一项可植入微器件用于胰腺癌患者原位评估药物反应的初步研究

Background Standard of care for both early and late-stage pancreatic ductal adenocarcinoma (PDAC) depends in part on effective multi-agent chemotherapy, yet fewer than half of patients respond to their therapy. Although gene expression profiling has identified transcriptomic subsets of PDAC with differential chemotherapy sensitivity, there are currently no in vivo tests to derive patient-specific drug response data. Implantable microdevices (IMDs) address this gap by allowing for the delivery of up to 18 wells containing microdoses of therapeutics directly to the tissue, separated sufficiently such the effect of each well can be analyzed and provide rapid pharmacodynamic readouts without systemic toxicity. IMDs have been evaluated in other solid tumors but never in PDAC. This investigator-initiated clinical trial aims to establish the safety and feasibility of IMD implantation and retrieval during pancreatectomy and to generate individualized drug sensitivity profiles. Trial Design This single-institution pilot study will enroll 10 chemotherapy-naïve patients with resectable PDAC. Each patient will undergo intra-operative placement of the IMD and 4-hour incubation period before resection of the tumor/device en-bloc. The IMD contains triplicate reservoirs of the 5 standard chemotherapy agents for PDAC: gemcitabine, nab-paclitaxel, oxaliplatin, 5-fluorouracil, and SN-38 (active metabolite of Irinotecan) as well as 1 poly-ethylene glycol control well and 2 doxorubicin wells, which allows for confirmation of drug diffusion via autofluorescence. The primary endpoint is safety, defined as the occurrence of any serious adverse event or ≥2 grade 3-4 adverse events constituting individual patient safety failure. Secondary endpoints include the feasibility of IMD placement, retrieval, and processing such that >50% of the drug wells are of sufficient quality for histopathologic assessment and the ability to create an apoptotic/proliferation ratio for each drug in >50% of patients. Exploratory Analysis IMD-derived in vivo drug response profiles will be directly compared with high-throughput drug sensitivity screening performed using patient-derived organoids, an emerging platform for individualized chemotherapy testing that requires prolonged ex vivo culture. In parallel, tissue exposed directly to chemotherapeutic agents will undergo comprehensive correlative analyses, including spatial transcriptomics and proteomics. These integrated, spatially resolved analyses are designed to identify biomarkers of drug response, elucidate mechanisms of therapeutic resistance, and characterize tumor-intrinsic and microenvironmental determinants of chemotherapy sensitivity. Conclusion This first-in-human study evaluates the use of implantable microdevices in PDAC and establishes a novel in vivo platform for rapid, patient-specific therapeutic profiling within the native tumor microenvironment. The trial is currently open and enrolling (NCT07254091).