnati, Ohio, USA

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• Recent advances in autologous CAR-T

cell therapies have brought clinically

meaningful benefit to patients with r/r

B-NHL. However, treatment delays

remain a significant challenge due to

the need for leukapheresis,

• Despite availability of autologous CAR-T cell therapies in the

2L LBCL setting, the following reasons were considered by

investigators when enrolling patients to the ANTLER clinical

trial: rapidly progressing disease, insurance rejection, not

wanting to go through apheresis, preference for an off-the-

shelf therapy and/or electing not to receive bridging therapy

BACKGROUND

• CB-010is a CD19-targeted allogeneic CAR-T cell therapy engineered with a PD-1 knockout employing a 4-1BB costimulatory domain. It is manufactured using Cas9 CRISPR hybrid RNA-DNA (chRDNA) technology, which allows for
  3 precise genome edits:

1 knockout of the TRAC gene to eliminate T cell receptor expression

CB-010

3 Edits

3 PD-1 KO

1st allogeneic anti-CD19CAR-T

cell therapy in the clinic with

EFFICACY

• Median overall follow-up at the time of data cutoff was 6.0 months (range 1-27), 16.8 months (range 2-27) for Part A and 3.7 months
	(range 1-11) for Part B
• For all patients infused, ORR was 76.1% (Table 5)
•	21 (45.7%) patients achieved a CR as best response
•	Median time to CR was 28 days (range 28-357) for all patients and all subgroups

HLA AND ASSOCIATION WITH PFS

• Patients who received CB-010 manufactured from a donor with at least 4 matched HLA alleles achieved longer PFS

Figure 5. Progression-free survival by level of HLA matching in all treated patients (N=46)

manufacturing time, and production

failure

while waiting for their autologous CAR-T cells to be

manufactured

2	site-specific insertion of a CD19-targeted CAR expression cassette into
	the TRAC locus
3	knockout of PDCD1, the gene encoding PD-1

for B cell	2	Anti-CD19
non-Hodgkin		CAR
lymphoma	1	TCR KO

checkpoint disruption via PD-1knockout (KO) to reduce T cell exhaustion

•	Median duration of CR was 6.7 months for all patients and the LBCL subgroup
•	Median duration of CR was not reached in the 2L LBCL RP2D subgroup

Table 5. Preliminary efficacy

METHODS

Figure 1. ANTLER clinical trial design

Part A: 3+3 dose escalation - completed (N=16)	Part B: dose expansion - enrolling
•	Eligibility: aggressive r/r B-NHL1 with ≥2 prior lines of	•	Eligibility: 2nd line LBCL2
	chemoimmunotherapy or primary refractory	• Exclusion: prior CD19-targeted therapy
•	Exclusion: prior CD19-targeted therapy	•	Objective: tumor response, RP2D

CB-010 TREATMENT AND RP2D

• Median time from confirmed eligibility to the start of lymphodepletion was 2 days (range 0-12)

- Median time from confirmation of eligibility to CB-010 infusion (including lymphodepletion) was 11 days (range 9-21)

• As of the cutoff date, 2 patients have completed the study in CR (defined as 24 months post CB-010 infusion), 16 are ongoing, and 28 have

discontinued, including 5 who died and 23 who experienced disease progression

• Based on the review and analysis of safety, efficacy, and PK data, 80×106 CAR-Tcells has been selected as the RP2D for CB-010

- The safety profile was similar across dose levels

- There was no significant difference in cytopenia recovery across dose levels

- The 80×106 CAR-T cell dose showed improved efficacy in 2L LBCL patients relative to the 40×106 and 120×106 CAR-T cell doses (Figure 2)

	All treated	LBCL	2L LBCL RP2D
	subgroup	subgroup
	(N=46)
	(N=40)	(N=20)
ORR, n (%)	35 (76.1)	29 (72.5)	15 (75.0)
DOR, months, median (range)	5.0 (0.7-23.0+)	2.1 (0.7-23.0+)	4.8 (0.7-19.8+)
CR rate, n (%)	21 (45.7)	17 (42.5)	10 (50.0)
Duration of CR, months, median (range)	6.7 (0.6-23.0+)	6.7 (0.6-23.0+)	NR (0.6-12.2+)
Follow-up time for CR, months, median (range)	12.2 (0.0-23.0)	9.0 (0.0-23.0)	5.2 (0.0-12.2)
Time to first CR, days, median (range)	28 (28-357)	28 (28, 357)	28 (28-357)
PR rate, n (%)	14 (30.4)	12 (30.0)	5 (25.0)

