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Journal Article Ppublish 6 citations

PubMed: 39321207 DOI: 10.1158/1078-0432.CCR-24-1853

Preclinical Evaluation of AZD6422, an Armored Chimeric Antigen Receptor T Cell Targeting CLDN18.2 in Gastric, Pancreatic, and Esophageal Cancers.

Clin Cancer Res 30(23):5413-5429

Authors: Allison M Barrett, Zachary T Britton, Rosa A Carrasco, Shannon Breen, Maria A S Broggi, Amanda L Hatke, Benjamin Clark, Chunning Yang, Sandrina Phipps, Lorenzo Ortiz, Brianna Janocha, Peter Zanvit, Nicolas A Giraldo, Philip L Martin, Jean-Martin Lapointe, Nathalie Harder, Georgina H Cornish, Bala N N R Attili, Yariv Mazor, Melissa Damschroder, Mark Cobbold, Gordon Moody, Emily E Bosco

Affiliations

  • Early Oncology Research, Gaithersburg, Maryland.
  • Biologics Engineering, Gaithersburg, Maryland.
  • Oncology Translational Medicine, Gaithersburg, Maryland.
  • Translational Pathology, Oncology R&D, AstraZeneca, Gaithersburg, Maryland.
  • Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom.
  • Computational Pathology, AstraZeneca, Munich, Germany.

Abstract

PURPOSE

Claudin 18.2 (CLDN18.2) is a surface membrane protein that is crucial for maintaining tight junctions in gastric mucosal cells and is highly expressed in gastric, esophageal, and pancreatic cancers. Thus, CLDN18.2 is suited for exploration as a clinical target for chimeric antigen receptor T-cell (CAR-T) therapy in these indications. Although CAR-T therapies show promise, a challenge faced in their development for solid tumors is the immunosuppressive tumor microenvironment, which is often characterized by the presence of immune and stromal cells secreting high levels of TGFβ. The addition of TGFβ armoring can potentially expand CAR-T activity in solid tumors. We report on the preclinical development of a CLDN18.2-targeting CAR-T therapy showing effectiveness in patient models with CLDN18.2-positive gastric, esophageal, and pancreatic tumors.

EXPERIMENTAL DESIGN

The lead lentivirus product contains a unique single-chain variable fragment; CD28 and CD3z costimulatory and signaling domains; and dominant-negative TGF-β receptor armoring, enhancing targeting and safety and counteracting suppression. We developed a shortened cell manufacturing process to enhance the potency of the final product AZD6422.

RESULTS

AZD6422 exhibited significant antitumor activity and tolerability in multiple patient-derived tumor xenograft models with various CLDN18.2 and TGF-β levels, as determined by IHC. The efficacy of armored CAR-T cells in tumor models with elevated TGFβ was increased in vitro and in vivo. In vitro restimulation assays established greater persistence and cytolytic function of AZD6422 compared with a traditionally manufactured CAR-T.

CONCLUSIONS

AZD6422 was safe and efficacious in patient-derived, CLDN18.2-positive murine models of gastrointestinal cancers. Our data support further clinical development of AZD6422 for patients with these cancers.

MeSH

Cells, Neoplasms, Receptors, Antigen, Receptors, Chimeric Antigen, Therapeutics, Esophageal Neoplasms, T-Lymphocytes, Receptors, Antigen, T-Cell, Preclinical Evaluation

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