With the recent publication of first-in-human clinical trial results of focused ultrasound-triggered drug delivery that could make a significant difference in the way that liver cancer is treated, the impressive work of the University of Oxford team led by Constantin Coussios, PhD, the Director the Institute of Biomedical Engineering and the Statutory Chair of Biomedical Engineering at Oxford, has been gaining the attention of physicians and researchers worldwide.
The 10-patients treated in the Phase I clinical study all suffered from unresectable and non-ablatable primary or secondary liver tumors refractory to standard chemotherapy. Researchers wondered whether focused ultrasound-triggered drug delivery to these tough lesions could make a difference. “On average, the technique enabled an almost four-fold increase in the drug concentration inside the tumor,” said Professor Coussios. “We were also pleased to see responses in several solid tumor types that do not typically respond to doxorubicin alone, including colorectal metastases in the liver.” More work remains to be done, and the group has plans to extend the technology to other solid organs and initiate a larger study to confirm clinical efficacy of FUS-mediated drug delivery across several chemotherapy treatment cycles.
Professor Coussios also directs the Oxford Centre for Drug Delivery Devices (OxCD3), an innovative collaborative endeavor between academic researchers, pharmaceutical companies, and medical device companies to bring ultrasound-enhanced drug delivery to the clinic across several indications. The unique translational work of the center fulfills its mission to serve as a “multi-disciplinary research and training environment for combinational engineering of biology, chemistry, and medical devices to improve drug delivery under a single roof.” In the case of solid tumors, improving drug delivery means getting the drug deeper into the tumor and reducing its side effects throughout the rest of the body.
Q & A with Professor Coussios
On the heels of his seminal publication in the Lancet Oncology, we asked Professor Coussios to tell us more about how he became interested in focused ultrasound, his current projects, and his plans for the future.
Focused Ultrasound Work
When and how did you get interested in focused ultrasound?
My interest in ultrasound started during my PhD in Cambridge under Prof. Shon Ffowcs Williams, when I began investigating the interactions between ultrasound and red blood cells both experimentally and theoretically. This led me to seek a first post-doctoral fellowship in therapeutic ultrasound, under Prof. Christy Holland at the University of Cincinnati, who introduced me to drug delivery, sonothrombolysis, and theranostic agents, such as liposomes and microbubbles. Under the Hunt Fellowship of the Acoustical Society of America, I then moved to Boston University to work under Prof. Ron Roy, where I had the opportunity to train in theoretical and experimental aspects of ultrasound-induced cavitation, active and passive cavitation detection, non-linear acoustics, and ultrasonically induced heating.
What are your areas of interest in focused ultrasound?
I am interested in all applications of acoustics and bubbles in noninvasive therapy and drug delivery. My three current focus areas are: oncological drug delivery using both cavitational and thermal ultrasound mechanisms; the design of novel sub-micron ultrasound-responsive drug delivery vehicles; and the further development of clinically relevant methods of passive acoustic mapping for cavitation imaging and other applications.
What mechanisms and clinical indications do you study?
My primary expertise is in the seeding, generation, mapping, and control of acoustic cavitation for therapeutic applications. Current clinical indications being investigated by our research group include: oncological drug delivery across the liver, kidney, and pancreas; thermal ablation and cavitation-enhanced thermal ablation of the liver, kidney, and pancreas; cavitation-mediated tissue fractionation for orthopedic applications, particularly the spine; and emerging applications of cavitation-mediated delivery, including intracellular and transdermal drug delivery.
What is the goal of your work?
Everything we do is ultimately patient-centric: as a research group, we seek to develop new platform technologies for delivering, optimizing, and monitoring focused ultrasound treatments that can be readily translated to the clinic by virtue of maximizing safety, efficacy, and cost-effectiveness. We are particularly interested in indications that demand the precision and noninvasiveness of focused ultrasound. Beyond oncology, we also like to stray into novel applications including the intervertebral disc and transdermal vaccination.
What are your funding sources?
The mechanistic and technology development studies within our research group are primarily supported by the UK’s Engineering and Physical Sciences Research Council, including under a national program grant supporting the OxCD3. Our clinical translation work is primarily supported by the UK’s National Institute for Health Research (NIHR), as well as several charities, including Cancer Research UK.
