Autologous T-cells engineered to express CARs targeting Mesothelin and Claudin18.2, for Unresectable locally advanced or metastatic pancreatic adenocarcinoma (Pancreatic Ductal Adenocarcinoma, PDAC), administered as two separate sequential infusions following lymphodepleting chemotherapy
Pancreatic cancer is one of the most lethal malignancies, with a poor prognosis in advanced stages. Mesothelin (MSLN) and Claudin 18.2 (CLDN18.2) are tumor-associated antigens overexpressed in pancreatic adenocarcinoma cells. Both are promising immunotherapy targets, as they are prevalent in pancreatic tumors while largely restricted in normal tissues. CAR-T cell therapies directed at these antigens have shown early evidence of safety and anti-tumor activity. For example, mesothelin-specific CAR T cells have achieved stable disease and metabolic tumor regression in initial trials without dose-limiting toxicity. Similarly, CLDN18.2-specific CAR-T cells yielded objective remissions (including complete remission) in refractory pancreatic cancer, albeit with some gastric mucosal toxicity due to low-level target expression in normal stomach. Targeting two antigens may improve tumor control by addressing antigen heterogeneity and reducing immune escape. This trial evaluates a dual-target CAR-T strategy, in which two separate CAR-T products (one for mesothelin, one for claudin18.2) are given sequentially.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
60
The intervention in this clinical trial involves a novel approach using Mesothelin and Claudin 18.2 Chimeric Antigen Receptor T (CAR T) cells combined with chemotherapy. The goal is to assess safety and efficacy in patients with specific hematologic malignancies. Treatment Regimen: Fludarabine Phosphate (Days -4 to -2): IV administration of fludarabine phosphate over 30 minutes on days -4 to -2. It's part of the preparatory regimen to enhance the body's response to CAR T-cell therapy. Cyclophosphamide (Day -2): IV cyclophosphamide over 60 minutes on day -2. Mesothelin and Claudin 18.2 Chimeric Antigen Receptor T Cells (Day 0): IV administration of investigational therapy, Mesothelin and Claudin 18.2 CAR T cells, over 10-20 minutes on day 0. Additional Doses: Eligible patients responding well to the initial Mesothelin and Claudin 18.2 CAR-T cell infusion without unacceptable side effects and sufficient CAR-T cell availability may receive 2 or 3 additional doses.
District One Hospital
Beijing, Beijing Municipality, China
RECRUITINGIncidence and severity of dose-limiting toxicities (DLTs) following chemotherapy preparative regimen and infusion of CD19/BCMA chimeric antigen receptor (CAR) T cells
Will be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at three dose levels until the maximum tolerated dose (MTD) is determined.
Time frame: 28 days
Rate of successful manufacture and expansion of the Mesothelin and Claudin 18.2 chimeric antigen receptor (CAR) T cells
satisfy the targeted dose level and meet the required release specifications outlined in the Certificate of Analysis (COA)
Time frame: 60 days
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