On May 29, 2024 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leader in T-cell immunotherapy, leveraging its novel allogeneic Epstein-Barr virus (EBV) T-cell platform to develop transformative therapies for patients with cancer and autoimmune diseases, reported preclinical data supporting the potential of ATA3219, an allogeneic, anti-CD19 chimeric antigen receptor (CAR) T-cell therapy candidate for the treatment of B-cell driven autoimmune diseases (Press release, Atara Biotherapeutics, MAY 29, 2024, View Source [SID1234643775]). Findings demonstrate that ATA3219 maintains comparable cytotoxic function and potency while inducing lower levels of pro-inflammatory cytokines compared to autologous benchmark CD19 CAR T cells. The data will be presented in a poster session at the International Society for Cell & Gene Therapy (ISCT) 2024 Annual Meeting taking place May 29 to June 1, 2024, in Vancouver, Canada.

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ATA3219 consists of allogeneic CD19-directed CAR EBV T cells that have been optimized to offer a potential best-in-class profile and off-the-shelf availability. It incorporates multiple clinically validated technologies including a modified CD3ζ signaling domain (1XX) that sustains potent effector function while modulating activation and inflammation; a less differentiated phenotype for robust expansion and persistence; and no modification of the endogenous T-cell receptor (no gene editing) as a key T-cell survival signal.

"Following exciting early clinical data with autologous CD19 CAR T in autoimmune patients, we believe there is an opportunity to further improve long-term efficacy, reduce toxicity and simplify treatment through our optimized allogeneic CD19 CAR T cells," said Cokey Nguyen, Ph.D., Executive Vice President, Chief Scientific & Technical Officer at Atara. "We are pleased to share promising preclinical data that shows ATA3219 mediates robust B-cell depletion against SLE and multiple sclerosis patient derived immune cells. Importantly, ATA3219 is an off-the-shelf option that shows a favorable inflammatory profile that may lead to less toxicity and improved tolerability in the clinic. We look forward to continued evaluation of ATA3219 for the treatment of non-Hodgkin’s lymphoma, lupus nephritis, and in a recently announced cohort expansion for severe SLE without lymphodepletion."

The ATA3219 preclinical data demonstrate potent CD19 antigen-specific cytotoxic activity against CD19+ targets in vitro and in vivo. Data highlights comparing ATA3219 to an autologous benchmark CD19 CAR T include:

More robust central memory cell population as a result of the 1XX co-stimulatory domain and optimized manufacturing process
Complete CAR-mediated B-cell depletion against SLE and MS patient peripheral blood mononuclear cells with comparable potency
Reduced inflammatory profile with decreased secretion of pro-inflammatory cytokines IFN-γ, TNF-α and IL-6, as well as T helper 2 (Th2) cytokines IL-4 and IL-5, while achieving comparable B-cell depletion
These preclinical results support advancing ATA3219 towards clinical evaluation in patients with B-cell driven autoimmune diseases.

ATA3219 is currently being investigated in a Phase 1 trial (NCT06256484) for the treatment of relapsed/refractory B-cell non-Hodgkin’s lymphoma (NHL) with initial clinical data expected in the fourth quarter 2024. Additionally, ATA3219 will be evaluated in a multi-center, Phase 1, open-label, single-arm, dose-escalation study for the treatment of LN with lymphodepletion and a separate cohort in severe SLE without lymphodepletion. Initial data for LN and severe SLE without lymphodepletion is anticipated in the first half and second half of 2025, respectively.

Poster Presentation Details:
Title: ATA3219: Allogeneic CD19 CAR EBV T Cells for the Treatment of B-Cell Driven Autoimmune Diseases
Presenting Author: Alfonso Brito, M.S., Preclinical & Translational Sciences, Atara Biotherapeutics, Inc., Thousand Oaks, CA
Date & Time: Wednesday, May 29, 2024, at 7:00 – 8:30 p.m. PDT
Poster Number: 1025
Session: Poster Networking Session 1
Location: Exhibit & Poster Hall, Vancouver Convention Centre, West Building

About ATA3219

ATA3219 combines the natural biology of unedited T cells with the benefits of an allogeneic therapy. It consists of allogeneic Epstein-Barr virus (EBV)-sensitized T cells that express a CD19 CAR construct for the treatment of CD19+ relapsed or refractory B-cell malignancies, including B-cell non-Hodgkin’s lymphoma and B-cell mediated autoimmune diseases including systemic lupus erythematosus (SLE) and lupus nephritis. ATA3219 has been optimized to offer a potential best-in-class profile, featuring off-the-shelf availability. It incorporates multiple clinically validated technologies including a modified CD3ζ signaling domain (1XX) that optimizes expansion and mitigates exhaustion, enrichment during manufacturing for a less differentiated phenotype for robust expansion and persistence and retains the endogenous T-cell receptor without gene editing as a key survival signal for T cells contributing to persistence.

Next-Generation Allogeneic CAR T Approach

Atara is focused on applying Epstein-Barr virus (EBV) T-cell biology, featuring experience in over 600 patients treated with allogeneic EBV T cells, and novel chimeric antigen receptor (CAR) technologies to meet the current limitations of autologous and allogeneic CAR therapies head-on by advancing a potential best-in-class CAR T pipeline in oncology and autoimmune disease. Unlike gene-edited approaches aimed at inactivating T-cell receptor (TCR) function to reduce the risk for graft-vs-host disease, Atara’s allogeneic platform maintains expression of the native EBV TCR that promote in vivo functional persistence while also demonstrating inherently low alloreactivity due to their recognition of defined viral antigens and partial human leukocyte antigen (HLA) matching. A molecular toolkit of clinically-validated technologies—including the 1XX costimulatory domain designed for better cell fitness and less exhaustion while maintaining stemness—offers a differentiated approach to addressing significant unmet need with the next generation CAR T.