Who are your team members?
The Biomedical Ultrasonics, Biotherapy, and Biopharmaceuticals Laboratory (BUBBL) consists of four principal investigators (Constantin Coussios, Robin Cleveland, Robert Carlisle, and Eleanor Stride) and approximately 35 post-doctoral and doctoral researchers. Our expanded clinical team includes HIFU specialists, Prof. Feng Wu, Mr. David Cranston, and Mr. Tom Leslie, leading interventional radiologists, Prof. Fergus Gleeson and Mr. Paul Lyon, leading oncologists, Prof. Mark Middleton and Dr. Rachel Kerr, and a clinical academic anesthetist, Mr. Sean Scott.
Who are your internal and external collaborators?
Internally, we collaborate extensively with the Oxford Departments of Oncology, Clinical Neuroscience, Surgical Sciences, the Jenner Institute for Vaccine Development, and the Weatherall Institute of Molecular Medicine.
Externally within the UK, we form part of the ThunDARR (https://thunddar.org/) network, involving close collaborations with the Institute of Cancer Research (Prof. Gail ter Haar) and all other UK institutions involved in therapeutic ultrasound research.
Internationally, we collaborate with the NIH (Dr. Brad Wood), the University of Washington (Prof. Larry Crum), the University of Urbana-Champagne (Prof. Ken Suslick), the University of Twente (Prof. Michel Versluis and Dr. Guillaume Lajoinie), and the University of Ulster (Prof. Tony McHale and Prof. John Callan).
What are your greatest achievements? Any major disappointments?
Our greatest achievement was the recent completion of the first-in-man trial of extracorporeally triggered oncological drug delivery (Lancet Oncology, 2018) and the establishment of the Oxford Centre for Drug Delivery Devices (www.drugdelivery.org) working with several pharmaceutical and medical device companies to bring ultrasound-enhanced drug delivery to the clinic across several indications. No major disappointments to date!
What do you see as impediments to your success?
There are no major impediments to future success. A key challenge for our community is the national and international funding and implementation of larger-scale, randomized clinical trials that can help make both the efficaciousness and health economic case for therapeutic ultrasound interventions over the current standard-of-care.
What is your research wish list?
To never have a finite research wish list…
Does the Focused Ultrasound Foundation play any role in your work?
The Foundation does not currently play a significant role in our work but could very well do so in the future.
How many patients have you treated?
Since 2004, we have treated more than 200 patients with focused ultrasound, both in the context of four consecutive clinical trials for liver ablation, kidney ablation, and drug delivery, and as private patients for ablation in the liver, kidney, pancreas, and uterine fibroids.
Do you have any clinical research highlight stories?
Under the work of Feng Wu, Gail ter Haar, David Cranston, James Kennedy, Rowland Illing, and Tom Leslie, the first highlight was the CE-marking of the first extracorporeal focused ultrasound device in Oxford in 2005. The second major highlight was the creation, in 2014, of Oxford University spin-out OxSonics (www.oxsonics.com), aimed at translating cavitation-enhanced drug delivery to the clinic. The third major highlight was the completion and publication of the first published study of FUS-triggered drug delivery in 2018 (Lancet Oncology), as described in the recent press release.
Any follow-up funding opportunities? What comes next?
Building on the momentum of the recent TarDox trial, we are keen to expand on translation and further clinical trials of ultrasound-mediated drug delivery, both in oncological and non-cancer indications, using current and emerging therapeutics.
Clinical Trial Results: Focused Ultrasound Helps Chemotherapy Reach Liver Tumors July 2018
JTU Article of the Month – FUS-Induced Drug Delivery in Liver Tumors November 2017
UK Invests in Creation of FUS Research Network April 2016
Celsion, Oxford University Using Thermodox and HIFU in Metastatic Liver Cancer Trial July 2012
ISTU Names Annual Award Winners June 2012
Key Focused Ultrasound Publications
P.C. Lyon, M.D. Gray, C. Mannaris, L. K. Folkes, M. Stratford, L. Campo, D.Y.F. Chung, S. Scott, M. Anderson, R. Goldin, R. Carlisle, F. Wu, M.R. Middleton, F.V. Gleeson, C-.C. Coussios. TARDOX: A Phase I trial Investigating the Safety and Feasibility of Ultrasound-Triggered Targeted Drug Delivery in Liver Tumours,, Lancet Oncol published July 9, 2018 at DOI: https://doi.org/10.1016/S1470-2045(18)30332-2.
