Abstract C084: iExplore: A phase I study of mesenchymal stem cell derived exosomes with KrasG12D siRNA for metastatic pancreas cancer patients harboring the KrasG12D mutation

作者：Brandon G. Smaglo, Valerie S. LeBleu, J. Jack Lee, Anirban Maitra, Raghu Kalluri, Katy Rezvani, Luisa M. Solis Soto, Mark W. Hurd, Indreshpal Kaur, Mayela Carolina Mendt Vilchez, Michelle L. Kirtley, Stacy L. Shaftoe, Maria Pia Morelli, Michael J. Overman, Dan Zhou, Robert A. Wolff, Janet Tu, Jason Willis, Ryan Huey, Michael S. Lee, Priya Bhosale, Suzanne Dworsky, Li Xu, Shubham Pant, Elizabeth J. Shpall · 发表于：Cancer Research · 年份：2024 · DOI：10.1158/1538-7445.panca2023-c084 · 被引用次数：9 · 研究领域：Extracellular vesicles in disease、Cancer Genomics and Diagnostics、Renal and related cancers

Abstract Introduction The safety, target engagement, and benefit of iExosomes, short interfering RNA targeting KrasG12D encapsulated within exosomes and intravenously administered, were explored in patients with advanced pancreatic cancer harboring a KrasG12D mutation. Methods The initial phase I protocol was a conventional 3+3 design with three escalating dose levels (levels 1-3) of iExosomes, defined as exosomal protein levels and containing equal amounts of siRNA. Lack of toxicity at the highest dose level subsequently guided protocol amendment to an adaptive design exploring further dose escalation, with one patient treated at each additional dose level (levels 4-6). The highest dose level safely tolerated would be considered the optimal biological dose (OBD). Treatments were administered over three consecutive 14-day cycles. Blood was collected from all patients to assess changes in KrasG12D circulating DNA in response to treatment. Pre and post treatment biopsies were obtained from patients treated at dose levels 4-6 to evaluate target engagement, including changes in phosphorylated ERK levels by immunohistochemistry. Results Twelve patients received multiple iExosome treatments at specified dose levels, and none experienced any related adverse events of any grade. No dose limiting toxicities were observed, and the OBD was determined to be 28.8 mg of iExosome protein, administered in 6 infusions. Levels of circulating KrasG12D DNA decreased over the course of therapy. L...