+ denotes censored observation

r/r B-NHL

Lymphodepletion	CB-010
-9 to -3DAYS	DAY 0	28 DAYS	3 MONTHS	6 MONTHS	9 MONTHS	12 MONTHS
				Safety and tolerability
Cyclophosphamide	SINGLE			Response assessment
(60 mg/kg/d for 2 days)
followed by	DOSE	Dose level 1: 40x106	CAR-T cells (N=8, completed4)
Fludarabine
(25 mg/m2/d for 5 days)3		Dose level 2: 80x106	CAR-T cells (N=5, completed4)

Dose level 3: 120x106 CAR-T cells (N=3, completed)

Dose expansion: 30th patient dosed; 80x106 CAR-T cells selected as RP2D

Will enroll ~20 patients at RP2D to prospectively evaluate partial (≥4) HLA matching, DSA screening

NCT04637763

1. Subtypes include: DLBCL, HGBL, tFL, PMBCL, FL (aggressively behaving with POD24 (high risk)), and MZL
2. LBCL subtypes include: DLBCL NOS, HGBL, transformed DLBCL from FL or MZL, and PMBCL
3. Clin Cancer Res. 2011 July 1; 17(13): 4550-4557.doi:10.1158/1078-0432.CCR-11-0116
4. Includes 2 backfill patients at dose level 1 and 2 backfill patients at dose level 2

Key trial endpoints

Primary endpoints	Secondary and exploratory endpoints
Dose escalation (Part A):	Dose escalation (Part A):	Dose expansion (Part B):
• DLTs, AEs, and SAEs	• Concentrations of CB-010 and lymphocyte	• DOR, disease control rate, PFS, levels of
Dose expansion (Part B):	subsets in blood, persistence of CB-010 in	CB-010 and lymphocyte subsets in blood
blood, ORR, and PFS	• Incidence of AEs and SAEs
• ORR

STUDY POPULATION

•	Overall, 46 patients with r/r B-NHL were treated with CB-010 in Parts A and B	• Median patient age was 65 years (range 21-82)
	and had reached at least 28 days post CB-010 infusion as of the data cutoff		with 10 (21.7%) patients ≥70 years old (Table 1)
	date of April 1, 2024	•	Median time since first diagnosis was 10.6 months
•	Of these, 40 patients had LBCL; 34 patients with LBCL received CB-010 as		(range 2.9-196.4)
	second-line treatment (2L LBCL)	•	Median prior lines of therapy was 1 (range 1-8)

Table 1. Patient demographics and disease characteristics

Patient and disease characteristics	All treated	Dose escalation	Dose expansion
(N=46)	(N=16)	(N=30)
Age, years, median (range)	65.0 (21-82)	66.0 (55-82)	63.0 (21-78)
Men, n (%)	36	(78.3)	14	(87.5)	22	(73.3)
ECOG performance status, n (%)
0	21	(45.7)	6 (37.5)	15	(50.0)
1	25	(54.3)	10	(62.5)	15	(50.0)
Months from diagnosis, median (range)	10.6 (2.9-196.4)	29.0 (2.9-196.4)	9.5 (4.9-79.6)
NHL subtype, n (%)
LBCL
DLBCL	26	(56.5)	7 (43.8)	19	(63.3)
HGBL	8 (17.4)	2 (12.5)	6 (20.0)
tFL	4	(8.7)		0	4 (13.3)
PMBCL	2	(4.3)	1	(6.3)	1	(3.3)
Other B-NHL
MCL	3	(6.5)	3 (18.8)		0
FL	2	(4.3)	2 (12.5)		0
MZL	1	(2.2)	1	(6.3)		0
Prior systemic therapies, median (range)	1	(1-8)	2	(1-8)	1	(1-1)
IPI score at screening, n (%)1
0 or 1	11	(23.9)	4 (25.0)	7 (23.3)
2	8 (17.4)	2 (12.5)	6 (20.0)
≥3	18	(39.1)	3 (18.8)	15	(50.0)
Maximum lesion diameter ≥7.5 cm, n (%)	10	(21.7)	3 (18.8)	7 (23.3)
Baseline LDH, U/L, median (range)	216 (126-1799)	202 (126-710)	233.5 (140-1799)
Baseline LDH > ULN, n (%)	23	(50.0)	5 (31.3)	18	(60.0)
LDH >2 x ULN, n (%)	7 (15.2)	1	(6.3)	6 (20.0)

