Development of a radiofrequency ablation platform in a clinically relevant murine model of hepatocellular cancer

Abstract

RFA is used in treatment of patients with hepatocellular cancer (HCC); however, tumor location and size often limit therapeutic efficacy. The absence of a realistic animal model and a radiofrequency ablation (RFA) suitable for small animals presents significant obstacles in developing new strategies. To establish a realistic RFA platform that allows the development of effective RFA-integrated treatment in an orthotopic murine model of HCC, a human cardiac radiofrequency generator was modified for murine use. Parameters were optimized and RFA was then performed in normal murine livers and HCCs. The effects of RFA were monitored by measuring the ablation zone and transaminases. The survival of tumor-bearing mice with and without RFA was monitored, ablated normal liver and HCCs were evaluated macroscopically and histologically. We demonstrated that tissue-mimicking media was able to optimize RFA parameters. Utilizing this information we performed RFA in normal and HCC-bearing mice. RFA was applied to hepatic parenchyma and completely destroyed small tumors and part of large tumors. Localized healing of the ablation and normalization of transaminases occurred within 7 days post RFA. RFA treatment extended the survival of small tumorbearing mice. They survived at least 5 months longer than the controls; however, mice with larger tumors only had a slight therapeutic effect after RFA. Collectively, we performed RFA in murine HCCs and observed a significant therapeutic effect in small tumor-bearing mice. The quick recovery of tumor-bearing mice receiving RFA mimics observations in human subjects. This platform provides us a unique opportunity to study RFA in HCC treatment.

Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response

“…18 21 25 Image-guided RFA offers a reliable and reproducible modality to treat hepatic lesions with minimal collateral damage to the surrounding hepatic parenchyma. 13…”

“…Sunitinib synergizes with RFA to improve anti-HCC immune response in the setting of HCC Sunitinib has the capacity to significantly improve RFA therapeutic efficacy. We have previously demonstrated that RFA resulted in apoptotic tumor death, 13 and that tumor-induced immunotolerance was suppressed by sunitinib. 18 25 Thus, we hypothesized that the improved therapeutic efficacy of the combinatorial treatment was Open access attributed to immune activation.…”

“… 14 Minimally invasive RFA is used as a first-line treatment option with significant advantages such as lower morbidity, minimized physiologic insult of surrounding tissues, reduced cost, shorter hospitalization time, and intra-procedural visualization for precise targeting. 13 16 Studies from Zerbini et al 17 and Mizukoshi et al 12 have demonstrated that RFA monotherapy is able to activate tumor-specific T-cell response, but this effect is not sufficient to control HCC, evidenced by tumor recurrence and inferior outcomes. These findings drive us to think about whether we can develop a novel RFA-integrated therapy which can effectively activate anti-HCC immune response to overcome RFA’s limitation including incomplete ablation, tumor recurrence, and inferior outcomes.…”

Development of inCVAX, In situ Cancer Vaccine, and Its Immune Response in Mice with Hepatocellular Cancer

“…The preparation of a clinically relevant murine model of HCC was made as described [ 21 , 22 ]. Briefly, potential oncogenic hepatocytes were isolated from young male MTD2 mice.…”

“…As our previous performance [ 22 ], liver or tumor biopsies were freshly harvested from normal and tumor-bearing mice and frozen immediately by keeping tissue jar in a beaker of 2-methylbutane in dry ice. The frozen tissues were initially stored at −80°C, and transferred to −20°C on the day before sectioning on a cryostat (MICRON, HM 525, Thermo Scientific).…”