Dual-target CLDN18.2/HER2 CAR-NK Cells for Advanced Gastric/GEJ Cancer

This draft is intentionally modeled on current CLDN18.2- and HER2-directed cell-therapy studies on ClinicalTrials.gov and related primary publications. The key strategic choice is that HER2 and ERBB2 are treated as the same target; therefore the meaningful dual-target construct in gastric/GEJ cancer is CLDN18.2 plus HER2. The study is designed as a biomarker-driven, non-randomized phase 1/2 program. In phase 1, patients will receive fludarabine/cyclophosphamide lymphodepletion on Days -5 to -3, followed by three infusions of EB-DT-CAR-NK on Days 0, 3, and 7. A 3+3 dose-escalation structure with three planned dose levels will be used to determine dose-limiting toxicities, maximum tolerated dose, and/or recommended phase 2 dose.

In phase 2, patients will receive the recommended dose on the same schedule in an expansion cohort focused on CLDN18.2-positive gastric/GEJ adenocarcinoma, with prespecified subgroup analyses by HER2 status. The study will assess safety, objective response rate, disease control, durability, survival outcomes, and CAR-NK expansion/persistence. Correlative studies will explore the relationship between baseline CLDN18.2/HER2 expression and clinical outcome.

Inclusion criteria

• Signed informed consent before any study-specific procedure.
• Age 18 to 75 years.
• Histologically confirmed unresectable locally advanced or metastatic gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.
• Central confirmation of CLDN18.2-positive disease by immunohistochemistry, defined for this draft as membranous CLDN18.2 expression in at least 10% of tumor cells. HER2 testing is required for all subjects; HER2-positive disease is defined as IHC 3+ or IHC 2+/ISH+ using gastric/GEJ testing criteria.
• Disease progression after at least 2 prior systemic regimens for advanced disease, including a fluoropyrimidine and platinum agent unless contraindicated or not tolerated. If HER2-positive, prior HER2-directed therapy is expected unless unavailable, contraindicated, or not tolerated.
• At least 1 measurable lesion according to RECIST v1.1.
• ECOG performance status 0 or 1.
• Life expectancy of at least 12 weeks.
• Adequate hematologic, renal, hepatic, pulmonary, and cardiac function.
• Recovery of prior treatment-related toxicities to Grade 1 or baseline, except alopecia or stable endocrine replacement therapy.
• Willingness to provide archival tumor tissue or fresh biopsy material if archival tissue is inadequate for central biomarker confirmation.
• Negative pregnancy test for women of childbearing potential and agreement to use effective contraception during the protocol-defined period

Exclusion criteria

• Prior CLDN18.2-targeted or HER2-targeted genetically modified cell therapy (CAR-T, CAR-NK, TCR-T, or similar).
• Active or untreated central nervous system metastases or leptomeningeal disease.
• Active uncontrolled infection, including uncontrolled HBV, HCV, or HIV viremia.
• Active autoimmune disease requiring systemic immunosuppression.
• Clinically significant uncontrolled cardiovascular disease, including recent myocardial infarction, unstable angina, uncontrolled arrhythmia, or severe heart failure.
• Active gastrointestinal perforation, uncontrolled upper GI bleeding, clinically significant bowel obstruction, or unstable gastric ulcer.
• History of solid-organ transplantation or prior allogeneic hematopoietic stem-cell transplantation with active graft-versus-host disease.
• Requirement for systemic corticosteroids above physiologic replacement (for example, >10 mg/day prednisone equivalent) within 7 days before lymphodepletion.
• Pregnancy or breastfeeding.
• Another active malignancy requiring systemic therapy, except for adequately treated non-melanoma skin cancer, carcinoma in situ, or other protocol-allowed low-risk malignancies.
• Any medical, psychiatric, or social condition that, in the investigator's judgment, would make study participation unsafe or would interfere with interpretation of study results.