On December 11, 2023 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 on ATA3431, a next-generation allogeneic CD20/CD19-dual targeted chimeric antigen receptor (CAR) EBV T-cell therapy candidate (Press release, Atara Biotherapeutics, DEC 11, 2023, View Source [SID1234638409]). Findings support ATA3431 advancement into clinical testing, initially focused on the treatment of B-cell malignancies. The data will be presented in a poster presentation at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting taking place December 9-12, 2023, in San Diego.

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"We’re very excited that ATA3431 is progressing towards an IND submission in 2025 with such a compelling and competitive profile," said Cokey Nguyen, Ph.D., Executive Vice President, Chief Scientific & Technical Officer at Atara. "Our EBV T-cell technology is well validated with over 500 patients treated across our portfolio, and allogeneic EBV T-cell based CD19 targeting is further supported by long-term academic outcomes data with an earlier-generation allogeneic EBV CD19 T-cell construct.1 Building on this robust experience, these preclinical findings provide strong proof-of-concept reinforcing the potential of ATA3431 as a best-in-class approach which we look forward to further evaluating in the clinic."

ATA3431 is an allogeneic, bispecific CAR directed against CD20 and CD19, built on Atara’s EBV T-cell platform that does not require T-cell receptor (TCR) or human leukocyte antigen (HLA) gene editing. The design consists of a tandem CD20-CD19 design, with binders oriented to optimize potency. ATA3431 also incorporates the clinically validated 1XX costimulatory domain that enhances stemness and modulates exhaustion to extend functional persistence.

Compared to an autologous CD20/CD19 CAR-T benchmark, the ATA3431 preclinical data demonstrate potent antitumor activity, long-term persistence, and superior tumor growth inhibition. Data highlights include:

In functional evaluation, ATA3431 showed stable CAR expression with a predominantly CD8+ T-cell distribution. The 1XX signaling domain and optimized manufacturing process that enriches for a less differentiated phenotype yielded a high central memory population compared with autologous CD20/CD19 bispecific CAR-T cells, achieving consistent killing of CD20+ and/or CD19+ tumor cells following repeated in vitro challenges.
ATA3431 demonstrated minimal alloreactivity against HLA mismatched targets due to the inherent ability of EBV T cells to recognize defined viral antigens. The cells also showed HLA-independent activity against CD20+/CD19+ targets in vitro.
ATA3431 mediated highly potent tumor growth inhibition in a lymphoma animal model that correlates with long-term persistence without additional exogenous cytokine support.
ATA3431 showed superior in vivo anti-tumor efficacy, survival, and functional persistence, in both CD19 high- and low-expressing lymphoma models, compared to autologous benchmark CAR-T cells with no observed treatment-related toxicities. This demonstrates ATA3431’s potential to overcome antigen escape, which is hypothesized to be a major cause of treatment resistance or disease relapse with current CD19-targeted CAR-T treatment.
Separately, an academic study presented long-term follow-up data on heavily pre-treated patients infused with an earlier generation off-the-shelf CD19 targeted EBV CAR T-cell construct in B-cell lymphoma and acute lymphoblastic leukemia. Encouraging overall survival of up to three years was observed in 12 patients with relapsed/refractory B-cell malignancies after hematopoietic cell transplant (HCT) treated with 3rd party donor derived allogeneic EBV CD19 CAR T.1

ATA3431 Poster Presentation Details:

Title: ATA3431: Allogeneic CD19/CD20 Bispecific CAR EBV T-cells for the Treatment of B-Cell Malignancies

Presenting Author: Seung Sarah Cha, PhD, Atara Biotherapeutics, Thousand Oaks, CA
Date & Time: Monday, December 11, 2023, 6-8 p.m. PST
Abstract Number: 4800
Poster Session: 703. Cellular Immunotherapies: Basic and Translational: Poster III
Location: San Diego Convention Center, Halls G-H
Next-Generation Allogeneic CAR-T Approach

Atara is focused on applying Epstein-Barr virus (EBV) T-cell biology, featuring experience in over 500 patients treated, 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, EBV T cells maintain expression of native TCRs 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.