Safety and efficacy of high frequency electrochemotherapy - clinical device development

Introduction: More than 20 000 patients have been treated with electrochemotherapy in more than 150 hospitals in Europe alone since the development of the first clinical device in 2006. Moreover, there are currently tens of ongoing clinical trials worldwide for evaluating electroporation-based treatments. However, currently used electrochemotherapy pulses cause pain and strong muscle contraction. High-frequency electroporation pulses in electrochemotherapy will reduce muscle contraction and excitation of nerves, thereby reducing unpleasant sensations, movement of tissue and electrodes during treatment, and improving the safety of electrochemotherapy near nerves. For this reason, we have studied and shown in a recent human study that high-frequency electrical pulses are less painful and cause negligible muscle contraction. With preliminary in vitro study we have also shown, that high-frequency electrochemotherapy can be as effective as standard electrochemotherapy. Background: Standard electrochemotherapy pulses are monophasic trapezoidal pulses with a duration of 100 µs and a pause between pulses of 100 µs up to 1000 ms. By shortening the duration of pulses to a few µs, the pause between pulses to a range between 1 µs and 1 ms, and introducing bipolar pulses, the volume and magnitude of electrical stimulation can be significantly decreased. Aims: In order to translate high-frequency electrochemotherapy into clinical practice, we have to develop a clinical high-frequency electroporation device and provide missing preclinical data to begin clinical evaluation of the high-frequency electrochemotherapy. This will enable the treatment of larger and deep lying tumours also with only conscious sedation, therefore reducing the requirements for anaesthesia with full muscle relaxation. This also has the potential to enable using electrochemotherapy on an out-patient basis and improving access in the scope of palliative care for frail patients. Expected research outcomes: To achieve the above stated aims, a clinical device for high-frequency electrochemotherapy will be developed. Since the generation of bipolar pulses requires specialized hardware with a special emphasis on safety, detailed studies on safety will be done. We will also develop and numerically optimize specialized applicator for high-frequency electrochemotherapy, since standard electroporation applicators do not meet the emission standards when used with high-frequency pulses. To provide necessary preclinical data, we will first analyse high-frequency electroporation in vitro on murine melanoma cells using Design of Experiments; optimise intracellular delivery of cisplatin by high-frequency pulses in vitro; and test this optimized high-frequency protocols in vivo for antitumor effect, safety and tolerability. The expected results will allow clinical evaluation of high-frequency electrochemotherapy. This will concurrently accelerate the development of clinical high-frequency gene electrotransfection, clinical high-frequency irreversible electroporation, and high-frequency cardiac pulsed field ablation.