Innovative drug delivery techniques show promise in clinical trials

Pancreatic cancer has a limited response to chemotherapy treatment, due to the movement of anti-cancer drugs from the blood into tumour cells being limited by cellular mechanisms such as poor perfusion, high stromal content and raised interstitial pressure. One way to overcome these challenges and increase the toxic effect of chemotherapy treatment on a tumour would be to increase drug dosage. However, this would result in the damage of healthy non-tumour cells, and would likely result in unacceptable toxicity to patients.

The aim of Professor Constantin Coussios and his team in the Institute Biomedical Engineering is to develop of drug delivery system capable of enhancing drug penetration into and around a tumour, whilst minimising toxicity to the patient. The team has so far found a successful approach, by increasing drug uptake into tumours through warming of the body, which causes vasodilation.

By using focused ultrasound (FUS) to generate heat, only defined areas (approximately the size of a grain of rice) are targeted for treatment. In combination, chemotherapy drugs such as doxorubicin can be encapsulated in a heat-sensitive lipids (ThermoDox®), so that the active drug is only released when a specific temperature is reached at a specified location, as defined by the position of the FUS beam.

Research fellows Dr Michael Gray (Dept of Engineering) and Dr Laura Spiers (Dept of Oncology) have been working with the Department of Pathology in the Oxford University Hospitals NHS Foundation Trust, to help characterise the efficacy of this approach, by assessing thermal and acoustic ultrasound properties of the ex vivo pancreas.

This new knowledge will be directly applied to patients in the new early phase clinical trial, PanDox (targeting pancreatic cancers with focused ultrasound and doxorubicin chemotherapy). This builds on the successful TarDox trial, which already demonstrated FUS-induced heating resulted in improved delivery of the ThermoDox® encapsulated chemotherapy drugs to liver metastases from various primary cancers.

The effect in the TarDox trial was such that a positive response to therapy from the tumour was seen after only a single treatment cycle in 4 out of 7 patients, even in cancers as colorectal adenocarcinoma (which is not known to respond to conventionally administered doxorubicin). These results suggest that if the cytotoxic threshold needed to successfully treat a tumour can be reached, then a positive response may be achieved without unacceptable toxic consequences on the patient.

The upcoming PanDox trial translates this approach to patients with non-resectable pancreatic adenocarcinomas. It will combine focused ultrasound to generate heat with ThermoDox® delivered into the blood.

The main aim of PanDox is to determine whether this novel approach to treating pancreatic cancer can enhance the amount of drug delivered to tumours that cannot be surgically removed. Secondary aims will assess tumour response and procedural safety. The first patients will be recruited from early 2021.

About the PanDox Team

Prof Constantin Coussios, PanDox Priniciple Investigator, is the Director of the Institute of Biomedical Engineering. His area of interest is in the study of drug delivery systems and improvement of delivery into tumours.  He founded and heads the Biomedical Ultrasonics, Biotherapy and Biopharmaceuticals Laboratory (BUBBL), a research group of 4 faculty and some 45 researchers working on a wide array of therapeutic applications. He is also serves as the Director of the Oxford Centre for Drug Delivery Devices.

Dr Laura Spiers is a doctor of Medical Oncology. She is currently undertaking a DPhil in Oncology with the Institute of Biomedical Engineering, investigating ultrasound-enhanced drug delivery.

Dr Michael Gray is a Senior Research Fellow, interested in the clinical therapeutic potential of ultrasound.