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Clinical Trial Takes Aim at Promising Target in Advanced Gastric, Pancreatic Cancers

Claudin 18.2, a tight junction protein that supports epithelial cell polarity and selective paracellular molecule transport, has become a biomarker of growing interest in the search for more-effective therapies for advanced gastric and pancreatic cancers, which have a very poor prognosis. Although present in healthy gastric mucosa — but usually not in other healthy tissue — it is over-expressed in several types of cancer, including both primary and metastatic gastric and pancreatic tumors, making it an ideal target for those disease sites.

Its accessibility to effector immune cells appears to increase during tumorigenesis. In healthy gastric mucosa, Claudin 18.2 is confined to tight junctions — the barrier between epithelial cells — but disruption of cell polarity exposes it on the cell surface, making it more accessible to immune cells.

In a bid to exploit that potential weakness, a phase 1 clinical trial underway at Roswell Park Comprehensive Cancer Center employs Claudin 18.2-specific CAR T cells to bind to and destroy the cancer cells. Christos Fountzilas, MD, FACP, Co-Leader of the Gastrointestinal Clinical Disease Team and Associate Director for Solid Tumors, Early-Phase Clinical Trials Program at Roswell Park, serves as Site Principal Investigator of the study, “Claudin 18.2-Targeted Chimeric Antigen Receptor T Cells in Subjects with Unresectable, Locally Advanced, or Metastatic Gastric, Gastroesophageal Junction (GEJ), Esophageal, or Pancreatic Adenocarcinoma.

“CAR T cells are a way to restore the immune system against cancer,” explains Dr. Fountzilas. “They have resulted in remarkable outcomes in patients with leukemias, lymphomas — hematologic malignancies in general — because they can remain in the body, expand, and find and kill cancer cells continuously. We hope the outcomes that have been observed with CAR T cells in hematologic cancers can be translated into solid tumors.”

He notes that Claudin 18.2 is a promising target for the CAR T cells because it is selectively over-expressed in cancer, which limits the effects on healthy cells. “The main normal-tissue Claudin 18.2 is expressed in the gastric mucosa.”

The study comprises two parts: Part A, dose escalation, and Part B, dose expansion. In part A, patients with gastric, GEJ or esophageal adenocarcinoma will receive treatment with the autologous CAR T-cell therapy LB1908 at a protocol-defined dose level. Dosage will increase in subsequent patients in keeping with protocol-defined dose-limiting toxicities.

Part A will focus on characterizing the safety and tolerability of LB1908 and identifying the recommended dose expansion to be evaluated in part B. Part B will also enroll patients with pancreatic adenocarcinoma and will aim to identify the recommended dose for an anticipated phase 2 clinical trial.

The clinical trial is sponsored by Legend Biotech USA Inc., which expects to enroll 56 patients, ages 18-75.

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