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.

A businessman, philanthropist and statesman, the Honorable Nicholas Frank Taubman, has become a Charter Member of the FUSF Council. Formed in 2008, the Council is an advisory team that works closely with the Chairman and members of the Board of Directors.

 

“We are proud and excited to have Ambassador Taubman join the Council. His experience as a diplomat and business leader will add an important dimension to our work,” notes Dorothy Batten, a member of the Foundation’s board of directors and co-chair of the council.

 

Taubman served as President and Chief Executive Officer of Advance Auto Parts between 1969 and 2005, when he became the 42^nd U.S. Ambassador to Romania, a position he held until December 2008. Taubman now serves as president of Mozart Investments in Roanoke.

 

A native of Roanoke, Virginia, Taubman graduated from Mercersburg Academy and earned a Bachelor of Science degree in economics from the Wharton School at the University of Pennsylvania. He received an honorary degree from Hollins University in 2005.

 

Taubman and his wife, Jenny, are the largest donors to the new Taubman Museum of Art in downtown Roanoke, which was named in their honor.

About the FUSF Council

The FUSF Council is an advisory team that supports the FUSF Chairman and Board of Directors. The Council is co-led by Dorothy Batten and Charles H. Seilheimer, Jr. In addition to Ambassador Taubman, the Council’s Charter Members are John B. Adams, Jr., Jane P. Batten, Edgar M. Bronfman, Sr., Thomas N. and Nancy J. Chewning, Cecilia S. Howell, Paula F. Newcomb, Mary Lou Seilheimer, and Alice H. Siegel.

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.”

The Departments of Radiation Oncology and Biomedical Engineering at the University of Virginia Health System launched a new FUS speakers’ series in January funded by the FUSF.

 

The first featured speaker was Chandan Guha, M.D., PhD, a world-class expert in tumor vaccines and director of Translational Research and Vice Chairman of the Department of Radiation Oncology at Montefiore Medical Center in Bronx, New York. His January 14 talk was entitled, “Ionizing radiation and ultrasound enhanced in situ tumor vaccines.”

 

Guha discussed results of some promising experiments in which he used both low and high intensity focused ultrasound (FUS) to stimulate different immunologic responses that could enhance cancer treatment. In particular, he found that focused ultrasound induced cellular protein unfolding and induced a cellular stress response, known as unfolded protein response.

 

By using nonablative, low energy FUS as a first step in his research, Guha hypothesized that he could induce protein unfolding and increase the expression of chaperone proteins – such as heat shock proteins (HSPs) – that try to repair protein misfolding. Overwhelming the immune system in this manner, he believed, would cause intratumoral misfolded proteins to be broken down by the proteosome and eventually increase the number of proteosome-processed, antigenic peptides that bind to HSPs.

 

As a second step, Guha exposed tumors to ablative, high energy FUS one to two days after using low intensity FUS. He believed this would induce cell death and cause the release of intra-tumoral peptide antigens into the extracellular compartment and into the blood stream, resulting in an autologous in-situ tumor vaccination.

 

Results, said Guha, indicate that sequential exposures of low and high FUS can stimulate the body’s own immune system to fight and eradicate cancer cells throughout the body.

 

Following Guha’s talk, James M. Larner, M.D., professor and chairman of UVA's Department of Radiation Oncology and director of the new FUS Center, offered the following statement:

 

“Dr. Guha has been the first to demonstrate that focused ultrasound treatment enhances antigen presentation to dendritic cells. His finding has significant clinical potential. Given that the University of Virginia has a strong peptide vaccine program led by Dr. Craig Slingluff, we are excited by the possibility of collaborations between Dr. Guha’s group and the University of Virginia, not only in the area of antigen presentation but also in several other areas as well. We are grateful to the Focused Ultrasound Foundation for allowing Dr. Guha to share his observations with leading FUS researchers at UVA and are optimistic about the possibilities of productive collaborations.”

 

The next speaker in the series will be Nathan J. McDannold, Ph.D., FUS Program research director at the Brigham and Women’s Hospital in Boston. His talk is scheduled for March 24.