1 IPI scores were not recorded for all patients

- CB-010 PK profile was independent of dose level

Table 2. Dose for all treated patients

			CAR-T cell dose		Total
Study phase	40×106	CAR+ T cells	80×106 CAR+ T cells	120×106 CAR+ T cells
(N=46)
	(N=14)	(N=23)	(N=9)
Dose escalation		8	5	3	16
Dose expansion		6	18	6	30

SAFETY AND TOLERABILITY

Table 3. Treatment-emergent adverse events in ≥20% of all patients

	All treated			LBCL		2L LBCL RP2D
System organ class, n (%)		subgroup		subgroup
	(N=46)
Preferred term, n (%)					(N=40)		(N=20)
	Any grade	Grade ≥3	Any grade	Grade ≥3	Any grade	Grade ≥3
Any TEAE	46 (100)	41	(89.1)	40 (100)	35	(87.5)	20 (100)	18	(90.0)
Thrombocytopenia	30 (65.2)	29	(63.0)	26 (65.0)	25	(62.5)	12 (60.0)	11	(55.0)
Anemia	27 (58.7)	24	(52.2)	24 (60.0)	22	(55.0)	13 (65.0)	11	(55.0)
Neutropenia	22 (47.8)	19	(41.3)	18 (45.0)	15	(37.5)	10 (50.0)	8 (40.0)
White blood cell count	15 (32.6)	14	(30.4)	14 (35.0)	13	(32.5)	9 (45.0)	8 (40.0)
decreased
CRS	26 (56.5)		0	23 (57.5)		0	13 (65.0)		0
Infections	22 (47.8)	10	(21.7)	19 (47.5)	8 (20.0)	9 (45.0)	6 (30.0)
Hypokalemia	11 (23.9)		0	9 (22.5)		0	4 (20.0)		0
Pyrexia	11 (23.9)		0	10 (25.0)		0	2 (10.0)		0
ICANS	10 (21.7)	3	(6.5)	8 (20.0)	2	(5.0)	5 (25.0)	1	(5.0)
Diarrhea	10 (21.7)		0	7 (17.5)		0	3 (15.0)		0

• The most common grade ≥3 TEAEs were	Table 4. Notable treatment-emergent adverse events
thrombocytopenia (63.0%), anemia (52.2%), and
neutropenia (41.3%) (Table 3)				All treated
- 37 out of 46 patients (80%) recovered from
TEAE, n (%)			(N=46)
cytopenias to grade ≤2 by day 35 post
CB-010 infusion
	Any grade		Grade ≥3
• GvHD was not observed in any patients
Cytopenias1	38	(82.6)		38 (82.6)
• TEAEs associated with CB-010 are shown in Table 4
- Median time to ICANS onset was 7.5 days
CRS	26	(56.5)		0
(range 6-34), and median duration was 2 days
(range 1-27)
Infections	22	(47.8)		10 (21.7)
- Median time to CRS onset was 3 days
(range 0-22), and median duration was 3 days
ICANS	10	(21.7)		3 (6.5)2
(range 1-19)
• Five patients died due to AEs following	HLH	1	(2.2)		0
CB-010 infusion, one of which was possibly related
GvHD
to CB-010 per investigator		0	0

• This death was due to complications of a

bladder perforation in the context of a BK virus	1 Includes TEAE records with preferred terms neutropenia, neutrophil count decreased, thrombocytopenia, platelet
count decreased, and anemia
hemorrhagic cystitis	2 2 grade 3 events, 1 grade 4 event, 0 grade 5 events; all events resolved with supportive care

Figure 2. Efficacy outcomes in all patients by CB-010 dose (N=46)

Subtype	PLoT ≥4 HLA

40M dose

*

RP2D
					*
80M
				*

													CR: complete response
dose													PR: partial response
												disease
													SD: no response/stable
120M													Death
													PD: progressive disease
	SINGLE		1	3	6	9	12	15	18	21	24
	CB-010
	DOSE					Months from CB-010 infusion

As of April 1, 2024, data collection ongoing, efficacy based on Lugano criteria *Denotes patient that did not have an efficacy assessment

TRANSLATIONAL ANALYSES

Figure 3. Pharmacokinetics parameters	Figure 4. Changes in B cells, T cells,
	and NK cells over time in all patients