P.C. Lyon, L.F. Griffiths, J. Lee, D. Chung, R. Carlisle, F. Wu, M.R. Middleton, F. Gleeson, C.-C. Coussios. Clinical Trial Protocol for TARDOX: a Phase I Study to Investigate the Feasibility of Targeted Release of Lyso-Thermosensitive Liposomal Doxorubicin (ThermoDox®) using Focused Ultrasound in Patients with Liver Tumours, J Ther Ultrasound 2017;5(1):28.
R. Myers, C. Coviello, P. Erbs, C. Rowe, J. Kwan, J. Foloppe, C, Crake, S. Finn, E. Jackson, J.-M. Balloul, C. Story, C.-C. Coussios, R. Carlisle. Polymeric Cups for Cavitation Mediated Delivery of Oncolytic Vaccinia Virus, Mol Ther 24(9): 1627–1633 (2016).
J.J. Kwan, R. Myers, C.M. Coviello, S.M. Graham, A.R. Shah, E. Stride, R.C. Carlisle, C.-C. Coussios. Ultrasound-Propelled Nanocups for Drug Delivery, Small 2015;11:5305-5314.
S. Mo. R. Carlisle, R. Laga, R. Myers, S. Graham, R. Cawood, K. Ulbrich L. Seymour, C.-C. Coussios. Increasing the density of nanomedicines improves their ultrasound-mediated delivery to tumours, J Controlled Release 2015;210:10-18.
J. Choi, R. Carlisle, C. Coviello, L. Seymour, C.-C. Coussios. Non-Invasive and Real-Time Passive Acoustic Mapping of Ultrasound-Mediated Drug Delivery, Phys Med Biol 2014;59:4861-4877.
R. Carlisle, J. Choi, M. Bazan-Peregrino, R. Laga, V. Subr, L. Kotska, K. Ubrich, C.-C. Coussios, L.W. Seymour. Polymer Stealthing and Focused Ultrasound to Enable Tumor Accumulation and Penetration of Virotherapy, J Natl Cancer Inst 2013;105(22):1701–1710.
C. Jensen, R. Ritchie, M. Gyongy, J.R.T. Collin, T. Leslie, C.-C. Coussios. Spatio-Temporal Monitoring of HIFU Therapy by Passive Acoustic Mapping, Radiology 2012;262(1):252-261.
C.D. Arvanitis, M. Bazan-Peregrino, B. Rifai, L.W. Seymour, C.-C. Coussios. Cavitation-Enhanced Extravasation for Drug Delivery, Ultrasound Med Biol 2011;37(11):1838-1852.
N. Hockham, A. Arora, C.-C. Coussios. A Real-Time Controller for Sustaining Thermally Relevant Acoustic Cavitation during Ultrasound Therapy, IEEE Trans Ultrason Ferroelectr Freq Control 2010;57(12):2685-2694.
M. Gyongy, C.-C. Coussios. Passive Spatial Mapping of Inertial Cavitation during HIFU Exposure, IEEE Trans Biomed Eng 2010;57(1):48-56.
M. Gyongy, M. Arora, J. A. Noble, C.-C. Coussios. Use of Passive Arrays for Characterization and Mapping of Cavitation Activity during HIFU Exposure, Proc IEEE Ultrason Symp 2008:871-878, DOI: 10.1109/ULTSYM.2008.0210.
C.-C. Coussios, R.A. Roy. Applications of Acoustics and Cavitation to Non-Invasive Therapy and Drug Delivery, Annu Rev Fluid Mech 2008;40:395-420.
C.-C. Coussios, C.H. Farny, G. ter Haar, R.A. Roy. Role of Acoustic Cavitation in the Delivery and Monitoring of Cancer Treatment by High Intensity Focussed Ultrasound (HIFU), Int J Hyperthermia 2007;23(2):105-120.
G. ter Haar, C.-C. Coussios. HIFU: Physical Principles and Devices, Int J Hyperthermia 2007;23(2):89-104.