Caribou Biosciences : CB-010 ANTLER Case Study iwCAR-T 2024

CB-010 ANTLER Phase 1 trial:

Results from dose escalation phase

Allogeneic anti-CD19CAR-T cell with a PD-1 knockout for r/r B cell non-Hodgkin lymphoma (B-NHL)

April 20, 2024

iwCAR-T meeting (Miami, FL)

Loretta J. Nastoupil, MD

MD Anderson Cancer Center Houston, TX

CB-010 has a PD-1 KO designed to reduce CAR-T cell exhaustion

CB-010

Armored with 3 genome edits

	PD-1 KO	1
Anti-CD19 CAR		3
TCR KO		2
2	PD-L1
1
CD19

MHC I	3

NHL cell

TRAC gene knockout (KO)

• Eliminates TCR expression, reduces GvHD risk

Anti-CD19 CAR site-specific insertion into TRAC locus

• Eliminates random integration, targets tumor antigen

PD-1 KO for enhanced antitumor activity

• Reduces CAR-T cell exhaustion
• Potentially contributes to initial tumor debulking

1st CAR-T in the clinic with	Cas9 chRDNA editing for
checkpoint disruption via	reduced off-target editing and
PD-1 KO1	enhanced genomic integrity

	CAR: chimeric antigen receptor; KO: knockout; CD: cluster of differentiation; chRDNA: CRISPR hybrid RNA-DNA; CRISPR: clustered
2	regularly interspaced short palindromic repeats; PD-1: programmed cell death protein 1; TCR: T cell receptor; TRAC: T cell receptor
alpha constant; scFv: single-chain variable fragment
	1 To Caribou's knowledge.

Anti-CD19 scFv FMC63 with a 4-1BB costimulatory domain

ANTLER CB-010 Presentation @ iwCAR-T | April 20, 2024

CB-010 ANTLER Phase 1 trial:

Dose escalation complete and enrolling 2L LBCL patients in dose expansion

Part A: 3+3 dose escalation - completed (N=16)

• Eligibility: aggressive r/r B-NHL1 with ≥2 prior lines of chemoimmunotherapy or primary refractory
• Exclusion: prior CD19-targeted therapy

Part B: dose expansion - enrolling

• Eligibility: 2nd line LBCL2
• Exclusion: prior CD19-targeted therapy
• Objective: tumor response, RP2D

r/r B-NHL

Lymphodepletion

-9 to -2DAYS

Cyclophosphamide

(60 mg/kg/d for 2 days)

followed by Fludarabine

(25 mg/m2/d for 5 days)3

NCT04637763

CB-010

DAY 0

28 DAYS

3 MONTHS

6 MONTHS

9 MONTHS

12 MONTHS

Safety and tolerability

Response assessment

SINGLE

DOSE

Dose level 1: 40x106 CAR-T cells (N=8, completed4)

Dose level 2: 80x106 CAR-T cells (N=5, completed4)

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

Dose expansion: Enrolling patients (30th patient dosed; enrolling ~20 additional patients to prospectively evaluate partial HLA matching, DSA screening)

	DSA: donor specific antibody; HLA: human leukocyte antigen
3	1 Subtypes include: DLBCL, HGBL, tFL, PMBCL, FL, MZL, MCL (Note, FL subtype is aggressively behaving, with POD24 (high risk))
2 LBCL subtypes include: DLBCL, HGBL, PMBCL, tFL
	3 Clin Cancer Res. 2011 July 1; 17(13): 4550-4557.doi:10.1158/1078-0432.CCR-11-0116	ANTLER CB-010 Presentation @ iwCAR-T | April 20, 2024
	4 Includes 2 backfill patients at dose level 1 and 2 backfill patients at dose level 2

