(P 290) PRE-CLINICAL STUDY OF TUMOR TREATING FIELDS (TTFIELDS) ALONE OR IN CONJUNCTION WITH SYSTEMIC THERAPIES IN SELECTED BONE- AND SOFT-TISSUE SARCOMAS

Objective: Tumor Treating Fields (TTFields) are a novel anti-cancer modality currently approved in glioblastoma and pleural mesothelioma. Clinical trials are on-going in other cancer types. The fields are delivered via the continuous application of low-intensity (1-3 V/cm), intermediate-frequency (100-500 kHz), alternating electric fields to the region of the tumour. When either used alone or in conjunction with cytotoxic chemotherapies or checkpoint inhibitors, TTFields have been well tolerated as reported in large clinical trials and in clinical practice. Although TTFields application in vitro and in vivo was shown to inhibit growth of various cancerous cell lines, their effect on bone- and soft-tissue sarcoma cell lines have yet been reported. Through in-vitro studies, we investigate potential effects of TTFields in bone- and soft-tissue sarcomas and also investigate the potential for synergism of activities with conventional systemic sarcoma therapies.

Methods: Five bone- and soft-tissue sarcoma cell lines (GCT, HT1080, ISO-HAS-B, SJSA-1 and SW982) were used in the experiments. According to growth rate of individual cell lines, 20,000 to 30,000 cells were plated on a 22mm diameter round cover glasses and transferred to TTFields ceramic dishes after plating. Cells underwent 72hr 200kHz TTFields treatment. For the control group, the cover glasses were placed in a 6 well plates. All data were obtained in triplicate wells. Cells were collected by trypsinization at end of experiment and counted by either flow cytometry equipment BD AccuriC6 or BioradTC20 cell counter. Two intensities of TTFields (0.76V/cm and 1.62V/cm) were tested. Potential synergism with known active systemic therapeutic agents including doxorubicin and pazopanib were explored.

Results: All cell lines were sensitive to 1.62V/cm TTFields, ranging from 40% to 90% of cells decrease compared with their control cell numbers. Inhibitions were less pronounced in all cell lines but to different extents when treated at lower intensity (0.76V/cm). HT-1080 remained most sensitive even at lower intensity, whereas no effects were observed on GCT and ISO-HAS-B. Moreover, congruent dose-response from nanomolar to micromolar concentrations of doxorubicin in control group (incubated over 72hrs without TTFields) was observed. Preliminary testing for potential synergism between TTFields and doxorubicin showed concentrations of doxorubicin required to achieve similar percentage of inhibitory effect is consistently lower in TTFields-treated vs. TTFields non-treated group. Pazopanib was tested specifically in ISO-HAS-B (angiosarcoma cell line). Potential for synergistic activity was also seen.

Conclusion: TTFields are active in both bone- and soft-tissue sarcomas. Whilst the magnitude of activity differs between different sarcoma subtypes, there is potential for TTFields use in this heterogenous group of diseases as a novel therapeutic option. Moreover, achievement of similar percentage of inhibitory effects despite lower doses of systemic therapies when treated in conjunction with TTFields opens possible strategies for dose optimization of otherwise toxic systemic treatments. This may include the possibility for dose reduction and reduction of dose-intensity thus allowing for prolongation of use of effective treatments which have cumulative non-reversible toxicities, including anthracyclines. Further pre-clinical studies are planned, and clinical window-of-opportunity studies will be necessary to validate this approach.

Funding/Support:
Novocure for support of equipment and consumables to conduct these experiments.