Abstract

Tumour physiology presents a formidable barrier to the delivery of current and emerging anticancer therapeutics, including small-molecule-containing nanomedicines, oncolytic viruses, and therapeutic antibodies. The thermal and mechanical effects produced by ultrasound have a major role to play in enabling therapeutics to overcome the elevated intratumoural pressure, sparse vascularity and dense extracellular matrix encountered in the majority of solid tumours, in order to achieve better intratumoural distribution and therapeutic efficacy. We will start with a brief presentation of the results and lessons learned from the first-in-man trial of remotely activated oncological drug delivery (TarDox, Lancet Oncology 2018), which exploited the thermal effects of extracorporeal ultrasound in order to trigger the release of a small molecule from thermosensitive liposomes. The 10-patient Phase I study demonstrated a significant enhancement (3.7-fold) in the intratumoural dose of doxorubicin in liver tumours following ultrasound for the same systemic dose of the drug, with subsequent radiological response observed in several tumour types that do not typically respond to doxorubicin. We will then present a novel technique exploiting a mechanical effect of ultrasound, known as acoustic cavitation, to enable convective transport and delivery of therapeutics in solid tumours. This approach presents the additional benefit of not requiring modification or encapsulation of the drug and the use of lower-intensity ultrasound delivered from a portable device. Sub-micron cavitation-inducing particles co-administered with oncolytic viruses, antibody-drug conjugates or checkpoint inhibitors (aPDL1, aPD1) have been shown to increase both the penetration and total dose delivered to tumours, and to significantly enhance the therapeutic efficacy of these emerging therapeutics even at a reduced systemic dose. Most recently, we found that the combination of drug and cavitation was critical in producing sustained innate and adaptive immune responses.