Abstract
BackgroundChemotherapy regimens that include the utilization of gemcitabine are the standard of care in pancreatic cancer patients. However, most patients with advanced pancreatic cancer die within the first 2 years after diagnosis, even when treated with standard of care chemotherapy. This study aims to explore combination therapies that could boost the efficacy of standard of care regimens in pancreatic cancer patients.MethodsIn this study, we used PV-10, a 10% solution of rose bengal, to induce the death of human pancreatic tumor cells in vitro. Murine in vivo studies were carried out to examine the effectiveness of the direct injection of PV-10 into syngeneic pancreatic tumors in causing lesion-specific ablation. Intralesional PV-10 treatment was combined with systemic gemcitabine treatment in tumor-bearing mice to investigate the control of growth among treated tumors and distal uninjected tumors. The involvement of the immune-mediated clearance of tumors was examined in immunogenic tumor models that express ovalbumin (OVA).ResultsIn this study, we demonstrate that the injection of PV-10 into mouse pancreatic tumors caused lesion-specific ablation. We show that the combination of intralesional PV-10 with the systemic administration of gemcitabine caused lesion-specific ablation and delayed the growth of distal uninjected tumors. We observed that this treatment strategy was markedly more successful in immunogenic tumors that express the neoantigen OVA, suggesting that the combination therapy enhanced the immune clearance of tumors. Moreover, the regression of tumors in mice that received PV-10 in combination with gemcitabine was associated with the depletion of splenic CD11b+Gr-1+ cells and increases in damage associated molecular patterns HMGB1, S100A8, and IL-1α.ConclusionsThese results demonstrate that intralesional therapy with PV-10 in combination with gemcitabine can enhance anti-tumor activity against pancreatic tumors and raises the potential for this strategy to be used for the treatment of patients with pancreatic cancer.
Highlights
The intralesional injection of PV-10 can induce the destruction of injected tumors and simultaneously induce a systemic immune response that promotes the regression of distal, uninjected tumors [1, 2]
PV-10 is a solution of the xanthene dye, rose bengal disodium, that is currently being investigated in multiple clinical trials as an anti-cancer agent for multiple malignancies including cutaneous melanoma (NCT02557321) and metastatic liver cancer (NCT00986661) [3, 4]
We demonstrated that the release of the damage associated molecular pattern (DAMP), high mobility group box 1 (HMGB1), from PV-10 injected tumors induced the activation of dendritic cells (DCs) which subsequently primed anti-tumor T cell responses in lymph nodes
Summary
The intralesional injection of PV-10 can induce the destruction of injected tumors and simultaneously induce a systemic immune response that promotes the regression of distal, uninjected tumors [1, 2]. Previous reports from our group have demonstrated that the direct injection of PV-10 into murine melanoma tumors can completely eliminate injected lesions and can promote the regression of distal uninjected (“bystander”) lesions in the skin and lungs [1]. We demonstrated that the release of the damage associated molecular pattern (DAMP), high mobility group box 1 (HMGB1), from PV-10 injected tumors induced the activation of dendritic cells (DCs) which subsequently primed anti-tumor T cell responses in lymph nodes. Chemotherapy regimens that include the utilization of gemcitabine are the standard of care in pancreatic cancer patients. This study aims to explore combination therapies that could boost the efficacy of standard of care regimens in pancreatic cancer patients
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call