ANTLER dose escalation: baseline and disease characteristics

Characteristics	Total (N=16)
Median age, years (range)	66 (55-82)
Male, n (%)	14	(88)
ECOG performance status, n (%)
0	6	(38)
1	10	(62)
Time since first diagnosis, years
Median (range)	2.4 (0.2-16.4)
Non-Hodgkin lymphoma subtype, n (%)
LBCL	10 (63)
DLBCL	7	(44)
HGBL	2	(13)
PMBCL	1	(6)
Other B-NHL	6 (38)
MCL	3	(19)
FL1	2	(13)
MZL	1	(6)
CD19+ disease, n (%)	16	(100)
Prior systemic therapies, median number (range)2	2 (1-8)

DLBCL: diffuse large B cell lymphoma; FL: follicular lymphoma; HGBL: high-grade B cell lymphoma; MCL: mantle cell lymphoma; MZL: marginal zone lymphoma;

4 PMBCL: primary mediastinal large B cell lymphoma 1 Aggressively behaving, with POD24 (high risk)

2 Patients are CD19 CAR-T naïve

ANTLER CB-010 Presentation @ iwCAR-T | April 20, 2024

CB-010 has generally well-tolerated safety profile (N=16)

No DLTs at dose level 2 or dose level 3, no Grade 3+ CRS, no GvHD observed

	AEs of special	ANTLER dose escalation (N=16)
	interest	CRS	ICANS1	Infections2, 3
	Any grade, N (%)	7 (44%)	4 (25%)	7 (44%)
	Grade 1	4 (25%)	2 (13%)	2 (13%)
	Grade 2	3 (19%)	-	4 (25%)
	Grade 3	-	1 (6%)	1 (6%)3
	Grade 4	-	1 (6%)	-
	Median time to	3.5 (1,7)	7.5 (5,10)	27.0 (0, 279)
	onset,
	days (range)
	Median duration,	3.0 (1,9)	2.0 (1,34)	14.0 (2,63)
	days (range)

		CRS	ICANS	Infections
		Gr 3+	Gr 3+	Gr 3+
	CB-010	0%	13%	6%
	ANTLER Phase 1
	Kymriah	23%	15%	41%
	Phase 24
	Yescarta	13%	31%	29%
	Phase 1/25
	Breyanzi	4%	12%	23%
	Phase 16

AE: adverse event; CRS: cytokine release syndrome; DLT: dose-limiting toxicity; GvHD: graft-versus-host disease;
ICANS: immune effector cell-associated neurotoxicity syndrome; TEAE: treatment-emergent adverse event
1 Four total events, 2 Grade 1; 2 Grade 3+ at dose level 1, both with complete resolution of symptoms with supportive care.
2 Infection events reported were on or after CB-010 infusion, with highest grade reported per patient.
3 Grade 3 cellulitis (right antecubital) occurred after CB-010 infusion and was unrelated to CB-010 per the investigator.
4 Kymriah: USPI, NCT02445248, Schuster NEJM 2019, N=111
5 Yescarta: USPI, NCT02348216, N=101
5 6 Breyanzi: USPI, NCT02631044, N=192
As of May 4, 2023 data cutoff date	ANTLER CB-010 Presentation @ iwCAR-T | April 20, 2024

Months from CB-010infusion

CB-010 ANTLER dose escalation efficacy assessment (N=16)

Overall depth and duration of response

		Prior #	Best		SINGLE
Subtype	Dose		CB-010
Rx	Resp.	Pt # DOSE
FL1	40M	8	CR	1
DLBCL	40M	4	CR	4
DLBCL2	80M	1	CR	7
DLBCL2	80M	1	CR	8
PMBCL3	40M	2	CR	5
MCL	40M	2	CR	134
DLBCL	80M	2	CR	9
MZL	80M	4	PR	154
MCL	40M	4	CR	2
FL1	40M	2	CR	3
DLBCL	40M	2	CR	6
DLBCL	120M	2	CR	10
HGBL2	40M	1	PR	144
MCL	80M	2	PR	164
HGBL2	120M	1	PR	12
DLBCL	120M	2	SD	11

1

6-month

benchmark

*

*

CR: complete response

PR: partial response

SD: stable disease

PD: progressive disease

Overall r/r B-NHL

94% ORR5 in patients treated with CB-010 across all

dose levels (15 of 16)

