Postdoctoral Fellow University of Missouri, Columbia Columbia, Missouri, United States
Introduction/Rationale: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related mortality, due to therapeutic resistance driven by a fibrotic and immunosuppressive TME and poor antigen presentation. In 2021, Chabu CY et al. reported the use of an iRFP-fluorescent attenuated strain of S. typhimurium (CRC2631) designed serve as cancer immunotherapy. Here, we report the use in PDAC models of an implemented strain of CRC2631 that couples enhanced tumor colonization and immune activation with shRNA-mediated intra-tumoral CMTM6 to lyophilization for scalable and low-cost platform for PDAC treatment.
Methods: The safety and immunological profile of lyophilized iSTORM (iSTORM-0L) was evaluated in unchallenged FVB/nJ and C57BL/6J mice. Specimens received four doses of iSTORM-0L (5×10⁷ or 5×10⁸ CFU), cultivated iSTORM (5×10⁷ or 1×10⁹ CFU), or PBS, in i.p. Health monitoring, plasma cytokines, blood chemistry, flow cytometry-based immune profiling, and blinded histopathology of liver and kidney were assessed through day 32. Based on toxicology results, iSTORM-0L was evaluated in combination with PD-1 and PD-L1 blockade in orthotopic PDAC and KRAS/STK11-mutant NSCLC models (KPC-Luc and KPL: 500.000 cells/mouse in the flank), respectively. Tumor growth and immune profiles were assessed through all the study, and right after treatment, respectively.
Results: iSTORM-0L treatment increased activated CD8⁺ T-cell populations (p>0.05), reduced exhaustion-prone subsets (p>0.01), and enhanced antigen-presentation gene and cellular signatures, resulting in improved tumor control compared with the parental CRC2631 strain.
Conclusion: This study presents a next-generation microbial immunotherapy that integrates tumor-selective targeting, CMTM6 blockade, and clinical readiness through lyophilization and intrinsic biocontainment. iSTORM-0L demonstrated enhanced immune activation and superior tumor control compared with parental CRC2631 in murine PDAC models, supporting its potential as a treatment for solid tumors.
