Needham’s Liposomes Headed to Liver Cancer Trials Via Celsion Corporation

A cancer treatment technology developed by Duke materials engineer David Needham and radiation oncologist Mark Dewhirst has started Phase III human clinical trials in both Hong Kong and the United States.

The technology is a heat-sensitive engineered capsule called a liposome containing the frequently-used chemotherapy drug doxorubicin.

The invention was prompted when Dewhirst asked Needham in the early 1990s for something that releases a drug when heated to just above body temperature. Having worked on lipid membranes for more than 10 years at that point in Cambridge University, U.K., University of British Columbia, Vancouver Canada, and then as an assistant professor at Duke, Needham turned to liposomes -- membrane-bound capsules made from the same lipids that surround every cell in the human body.

Various formulations of liposomes have been tested since the early 1970s, but no one had figured out how to release the drug once the liposome reached the tumor.

Needham’s experiments focused on how membrane-like molecules called lysolipids, that were soluble in water could also enter and leave cell membranes. This work led to the creation of thermal-sensitive liposomes that could release its doxorubicin after a temperature increase of only a few degrees above body temperature. Dewhirst and his colleagues in Radiation Oncology at Duke already used low levels of focused microwave to heat the site of the tumor.

“I figured that lysolipids might do the trick, because when added to blood in a test tube they can cause red blood cell membranes to leak hemoglobin,” said Needham. He conceived of using lysolipid molecules already trapped in a solid lipid membrane. The idea was to warm the lipid membrane until it melted, so the lysolipid would facilitate drug release and, if done in a tumor, this anti-cancer drug would be available to kill tumor cells.

That idea worked. It turned out that the liposomes released their drug in only a few seconds as they were flowing through the warmed blood vessels of the tumors and this resulted in the blood vessles being shut down. The treatment was anti-vascualr as well as being anti-neoplastic. It has resulted in two main patents awarded to Needham by the U.S. Patent Office, with research funded by a one-year, $40,000 grant from the North Carolina Biotechnology Center to get the project rolling, and a five-year grant from the National Cancer Institute (NCI). This NCI grant was instrumental in helping Dewhirst and colleagues renew their $18 million program project grant on hyperthermia – which funded additional research necessary to show how Needham’s liposomes worked in animals and to translate it to humans.

In 1999, Dewhirst’s team showed that when injected into animals with their tumor already warmed by hyperthermic treatment, the liposomes could stop the tumor from growing further and in fact eradicate it completely. The researchers found that tumors had disappeared between 15 and 60 days after hyperthermia treatment. By comparison, animals that did not get treatment had their tumors grow five times larger in just ten days.

The researchers reported in the March, 2000, issue of the Journal of Cancer Research that this new strategy had actually “cured” mice of their tumors.

Most recently, at the May 2007 meeting of the Society for Thermal Medicine in Washington, D.C., Duke radiation oncologist Zeljko Vujaskovic and colleagues presented dramatic results for a female patient treated for chest wall recurrence of breast cancer after mastectomy. After receiving this new treatment in a phase 1 trial, the patient experienced complete response of her chest wall cancer (cancer completely disappeared) when given an amount of drug that was less than the maximally tolerated dose.

Duke licensed this new approach to Celsion Corp. in Nov 1999, and researchers from Duke and other universities have been conducting studies and trials with the goal of bringing this therapy to patients through the process of human clinical trials.