Abstract 4753: Ablation of N1-S1 hepatocellular carcinoma in rat livers with nanosecond pulsed electric fields and induction of protective immunity.

Abstract

Abstract Nanosecond pulsed electric fields (nsPEFs) could be used to ablate local tumor masses through minimally invasive or open surgery delivery, but further pre-clinical studies are needed. NsPEFs not only induces permanent permeabilization of cells, but also impacts intracellular organelles and result in apoptosis and other forms of cell death in vitro and in vivo. Hepatocellular carcinoma (HCC) is the third most common cancer cause of mortality worldwide. A diagnosis of HCC carries a guarded prognosis, especially when metastasis is documented. Presently, reliable, curative treatments without recurrence for very early, early, and intermediate HCC stages are still in urgent need of attention. In these studies, we specifically test the efficacy of nsPEFs in an orthotopic HCC rat tumor model. Orthotropic insertion of stably transfected (mcherry and/or luciferase) N1-S1 cells in Sprague Dawley rat livers was used as a model for treating HCC. Cells were treated with pulses with 100 ns duration and electric field strengths of 50 kV/cm. Different pulse numbers were applied. Recent results suggest that treatments of 300 or 500 pulses were more effective when separated by a 6 minute interval than when applied as a continuous, uninterrupted single treatment. However over time and treatment of more than 20 animals, 1000 nanosecond pulses treatment consistently showed successful ablation by effectively inducing tumor cell death. A single treatment of 1000 nsPEFs successfully induces cell apoptosis by activating caspase-9, caspase-3, but not caspase-8 in some cells, indicating induction of intrinsic apoptosis mechanisms as well as caspase-independent cell death, like that observed in vitro with human Jurkat cells. More importantly, rats successfully treated with 1000 pulses showed protective responses to a second N1-S1 intra-hepatic challenge injection of N1-S1 cells, suggesting a host immune response, which is under exploration. As an ideal potential therapy for HCC, nsPEFs treatment did not show any damaging impact on liver blood flow. These studies demonstrate for the first time, successful intra-hepatic treatment of HCC with a potential induction of immunogenic cell death and a host immune response after nsPEF ablation. Citation Format: Ru Chen, Nova Sain, Tye Harlow, Peter Shires, Gary Long, Ricahrd Heller, Stephen Beebe. Ablation of N1-S1 hepatocellular carcinoma in rat livers with nanosecond pulsed electric fields and induction of protective immunity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4753. doi:10.1158/1538-7445.AM2013-4753