Caribou Biosciences : CB-010 ANTLER Case Study

Abstract ID: 1597488

Durable complete response achieved in a relapsed/refractory diffuse large B cell lymphoma (DLBCL) patient treated with a CRISPR-edited allogeneic anti-CD19CAR-T cell therapy with a PD-1 knockout: Case report from the CB-010 ANTLER trial

Elizabeth Brem1, Lauren Pinter-Brown1, Christina Kirk1, Emiri Matsuda1, Blake Johnson1, Ashley Hammad2, Donna Mastey2, Shally Chung2, Kalin Bird2, Ben Thompson2, Guy Ledergor2, Franco Davi2, Ashraf Garrett2, Elizabeth Garner2, Enrique Zudaire2, Steven Kanner2, Tonia Nesheiwat2, Socorro Portella2, Syed Rizvi2, Susan O'Brien1

1University of California Irvine, Irvine, CA 2Caribou Biosciences, Inc., Berkeley, CA

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

Patient case presentation

PET/CT scans: ongoing CR through month 21

Key attributes	CB-010	Conventional allogeneic
anti-CD19CAR-Ts
Cas9 chRDNA editing for enhanced	CB-010	allogeneic anti-CD-
genomic integrity	1Conventional9 CAR-Ts
• Reduced off-target editing and	CB-010	Conventional allogeneic
genomic rearrangements	anti-CD-19CAR-Ts
TRAC gene knockout (KO)	CB-010
• Eliminates TCR expression, reduces	CB-010	Varies
GvHD risk
Anti-CD19 CAR site-specific insertion
into TRAC locus		Varies
• Eliminates random integration,	CB-010
anti-CD-19CAR-Ts
targets tumor antigen
PD-1 KO for enhanced antitumor	CB-010	Conventional allogeneic
activity	anti-CD-19CAR-Ts
• Potentially better therapeutic index	CB-010	Conventional allogeneic
anti-CD-19CAR-Ts
via initial tumor debulking

CB-010 CAR construct uses an anti-CD19 scFv FMC63 with a 4-1BB costimulatory domain

CB-010

PD-1 KO

	Anti-CD19
TCR KO	CAR

PD-L1

NHL cell

CD19

MHC I

NHL cell

Program: CB-010

Healthy donor leukapheresis-derived T cells

Tumor antigen:

CD19

Indication:

r/r B cell non-Hodgkin lymphoma (B-NHL)

Status:

Ongoing Phase 1 trial enrolling 2L LBCL

patients in dose expansion

Patient demographics

Age	Sex	Race	Ethnicity	Height	Weight	BMI	BSA
68	Male	Not reported	Hispanic or Latino	172.7 cm	129.5 kg	43.4 kg/m2	2.49 m2

Medical history and disease characteristics

Tumor subtype	DLBCL (GCB)	Relevant past medical history:	DLBCL confirmed per local
		• Type II diabetes	pathology report, CD19+ at
Stage	III	• Obesity	diagnosis and at the time of
		• Hypertension	enrollment in ANTLER trial
Years since	9 (Sep 2013)
• Aortic stenosis, non-rheumatic
diagnosis
Prior lines anti-	4
cancer therapy

BMI: body mass index, BSA: body surface area, CD: cluster of differentiation; GCB: germinal center B-cell-like

4 prior lines of systemic anti-cancer therapy

CB-010

SINGLE

DOSE

Baseline

Day 28

Month 3

Month 6

Month 9

Month 12

Month 15

Month 18

Month 21

9 nodal locations at baseline (PET/CT)	Complete Response
9 nodal lesion locations: supraclavicular, common iliac, external
per Lugano criteria
iliac, inguinal, bilateral cervical, intraparotid, retroperitoneal,
bilateral iliac chain, and left inguinal

CR: complete response, CT: computed tomography, PET: positron emission tomography

CB-010 has a generally well-tolerated safety profile
No GvHD, CRS, ICANS, prolonged cytopenias or infections observed in this patient
Cytopenia recovery to ≤ Grade 1 by Day 28
CTCAE Term	Max Grade	Days to Recovery (Gr1) 1
Anemia	Grade 2	13 days
Platelet count decreased	Grade 4	3 days

CAR: chimeric antigen receptor; KO: knockout; CD: cluster of differentiation; chRDNA: CRISPR hybrid RNA-DNA; CRISPR: clustered 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