69% (11 of 16) achieved a CR5

• 44% (7 of 16) had ≥6-month CR5

• 24 months longest CR to date

As of June 20, 2023, data collection ongoing, efficacy based on Lugano

2

3

4

5

6

//

9

//

12

//

15

//

18

//

21

//

24

1 Aggressively behaving, with POD24 (high risk)

• Primary refractory disease

• Patient 5's 3-month scan conducted on day 63 post CB-010 as per investigator's discretion

6 4	Patients 13-16 are backfill patients at 40M and 80M
5	Certain patients converted from a CR or PR to PD at various assessment time points as indicated in the chart above	ANTLER CB-010 Presentation @ iwCAR-T | April 20, 2024
* Update on patient 4 presented at LLM congress (CR ongoing thru month 21) and patient 8 presented at EU CAR-T congress (CR ongoing thru month 15)

Subgroup efficacy profile supports 2L LBCL clinical development

		r/r B-NHL	r/r LBCL2	2L LBCL3
Endpoints		All patients	Subgroup	Subgroup
N, (%)		(N=16)	(N=10)	(N=4)
Overall response rate (ORR)1	15 (94%)	9 (90%)	4 (100%)
Complete response (CR) rate1	11 (69%)	7 (70%)	2 (50%)
≥6-month CR rate1	7 (44%)	5 (50%)	2 (50%)
CR at longest duration to date		24 months	18 months	12 months4

	1 Certain patients converted from a CR or partial response (PR) to progressive disease (PD) at various assessment time points.
7	2 Subgroup includes patient #4, 5, 6, 7, 8, 9, 10, 11, 12, and 14.
3 Four primary refractory patients were enrolled in dose escalation. Subgroup includes patient #7, 8, 12, and 14.

4 Patient #7 had a CR at 12 months, which converted from PR at the prior efficacy assessment.	ANTLER CB-010 Presentation @ iwCAR-T | April 20, 2024

Patient #8 case report (primary refractory DLBCL patient)

	Age	Sex	Race	Ethnicity	Height	Weight	BMI	BSA
	66	Male	Asian	Not Hispanic or Latino	162.6 cm	73.2 kg	28.5 kg/m2	1.79 m2

Medical history and disease characteristics

Tumor subtype	DLBCL
Stage at screening	IV
Years since diagnosis	1 (March 2022)
Prior lines anti-cancer	1
therapy	R-CHOP(Mar-Jun 2022)
	Primary refractory w/
	biopsy-confirmed
	disease progression July
	2022

Relevant past medical history:

• Hyperglycemia
• Hypertension
• Gastroesophageal reflux
• Hyperlipidemia
• Anemia
• Thrombocytopenia

DLBCL confirmed per local pathology report, CD19+ at the time of enrollment in ANTLER trial (Sep 2022)

8 Poster presentation at EHA/EBMT CAR-T meeting (Feb 2024; Valencia, Spain)

ANTLER CB-010 Presentation @ iwCAR-T | April 20, 2024

Patient #8: PR to CR conversion at month 6 with ongoing CR through month 15 (80M CB-010 dose)

	CB-010
	SINGLE
	DOSE
Baseline		Day 28

PR

Month 3

Month 6

CR

Month 9

Month 12

Month 15

PR at

D28

4 EXTRANODAL LOCATIONS AT BASELINE (PET/CT)

2 target lesions: right upper and mid medial thigh (skin)

2 non-targetlesions: right thigh soft tissue, proximal right tibia

9

Poster presentation at EHA/EBMT CAR-T meeting (Feb 2024; Valencia, Spain)

CR at

M6

PR to CR conversion at month 6 per Lugano criteria

ANTLER CB-010 Presentation @ iwCAR-T | April 20, 2024

Patient #8: Robust CAR-T cell expansion observed at day 10 with ctDNA undetectable by month 3

ctDNA undetectable by month 3

CAR-T cell expansion

observed at Day 10 in the

peripheral blood

10 Poster presentation at EHA/EBMT CAR-T meeting (Feb 2024; Valencia, Spain)

ANTLER CB-010 Presentation @ iwCAR-T | April 20, 2024