論文 - 詳細
| RRC ID | 86324 |
|---|---|
| 著者 | Barrett AM, Britton ZT, Carrasco RA, Breen S, Broggi MAS, Hatke AL, Clark B, Yang C, Phipps S, Ortiz L, Janocha B, Zanvit P, Giraldo NA, Martin PL, Lapointe JM, Harder N, Cornish GH, Attili BNNR, Mazor Y, Damschroder M, Cobbold M, Moody G, Bosco EE. |
| タイトル | Preclinical Evaluation of AZD6422, an Armored Chimeric Antigen Receptor T Cell Targeting CLDN18.2 in Gastric, Pancreatic, and Esophageal Cancers. |
| ジャーナル | Clin Cancer Res |
| 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. |
| 巻・号 | 30(23) |
| ページ | 5413-5429 |
| 公開日 | 2024-12-2 |
| DOI | 10.1158/1078-0432.CCR-24-1853 |
| PII | 748640 |
| PMID | 39321207 |
| PMC | PMC11609629 |
| MeSH | Animals Cell Line, Tumor Claudins* / genetics Claudins* / metabolism Esophageal Neoplasms* / drug therapy Esophageal Neoplasms* / immunology Esophageal Neoplasms* / pathology Esophageal Neoplasms* / therapy Humans Immunotherapy, Adoptive / methods Mice Pancreatic Neoplasms* / drug therapy Pancreatic Neoplasms* / immunology Pancreatic Neoplasms* / pathology Pancreatic Neoplasms* / therapy Receptors, Chimeric Antigen* / immunology Stomach Neoplasms* / drug therapy Stomach Neoplasms* / genetics Stomach Neoplasms* / immunology Stomach Neoplasms* / pathology Stomach Neoplasms* / therapy T-Lymphocytes / immunology Tumor Microenvironment / drug effects Tumor Microenvironment / immunology Xenograft Model Antitumor Assays* |
| IF | 10.107 |
| リソース情報 | |
| ヒト・動物細胞 | NUGC-4(RCB1939) |