The heat is on at Celsion

Small biotech is making giant strides in heat-mediated targeted drug delivery

 

Heat-sensitive nanotechnology is moving closer to dramatically changing cancer therapy. In the near future, this technology will be used to deposit chemotherapy directly onto tumors, minimizing toxic side effects and maximizing treatment efficacy. Though small in size (17 employees), Maryland-based Celsion Corporation is making a huge impact on this important and emerging area of medicine.

Founded in 1982 as Cheung Laboratories, Inc., Celsion specializes in developing products for heat-based medical treatments. In its early years, the company produced devices. It turned its attention to drug making in the late 1990’s after licensing a heat-activated liposomal technology from Duke University. That technology serves as the platform for the company’s first investigational nanomedicine, ThermoDox, a liposome-encased form of a potent, widely used cancer drug, doxorubicin.

In the future, Celsion expects to use its liposomal encapsulation technology for other therapeutics and indications.

 

First investigational drug: ThermoDox

One hundred nanometers in size, ThermoDox liposomes transport doxorubicin intact through a patient’s bloodstream to treatment sites (tumors) that have been heated to the level of mild hyperthermia (40-42 degrees Celsius; 104-107.6 degrees Fahrenheit). When activated by the heat, the liposomes restructure and create channels through which doxorubicin rapidly disperses into surrounding tissue, precisely where needed.

 

 

Two clinical trials are now evaluating ThermoDox as a treatment for primary liver cancer (the global 600-patient Phase III HEAT Study) and for recurrent chest wall breast cancer (the stateside 100-patient Phase I/II DIGNITY Study). The HEAT study is using radiofrequency ablation to both activate ThermoDox and destroy liver tumors. Expected to be completed by June 2010, the DIGNITY trial is using a non-ablative mild heat energy to trigger the drug’s release. Celsion expects to file New Drug Applications after completion of each study.

 

Later this year, the company will begin a randomized Phase II study to evaluate ThermoDox and radiofrequency ablation as a treatment for colorectal liver metastases. Montefiore Medical Center in New York City will be the lead site, and Celsion expects to add at least two other study locations in North America and in the Asia Pacific region. Launch of the new trial follows completion of a Phase I safety study involving 24 patients, 15 of whom had liver metastases from nine primary sites.


Combining MR-guided FUS with ThermoDox

Working in partnership with Royal Philips Electronics (parent company of Philips Healthcare), Celsion has also begun exploring the use of ThermoDox in combination with magnetic resonance-guided high intensity focused ultrasound (FUS) to treat various solid tumor cancers. Researchers at the U.S. National Cancer Institute, Sunnybrook Health Sciences Centre in Toronto and Université de Bordeaux in France have helped establish technical parameters for this combined therapy. Celsion is reported to be in discussions with the FDA regarding the launch of Phase I/II clinical trials to evaluate ThermoDox with MR-guided FUS in treating metastatic bone cancer and pancreatic cancer.

In recent weeks, the Center for Translational Molecular Medicine, a public-private research consortium based in the Netherlands, awarded 6.4 million Euro (approximately $8.7 million U.S.) to Celsion and Philips to develop FUS-mediated ThermoDox therapies for liver tumors and secondary bone tumors. Set to begin in May 2010, the project will be led by the University Medical Center Utrecht in the Netherlands. Also participating are Technical University Eindhoven in the Netherlands and the National Institutes of Health's Clinical Center in the U.S. As a first step, the group will conduct pre-clinical studies to assess doxorubicin drug delivery and to optimize MR-guided FUS performance in this application. According to Celsion, an Investigational New Drug submission is planned for 2010, following successful completion of the pre-clinical studies.

Written by Ellen C., McKenna

Trained as a neurologist, Thilo Hoelscher, M.D., has travelled a long way from his native Germany and his early clinical experiences at that country’s first stroke unit. Now an assistant professor in the Departments of Radiology and Neurosciences at the University of California San Diego, he is Director of its Brain Ultrasound Research Laboratory and working once again on the forefront of medicine.