CB-010 ANTLER Phase 1 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

r/r B-NHL

							DLBCL confirmed CD19+
							Enrollment into ANTLER trial
	R-CHOP		BEAM + ASCT			CB-010
				Best response: CR
1	Best response: CR		3 Best response: unknown
	D/C: completed treatment	D/C: completed treatment
2013	2014	2015	2016	2017	2018	2019	2020	2021 - Ongoing

R-ICE	Ublituximab + Umbralisib
2 Best response: PR	4 Best response: PR
D/C: completed treatment	D/C: disease progression*

* Disease progression on Ublituximab + Umbralisib occurred in June 2021 prior to ANTLER enrollment

Neutrophil count decreased

Grade 4

7 days

Hemoglobin recovery

Platelet recovery

Neutrophil recovery

14

Lymphodepletion

Dose limiting toxicity

Lymphodepletion

Dose limiting toxicity

LD DLT

Lymphodepletion

Dose limiting toxicity

LD DLT

(LD) period

(DLT) evaluation period

LD DLT

(LD) period

(DLT) evaluation period

6

(LD) period

(DLT) evaluation period

300

Hemoglobin (g/dL)

12

Platelets (10^9/L)

Neutrophils (10^9/L)

4

200

10

Gr2

2

100

Gr2

Gr2

Gr3

Gr3

8

Gr3

0

200

400

600

200

400

600

200

400

600

CB-010

Days from Infusion

CB-010

Days from Infusion

CB-010

Days from Infusion

1Days to Recovery (Gr1) is defined as the date of the first occurrence of CTCAE Grade 1 or better after Maximum CTCAE Grade

Lymphodepletion	CB-010
-9 to -2 DAYS	DAY 0	28 DAYS	3 MONTHS	6 MONTHS	9 MONTHS	12 MONTHS
				Safety and tolerability
Cyclophosphamide				Response assessment
(60 mg/kg/d for 2 days)	SINGLE
followed by	DOSE

Fludarabine	Dose level 1: 40x106	CAR-T cells (N=8, completed4)
(25 mg/m2/d for 5
Dose level 2: 80x106	CAR-T cells (N=5, completed4)
days)3
Dose level 3: 120x106 CAR-T cells (N=3, completed)

Dose expansion: Enrolling patients (approximately 30 total)

NCT04637763

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 NOS, HGBL, PMBCL, tFL, tMZL
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

• 2023 Caribou Biosciences, Inc.

Patient timeline on ANTLER trial

		CR reported
Lymphodepletion*		on day 28 scan
Nov 1-7, 2021	Nov 10, 2021	Dec 10, 2021

SINGLE

DOSE

CB-010 infusion

(dose level 1: 40x106 CAR-T cells)

* Cyclophosphamide (60 mg/kg/d for 2 days) followed by Fludarabine (25 mg/m2/d for 5 days)

CR ongoing

through month 21

Aug 2, 2023

CB-010: ANTLER Phase 1 trial summary

• CB-010is the first allogeneic CD19-directedCAR-T cell therapy in the clinic with a PD-1 knockout, a genome-editing strategy designed to enhance antitumor activity by limiting premature CAR-T cell exhaustion
• As previously reported, patients enrolled in the dose escalation portion of the ANTLER trial achieved a 94% ORR, 69% CR rate and a 44% CR rate at ≥ 6 months and CB-010 demonstrated a generally well tolerated safety profile (N =16)
• • Durable CRs observed with the longest ongoing CR through month 24
  • PR to CR conversions observed in 3 patients with LBCL
• In this case report, a heavily pretreated DLBCL patient received CB-010 (40 x 106 CAR-T cells) and no GvHD, CRS, ICANS, prolonged cytopenias, or infections were observed with ongoing CR through month 21
• Enrollment of 2L LBCL patients is ongoing in dose expansion

CB-010 was granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track,

and Orphan Drug designations by the FDA in 2022

"Caribou Biosciences" and Caribou's logo are registered trademarks of Caribou Biosciences, Inc.

CORRESPONDING AUTHOR: Elizabeth Brem, M.D. ([e-mail])	OCTOBER 18-21, 2023
University of California Irvine, Irvine, CA	NEW YORK CITY, NY