Molecular Enhancement of Thermal Ablation Therapies Using TNF-α-Coated Gold Nanoparticles in a Translational Model of Renal Tumors

Abstract

Thermal ablation therapies are currently used for the treatment of select renal masses. Such treatments are limited to tumors that are small (<3 cm diameter), exophytic, and away from vital structures such as ureter or intestine. Novel treatment approaches are geared towards increasing the size of the thermal lesion created, limiting damage to collateral normal tissues, reducing local recurrence and distant metastases as well as improving the imaging potential of the therapy. Previous studies have demonstrated the enhancement of thermal therapies in pre-clinical murine models of solid tumors by intravenously infusing 33 nm TNF-α and PEG coated gold nanoparticles (CYT-6091, Cytimmune Sciences Inc.) prior to ablation. This study investigates the enhancement of thermal ablation therapy by CYT-6091 in a translational animal model of renal tumors. New Zealand White rabbits (37 for radiofrequency ablation (RFA), 20 for cryoablation) had VX-2 tumors implanted into their bilateral kidneys. The tumors were allowed to grow for 14 days to a size of ∼1 cm. For RFA, the rabbits were split into 3 treatment groups of 10 rabbits each and a sham group of 7 rabbits. The groups were treated with CYT-6091 (200 μg/kg) only, RFA only, or CYT-6091 (200 μg/kg) followed 4 hours later by RFA. For cryoablation, 2 treatment groups of 10 rabbits each were used. The groups were treated with cryoablation only or CYT-6091 (200 μg/kg) followed 4 hours later by cryoablation. The kidneys were harvested 3 days later for RFA and 7 days later for cryoablation. Gross and microscopic measurements of the ablation size as well as histological analysis using H&E staining were performed. The RFA plus CYT-6091 group had a larger zone of complete cell death than the RFA only group when measured both on gross sectioning (0.32±0.03 vs. 0.22±0.07cm3, p=0.015) and on microscopic examination (0.30±0.07 vs. 0.23±0.03cm3, p=0.03). Overall this was a 23% increase in ablation volume. This difference in ablation size was due to a replacement of partially ablated tissue at the periphery in the RFA only group by completely ablated tissue in the RFA plus CYT-6091 group. Thus this zone of partially ablated tissue was smaller in the RFA plus CYT-6091 group than the RFA only group (0.08±0.02cm3 vs. 0.13±0.05cm3, p=0.01). Excessive tumor growth into the ablation lesion at day 7 following cryoablation prevented accurate measurements in these groups; however, a significant decrease in the rate of peritoneal carcinomatosis (metastases) was obtained in the cryo plus CYT-6091 group compared to the cryoablation alone group (1/10 vs. 8/10, p=0.04). We have shown that use of CYT-6091 prior to thermal ablation therapy in a rabbit kidney tumor model can minimize the zone of partial treatment at the periphery of the thermal lesion and thus maximize the complete kill zone in RFA while significantly decreasing the rate of metastases in cryoablation. These data provide preliminary evidence for the efficacy of adjuvant use of CYT-6091 for thermal ablation therapies in a large animal translational tumor model.