As a researcher and clinician, Hoelscher has extensive experience in using transcranial ultrasound as a diagnostic tool. In 2007, he learned about high intensity focused ultrasound and became intrigued with its potential to treat the human brain. Since then, he has completed hundreds of preclinical experiments with FUS and concentrated on developing therapies based on a clot-busting technique, transcranial sonothrombolysis. He recently received a multi-million dollar grant from the National Institutes of Health to study sonothrombolysis as a treatment for ischemic stroke.

Hoelscher, who received a FUSF fellowship in 2009, expects to begin pilot clinical trials in 2011 using FUS to treat stroke and believes success is inevitable. “Once it is approved for use in patients, FUS will be without equal – it will have no competition. In treating ischemic stroke, for example, it will dissolve blood clots and restore blood flow within seconds. Drugs like tPA won’t be necessary,” he says.

Hoelscher’s work has moved beyond exploring the thermal ablative capabilities of FUS to assessing its use in precise drug delivery and its ability to induce cellular mechanisms.

Noting that the pace of FUS research is accelerating, he says. “Our work has been booming during the last six to eight months. Everything has started to progress rapidly. Researchers from all over the place are interested in focused ultrasound. Ideas and new collaborations are popping up everywhere.”

Matt Eames - Brain Program Senior Project Engineer

Matt Eames, PhD, is supporting the development of technical infrastructure for clinical FUS.

Eames earned his doctorate in Biomedical Engineering at the University of Virginia in ultrasound. Funding for his position was made possible by an anonymous $1 million donation to the FUSF Brain Program.

Thilo Hölscher M.D.,Visiting Professor at UVA and the Foundation in January

Dr. Thilo Hölscher, Assistant Professor in both Radiology and Neurosciences at the University of California at San Diego, was a guest of the Focused Ultrasound Surgery Foundation and the University of Virginia Department of Neurosurgery on January 13-14, 2010.  Dr. Hölscher attended medical school at the University of Essen in Germany, and did his neurology residency training both there and at the University of Regensburg.  He began a research fellowship in transcranial ultrasound as a Co-Investigator on a P50 NIH grant at the University of California at San Diego in the summer of 2002, where he became an assistant professor in 2004.

Dr. Hölscher is one of the world’s foremost authorities on the use of focused ultrasound in the dissolution of intravascular clot in the treatment of stroke.  He has been instrumental in assisting the Brain Program of the Foundation in developing a comprehensive road map for the pre-clinical studies necessary to complete before beginning pilot clinical trials in patients.

The Foundation has funded Dr. Hölscher in several ways, including work he proposed to generate a skull data base of sound absorption coefficients in 150 skulls of a wide variety of shapes and thicknesses. Shear waves and significant acoustic characteristics are much more significant at lower frequencies (those used for certain transcranial FUS). This is important in offering the possibility of expeditious treatment of stroke patients by omitting the time-consuming process of calculating the correction algorithms for each individual patient.

The combined CT and sound field data acquired will be important to another ongoing FUSF study involving simulations to investigate the possible generation of standing waves or hot spots due to natural focusing within the skull (intracranial reflection). These studies are critical to the overall safety of FUS in the brain.

Dr. Hölscher presented his work to a multidisciplinary audience at UVA Medical Center on January 13, 2010.  He discussed the optimal power range for sonothrombolysis, the potential role of microbubble enhancement and even the possibility of replacing tPA (tissue Plasminogen Activator, a significant cause of hemorrhagic risk as currently employed with stroke patients) with microbubbles, greatly decreasing the risks of treatment.

Illustrating the global nature of his research interests, he finished his talk with a provocative review of the possibilities of inducing heat shock proteins, eradicating Lewy bodies in the treatment of Parkinson’s disease, and even vagal nerve stimulation using FUS to treat the gastrointestinal complications of traumatic brain injury.

Dr. Hölscher was recently awarded NIH RO1 funding as a multi-million dollar grant to study sonothrombolysis in the treatment of stroke.

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