Stuart J. Corr

Radiofrequency treatment alters cancer cell phenotype

The importance of evaluating physical cues in cancer research is gradually being realized. Assessment of cancer cell physical appearance, or phenotype, may provide information on changes in cellular behavior, including migratory or communicative changes. These characteristics are intrinsically different between malignant and non-malignant cells and change in response to therapy or in the progression of the disease. Here, we report that pancreatic cancer cell phenotype was altered in response to a physical method for cancer therapy, a non-invasive radiofrequency (RF) treatment, which is currently being developed for human trials. We provide a battery of tests to explore these phenotype characteristics. Our data show that cell topography, morphology, motility, adhesion and division change as a result of the treatment. These may have consequences for tissue architecture, for diffusion of anti-cancer therapeutics and cancer cell susceptibility within the tumor. Clear phenotypical differences were observed between cancerous and normal cells in both their untreated states and in their response to RF therapy. We also report, for the first time, a transfer of microsized particles through tunneling nanotubes, which were produced by cancer cells in response to RF therapy. Additionally, we provide evidence that various sub-populations of cancer cells heterogeneously respond to RF treatment.

Non-Invasive Radiofrequency Field Treatment to Produce Hepatic Hyperthermia: Efficacy and Safety in Swine

The Kanzius non-invasive radio-frequency hyperthermia system (KNiRFH) has been investigated as a treatment option for hepatic hyperthermia cancer therapy. The treatment involves exposing the patient to an external high-power RF (13.56 MHz) electric field, whereby the propagating waves penetrate deep into the tumor causing targeted heating based on differential tissue dielectric properties. However, a comprehensive examination of the Kanzius system alongside any associated toxicities and its ability to induce hepatic hyperthermia in larger animal models, such as swine, are the subjects of the work herein. Ten Yucatan female mini-swine were treated with the KNiRFH system. Two of the pigs were treated a total of 17 times over a five-week period to evaluate short- and long-term KNiRFH-associated toxicities. The remaining eight pigs were subjected to single exposure sessions to evaluate heating efficacy in liver tissue. Our goal was to achieve a liver target temperature of 43°C and to evaluate toxicities and burns post-treatment. Potential toxicities were evaluated by contrast-enhanced MRI of the upper abdomen and blood work, including complete metabolic panel, complete blood count, and liver enzymes. The permittivities of subcutaneous fat and liver were also measured, which were used to calculate tissue specific absorption rates (SAR). Our results indicate negligible KNiRFH-associated toxicities; however, due to fat overheating, liver tissue temperature did not exceed 38.5°C. This experimental limitation was corroborated by tissue permittivity and SAR calculations of subcutaneous fat and liver. Significant steps must be taken to either reduce subcutaneous fat heating or increase localized heating, potentially through the use of KNiRFH-active nanomaterials, such as gold nanoparticles or single-walled carbon nanotubes, which have previously shown promising results in murine cancer models.

TH-C-17A-11: Hyperthermia-Driven Immunotherapy Using Non-Invasive Radiowaves

PURPOSEnThe sad truth is that cancer is blamed for the death of nearly one in four people in the US. Immunotherapy offers hope for stimulating cancer immunity leading to targeted killing of cancer cells and a preventative measure for cancer recurrence. Unfortunately, the clinical efficacy of immunotherapy has not yet been established, however novel approaches are being developed, including combining immunotherapy with traditional chemotherapy, radiotherapy or thermal therapy. Therapeutics such as radiofrequency (RF) ablation and select chemotherapeutics induce mild anticancer immune responses. This project seeks to enhance the immune responses stimulated by these agents by co-delivery of nanoparticle-based chemotherapeutics and immune modulators in the presence of RF induced hyperthermia.nnnMETHODSnA 4T1 mouse model of breast cancer is used to test the ability of RF waves to enhance accumulation of nanoparticles in tumor tissue by increasing blood flow and extravation of nanoparticles from hyperpermeable vessels. Images of particle and cell trafficking in the tumor are captured using an integrated RF and confocal imaging system, and tumor growth is monitored by tumor bioluminescence and caliper measurements.nnnRESULTSnHere we demonstrate enhanced intratumoral blood flow induced by non-invasive RF waves and an increase in nanoparticle accumulation in the tumor. IL-12 is shown to have powerful anti-tumor effects leading to tumor regression and the release of Th1-biased cytokines. Doxorubicin nanoparticles combined with adjuvant nanoparticles exhibited superior antitumor effects to single agent therapy.nnnCONCLUSIONnRF therapy combined with nanotherapeutics is a promising approach to enhance the delivery of therapeutics to the tumor and to stimulate a tumor microenvironment that supports the development of cancer-specific immune responses. This research was supported by the National Institute of Health grant numbers U54 CA143837 and U54 CA151668, and the Kanzius Foundation.