A First-in-Human Phase 1, Multicenter, Open-Label Study of CB-010, a Next-Generation CRISPR-Edited Allogeneic Anti-CD19 CAR-T Cell Therapy with a PD-1 Knockout, in Patients with Relapsed/Refractory B Cell Non-Hodgkin Lymphoma (ANTLER Study)

Background: Autologous CAR-T cell therapies have shown significant benefit in the treatment of adults with relapsed/refractory B cell non-Hodgkin lymphoma (r/r B-NHL). However, these CAR-T cell therapies have inherent challenges including functional deficiencies in the patient's T cells that could yield an inconsistent or impaired product. In addition, the extended time and complexity in manufacturing the product can limit patient access and potentially require bridging therapy. CB-010 is an allogeneic, off-the-shelf anti-CD19 CAR-T cell therapy derived from healthy donor T cells; it is the lead program in Caribou's allogeneic CAR-T cell therapy platform. Patients (pts) receiving CB-010 do not require leukapheresis or bridging therapy. A next-generation CRISPR-Cas9 genome-editing technology developed at Caribou, which uses Cas9 and CRISPR hybrid RNA-DNA (chRDNA) guides to significantly reduce off-target editing, was implemented to generate 3 genome edits in the manufacture of CB-010: (i) knockout of the TRAC gene to eliminate TCR expression to reduce the risk of graft-versus-host disease (GvHD), (ii)site-specific insertion of a CD19-specific CAR into the TRAC locus, and (iii) knockout of the gene encoding PD-1, designed to limit premature CAR-T cell exhaustion and enhance antitumor activity. Statistically significant preclinical survival benefit across B-NHL subtypes and longer-duration efficacy in vivo compared to similar CAR-T cells without a PD-1 knockout support the clinical evaluation of CB-010.

Methods and Study Design: CB-010 is being investigated in a multicenter, Phase 1 clinical trial in pts with r/r B-NHL. A 3+3 dose escalation design followed by expansion at the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) is being utilized. Primary objectives are to determine the safety and tolerability of CB-010 and the RP2D. Additional key objectives include preliminary antitumor activity and pharmacokinetics (PK). After serially receiving lymphodepletion therapy with cyclophosphamide (60mg/kg/day for 2 days) and fludarabine (25mg/m²/day for 5 days), pts receive a single dose infusion of CB-010 and are followed for safety and efficacy. Initial antitumor activity, as well as time to progression, overall survival, and disease response as measured by Cheson criteria will be evaluated. The study is actively enrolling patients. Cohort 1 at an initial single dose of 40 million CAR-T cells has been completed successfully with 6 patients. Dose escalation of CB-010 is ongoing, and patients are being enrolled in cohort 2 to receive a single dose of 80 million CAR-T cells. The ANTLER Phase 1 trial is registered on clinicaltrials.gov (NCT04637763).

O'Brien:AbbVie, Alexion, Amgen, Aptose Biosciences, Astellas, AstraZeneca, Autolus, Bristol Myers Squibb, Celgene, DynaMed, Eli Lilly and Company, Gilead, GlaxoSmithKline, Janssen Oncology, Johnson and Johnson, Juno Therapeutics, MEI Pharma Inc, Merck, NOVA Resea: Consultancy; Acerta, Alliance, Beigene Ltd, Caribou Biosciences Inc, Gilead, Kite, Loxo Oncology, Mustang, Nurix Therapeutics Inc, Pfizer, Pharmacyclics, Regeneron, Sunesis, and TG Therapeutics.: Research Funding. Nastoupil:Genentech/Roche, MEI, Takeda: Other: DSMC; BMS, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, Genmab, Janssen, IGM Biosciences, Novartis, Takeda: Research Funding; ADC Therapeutics, BMS, Caribou Biosciences, Epizyme, Genentech/Roche, Gilead/Kite, Genmab, Janssen, MEI, Morphosys, Novartis, Takeda: Honoraria. Essell:BMS: Speakers Bureau; Gilead: Speakers Bureau. Nesheiwat:Caribou Biosciences: Current Employment, Current equity holder in publicly-traded company. Hammad:Caribou Biosciences: Current Employment, Current equity holder in publicly-traded company. Davi:Caribou Biosciences: Current Employment, Current equity holder in publicly-traded company. Chung:Caribou Biosciences: Current Employment, Current equity holder in publicly-traded company. Shamsi:Caribou Biosciences: Current Employment. Bryan:Caribou Biosciences: Current Employment, Current equity holder in publicly-traded company. Skoble:Caribou Biosciences: Current Employment, Current equity holder in publicly-traded company. Kanner:Caribou Biosciences: Current Employment, Current equity holder in publicly-traded company. Rizvi:Caribou Biosciences: Current Employment. Holmes:ADC Therapeutics, Adicet Bio, Artiva, Autolus, Bristol-Myers, Caribou Biosciences, Exuma Biotech, Genentech, Incyte, Kite, Novartis: Research Funding; Bristol-Myers, Kite: Honoraria; Karyopharm, Kite, Rigel, Seattle Genetics: Speakers Bureau; ADC Therapeutics, Astra-Zeneca, Bristol-Myers, Crispr Therapeutics, Epizyme, Janssen, Karyopharm, Kite, Novartis, Rigel, TG Therapeutics: Consultancy; Exuma Biotech: Membership on an entity's Board of Directors or advisory committees.