Preclinical Evaluation of AZD6422, an Armored Chimeric Antigen Receptor T Cell Targeting CLDN18.2 in Gastric, Pancreatic, and Esophageal Cancers
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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.
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- Authors
- Barrett, A. M., Britton, Z. T., Carrasco, R. A., Breen, S., Broggi, M. A. S., Hatke, A. L., Clark, B., Yang, C., Phipps, S., Ortiz, L., Janocha, B., Zanvit, P., Giraldo, N. A., Martin, P. L., Lapointe, J.-M., Harder, N., Cornish, G. H., Attili, B. N. N. R., Mazor, Y., Damschroder, M., Cobbold, M., Moody, G., & Bosco, E. E.
- Affiliations
- AstraZeneca (United States) (US)
- 4Translational Pathology, Oncology R&D, AstraZeneca, Gaithersburg, Maryland.
- AstraZeneca (United Kingdom) (GB)
- 6Computational Pathology, AstraZeneca, Munich, Germany.
- Corresponding author
- Barrett, Allison M.
- ORCID
- Barrett, Allison M.
- Britton, Zachary T.
- Carrasco, Rosa A.
- Breen, Shannon
- Broggi, Maria A.S.
- Hatke, Amanda L.
- Clark, Benjamin
- Yang, Chunning
- Phipps, Sandrina
- Ortiz, Lorenzo
- Janocha, Brianna
- Zanvit, Peter
- Giraldo, Nicolas A.
- Martin, Philip L.
- Lapointe, Jean-Martin
- Harder, Nathalie
- Cornish, Georgina H.
- Attili, Bala N.N.R.
- Mazor, Yariv
- Damschroder, Melissa
- Cobbold, Mark
- Moody, Gordon
- Bosco, Emily E.
- Venue
- Clinical Cancer Research
- Published
- 2024-09-25
- Volume
- 30
- Issue
- 23
- Pages
- 5413-5429
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC11609629
- OpenAlex
- W4402832395
- Cited by
- 43
- References
- 66
- Citations by year
- 2026: 21 · 2025: 22
- FWCI
- 7.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Clinical Cancer Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- N/A (N/A)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- claudin 18.2, chimeric antigen receptor T cells, CAR T-cell therapy, gastric cancer, pancreatic cancer, esophageal cancer, immunosuppressive tumor microenvironment, patient-derived xenografts, lentiviral vectors, T cell persistence, anticancer activity
- MeSH terms
- Receptors, Chimeric Antigen, Animals, Esophageal Neoplasms, Humans, Pancreatic Neoplasms, Stomach Neoplasms, T-Lymphocytes, Immunotherapy, Adoptive, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Claudins, Tumor Microenvironment
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