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
Authors: Smaglo Brandon G. , LeBleu Valerie S. , Lee J. Jack , Maitra Anirban , Kalluri Raghu , Rezvani Katy , Solis Soto Luisa M. , Hurd Mark , Kaur Indreshpal , Mendt Vilchez Mayela C. , Kirtley Michelle L. , Shaftoe Stacy L. , Morelli Maria Pia , Overman Michael J. , Zhou Dan , Wolff Robert A. , Tu Janet , Willis Jason A. , Huey Ryan W. , Lee Michael S. , Bhosale Priya R. , Dworsky Suzanne W. , Xu Li , Pant Shubham , Shpall Elizabeth J. 
Published: January 2024

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. Levels of phosphorylated ERK in tumor biopsies decreased while on treatment, dropping to undetectable levels in higher dose levels. Clinically, the best response observed was stable disease as per RECISTv1.1 criteria in three patients, one each at dose levels 1-3. Conclusions iExosome therapy targeting KrasG12D is a safe and well-tolerated treatment for metastatic pancreatic cancer. Decrease in levels of circulating KrasG12D DNA and suppression of downstream Kras signaling phosphorylated ERK in tissue biopsies support effective target engagement of iExosomes in patients. Considering preclinical studies that indicate iExosome treatment enhances immune mediated anti-tumor responses, a future trial design will explore iExosomes at the OBD in combination with immune checkpoint inhibition for the treatment of pancreatic cancer.
Citation Format: Brandon G. Smaglo, Valerie S. LeBleu, J. Jack Lee, Anirban Maitra, Raghu Kalluri, Katy Rezvani, Luisa M. Solis Soto, Mark Hurd, Indreshpal Kaur, Mayela C. Mendt Vilchez, Michelle L. Kirtley, Stacy L. Shaftoe, Maria Pia Morelli, Michael J. Overman, Dan Zhou, Robert A. Wolff, Janet Tu, Jason A. Willis, Ryan W. Huey, Michael S. Lee, Priya R. Bhosale, Suzanne W. Dworsky, Li Xu, Shubham Pant, Elizabeth J. Shpall. iExplore: A phase I study of mesenchymal stem cell derived exosomes with KrasG12D siRNA for metastatic pancreas cancer patients harboring the KrasG12D mutation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C084.