SS-3 Tumor Treating Fields: from the Petri dish to the patient

Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, antineoplastic treatment modality targeting rapidly dividing cancer cells using low intensity, alternating electric fields at cell-type-specific intermediate frequencies (100–500 kHz). TTFields therapy is approved for the treatment of newly-diagnosed and recurrent glioblastoma as well as malignant pleural mesothelioma, following clinical trials demonstrating efficacy and a favorable safety profile. Using novel in vitro and in vivo systems for TTFields application, research activities are being conducted to extend the understanding of the underlying mechanisms of action (MoA) and to assess additional means to improve treatment outcomes. The demonstrated antimitotic effects of TTFields discerned the positive combinatorial potential of TTFields with other agents targeting the division process. Subsequent to elucidation of anti-mitotic effects, other downstream effects of TTFields include induction of endoplasmic reticulum stress, up-regulation of autophagy and cell death, thus driving immunogenic cell death. Indeed, in several preclinical models, combining TTFields with immunotherapeutics demonstrated enhanced efficacy. Recently, additional novel effects of TTFields were characterized, including inhibition of DNA damage repair responses and induction of transient and reversible permeabilization of the blood brain barrier (BBB). These new findings offer potentially innovative means to optimize treatment outcomes by combining TTFields with radiation therapy and DNA damaging agents, as well as improved delivery of impermeant agents across the BBB. These scientific findings were instrumental in advancing the clinical pipeline of TTFields, which includes conduct of ongoing trials combining TTFields with a variety of modalities, in approved indications and in other solid malignant tumor types. The aim of this talk is to describe TTFields’ preclinical research activities and tools, and to specify how these study outcomes have defined and advanced the clinical pipeline.