Treating Pancreatic Ductal Adenocarcinoma Patients with Rintatolimod: Hitting Two Targets with One Arrow?

Abstract

Introduction: Rintatolimod (Ampligen©), a mismatched double-stranded RNA molecule, is a selective toll-like receptor 3 (TLR3) agonist that boosts antitumor immunity. Recently, the U.S. Food and Drug Administration granted Orphan Drug Designation status to Rintatolimod for the treatment of patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to investigate the direct effect of Rintatolimod on PDAC cells. Methods: Three PDAC cell lines (CFPAC-1, MIAPaCa-2, and PANC-1) were treated with various concentrations of Rintatolimod and their corresponding vehicle control. The proliferation and migration effects were examined using in-vitro assays and the molecular effect was examined by targeted gene expression profiling. Furthermore, human PDAC samples were used to validate the expression of TLR3 by immunohistochemistry. Results: Rintatolimod decreased the proliferation and migration ability of CFPAC-1 cells. In addition, it decreased the proliferation of MIAPaCa-2 cells and the migration of PANC-1 cells. However, it did not have a dual effect in MIAPaCa-2 and PANC-1 cells. Interestingly, TLR3 was highly expressed in CFPAC-1 cells, low expressed in MIAPaCa-2 and not expressed in PANC-1. Gene expression analysis revealed the upregulation of interferon-related genes, chemokines, interleukins and cell cycle regulatory genes. The heterogeneity of TLR3 expression was confirmed in human PDAC samples. Conclusion: intatolimod decreases the proliferation without increasing the migration ability of PDAC cells that express TLR3. The direct effect of Rintatolimod on tumor cells combined with its boosting effect on the immune system highlights the potential therapeutic effect in PDAC patients.