A PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF CB-010, A NEXT-GENERATION CRISPR-EDITED ALLOGENEIC ANTI-CD19 CAR-T CELL THERAPY, IN PATIENTS WITH REFRACTORY SYSTEMIC LUPUS ERYTHEMATOSUS (GALLOP)

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PV119 / #87 Poster Topic: AS15 - Lupus Nephritis-Clinical Background/Purpose Autologous CD19-directed CAR-T cell therapy led to deep depletion of aberrant B cells in lupus patients, leading to prolonged treatment-free remission in recent publications.[1] However, autologous CAR-T cell therapy is characterized by logistical challenges, including the need for leukapheresis, prolonged manufacturing and QC, and manufacturing failures. These may contribute to treatment delays and extended periods of treatment washout, compounding the risk for flares. Furthermore, the manufacturing time and logistics of autologous CAR-T cell therapies can limit their real-world feasibility and/or access for patients. CB-010 is an allogeneic, off-the-shelf anti-CD19 CAR-T cell therapy derived from healthy donor T cells. Patients receiving CB-010 do not require leukapheresis, thus eliminating the need for treatment washout preceding leukapheresis. CB-010 uses a next-generation genome-editing technology (chRDNA) to generate 3 genome edits: (i) knockout of the TRAC gene to eliminate TCR expression to reduce the risk of graft-vs-host disease, (ii) site-specific insertion of a CD19-specific CAR into the TRAC locus, and (iii) knockout of the gene encoding PD-1, designed to increase cytotoxic activity against B cells. Importantly, PD-1 knockout in CB-010 has demonstrated a statistically significant benefit in efficacy in in vivo preclinical studies. CB-010 also features an FMC63 scFv and a 4-1BB costimulatory domain, a combination used in recently published cases.[1] In the Phase 1 ANTLER trial in 46 relapsed or refractory B cell non-Hodgkin lymphoma patients, CB-010 was generally well tolerated, with no Grade 3 or higher CRS.[2] CB-010 was readily available, with a median of 2 days between the time of eligibility confirmation and the start of lymphodepletion in ANTLER patients. CB-010 led to deep B cell depletion and extended B cell aplasia in the ANTLER trial. Furthermore, in preclinical studies, CB-010 demonstrated lupus-specific B cell targeting both in vitro and in vivo , accompanied by suppression of autoantibody generation as a result of B cell targeting.[3] The combination of these preclinical data and encouraging safety and efficacy data from the ongoing ANTLER clinical trial, support the evaluation of CB-010 in a Phase 1 clinical trial for refractory lupus nephritis (LN) and extra-renal lupus (ERL) patients (GALLOP). Methods CB-010 is being investigated in an open-label, multicenter Phase 1 clinical trial in adult patients with LN and ERL (Figure 1). The GALLOP study will enroll approximately 20 patients. The primary objective is safety. Additional key objectives include preliminary efficacy, pharmacokinetics, and biomarkers of response (Figure 2). After lymphodepletion therapy with fludarabine (25 mg/m 2 /day on Days -5, -4, -3) and cyclophosphamide (20 mg/kg/day on Days -4, -3), patients receive a single infusion of 80 million CB-010 CAR-T cells and are followed for safety and efficacy. Initial efficacy including the SLEDAI-2K, DORIS, and PhGA scores, along with steroid usage and renal responses (LN cohort) will be evaluated. Fig 1. CB-010-mediated B cell aplasia in humanized mouse models NOG-EXL mice were engrafted with human CD34+ HSCs via tail vein injection. At 16 weeks post engraftment, animals were dosed intravenously with 1 × 10 7 CB-010 CAR+ T cells per animal. In-life sampling of peripheral blood was analyzed via flow cytometry every two weeks prior to CAR-T cell administration and every week post CAR-T cell administration. Human CD20+ cells as a percentage of total human CD45+ cells are plotted indicating B cell dynamics (A). Human CD3+ cells as a percentage of total human CD45+ cells are plotted indicating T cell dynamics (B). Significance determined by unpaired T test *p < 0.05, **p< 0.01, ***p < 0.001, ****p< 0.0001. Figure 2. Results Are not available for this trial-in-progress. Conclusions GALLOP is a Phase 1 clinical trial evaluating CB-010 in the treatment of LN and ERL, which has the potential to overcome key barriers to access to CAR-T cell treatment and rapidly deliver care to patients. References: [1.] Muller F. N Engl J Med 2024;390:1631-2. [2.] Hu B. J Clin Onc 2024;42:7025. [3.] Garner E. Accepted for presentation at ACR 2024.

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