• Peak expansion (Cmax) of CB-010 occurred between days 7 and 10	•	B cell levels remained under the limit of quantitation of the
post infusion
• Persistence of CB-010 was observed up to approximately 30 days		assay for over 100 days on average, supporting specific
	targeting of B cells by CB-010
based on ddPCR assay
•	B cells recover to normal levels by ~260 days
• No relationship between CB-010 dose and exposure
•	T cells and NK cells recovered approximately 3 weeks after
was observed
		completion of lymphodepletion

100

80

(%)	60
Rate
Survival	40

20

0

HLA Matching < 2 HLA Matching is 2-3 HLA Matching >= 4

13

20

13

0

								Median PFS (95% CI)
								14.4 months (1.74, NE)
								Median PFS (95% CI)
			Median PFS (95% CI)				2.8 months (1.94, 8.80)
			2.9 months (1.51, 5.88)
			HLA Matching < 2		HLA Matching is 2-3		HLA Matching >= 4
4	2	0
8	5	3	3	3	2	1	0
7	6	5	3	2	1	1	0
3	6	9	12	15	18	21	24	27	30

Months

Figure 6. Progression-free survival by level of HLA matching in patients with LBCL (N=40)

Median PFS (95% CI)

NR (1.58, NE)

Median PFS (95% CI)

2.8 months (2.04, 8.80)

Median PFS (95% CI)

2.1 months (0.95, 2.96)

IMPACT OF HLA ON CB-010 PK

Figure 7. PK by HLA match level

• Expansion and persistence of CB-010 were impacted by the level of HLA matching

CONCLUSIONS

• In this first-in-human Phase 1 trial in patients (N=46) with aggressive forms of r/r B-NHL,CB-010 demonstrated encouraging safety and antitumor activity
• • No GvHD, no grade ≥3 CRS, 6.5% of patients experienced grade ≥3 ICANS
  • Cytopenia recovery to grade ≤2 occurred in 80% of patients by day 35 after CB-010 infusion
  • For all patients infused, ORR was 76.1%, and 45.7% of patients achieved a CR as best response
• The RP2D has been determined to be 80×106 CAR-T cells
• The off-the-shelf availability of CB-010 allowed for lymphodepletion to begin a median of 2 days after confirmation of eligibility
• Higher HLA matching is associated with improved PFS in these data, and approximately 20 additional 2L LBCL patients with partial HLA matching (≥4 alleles) will be enrolled

ABBREVIATIONS	CORRESPONDING AUTHOR	American Society of Clinical Oncology Annual Meeting
2L LBCL: patients with large B cell lymphoma receiving second-line treatment; 2L LBCL RP2D: patients in the 2L LBCL subgroup who received 80x106 CAR-T cells; AEs: adverse events; AESIs: adverse events of special interest; B-NHL: B cell non-Hodgkin lymphoma; CAR: chimeric antigen receptor; chRDNA: CRISPR hybrid RNA-DNA;CI: confidence interval; CR: complete response; CRS: cytokine release syndrome; ddPCR: droplet digital polymerase chain	Boyu Hu, MD ([e-mail])	Hematologic Malignancies-Lymphoma and Chronic
reaction; DLBCL: diffuse large B cell lymphoma; DLTs: dose-limiting toxicities; DOR: duration of response; DSA: donor-specific antibodies; ECOG: Eastern Cooperative Oncology Group; FL: follicular lymphoma, aggressively behaving with POD24 (high risk); GvHD: graft-versus-host disease; HGBL, high-grade B cell lymphoma; HLA: human leukocyte antigen; HLH: hemophagocytic lymphohistiocytosis; ICANS: immune effector cell-associated neurotoxicity	Huntsman Cancer Institute, Salt Lake City, UT	Lymphocytic Leukemia
syndrome; IPI: International Prognostic Index; KO: knockout; LBCL: large B cell lymphoma; LDH: lactate dehydrogenase; LLOQ: lower limit of quantification; MCL: mantle cell lymphoma; MZL: marginal zone lymphoma; NE: not estimable; NK: natural killer; NOS: not otherwise specified; NR: not reached; ORR: overall response rate; PD: progressive disease; PFS: progression-free survival; PK: pharmacokinetics; PLoT, prior lines of therapy; PMBCL: primary		June 3, 2024 - Chicago, IL
mediastinal large B cell lymphoma; POD24: progression of disease within 24 months; PR: partial response; RP2D: recommended Phase 2 dose; r/r: relapsed/refractory; SAEs: serious adverse events; SD: stable disease; TCR: T cell receptor; TEAEs: treatment-emergent adverse events; tFL: transformed follicular lymphoma; ULN: upper limit of normal