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Novel lipoplex nanoparticle to be used in 1st human trial treating advanced solid cancer
August 25, 2005Washington D.C. - The first clinical trial of a biologic nanoparticle designed to give back to cancer patients the tumor-busting gene they have lost is expected to start in September at Georgetown University Medical Center.
The phase I clinical study will enroll 20 patients with advanced solid cancers (including most common tumor types), and is the culmination of more than a decade of work by a team of researchers led by Professor Esther H. Chang, Ph.D. at the Lombardi Comprehensive Cancer Center.
Their research has led to development of a tiny structure - measuring a millionth of an inch across - that resembles a virus particle that can penetrate deeply into the tumor and move efficiently into cells. The device is a "liposome" - a microscopic globule made of lipids - that is spiked on the outside with antibody molecules that will seek out, bind to, and then enter cancer cells including metastases wherever they hide in the body. These molecules bind to the receptor for transferrin that is present in high numbers on cancer cells.
Once inside, the nanoparticle, which the researchers call a "immunolipoplex," will deliver its payload - the p53 gene whose protein helps to signal cells to self-destruct when they have the kind of genetic damage characterized by cancer and by cancer therapies.
More than half of all cancer patients have cancer cells that have lost normal functioning of the p53 gene, so-called "guardian of the genome," and the Georgetown researchers believe that restoring the gene will improve the tumor-killing ability of traditional treatments.
"We are excited about the promise this nanoparticle has shown in animal tumor models, and are anxious to offer it to patients," said Chang, Professor in the Department of Oncology and Co-director of the Molecular Targets & Developmental Therapeutics Program at Georgetown.
The federal Food and Drug Administration granted approval for the trial to begin in late July. The work is being sponsored by grants from the National Institutes of Health and private foundations. Additional support comes from SynerGene Therapeutics, a biotech research firm with which Chang collaborates.
John Marshall, M.D., Director of Developmental Therapeutics and GI Oncology at Georgetown, will serve as the trial's principal investigator.
The researchers believe that immunolipoplex represents an advance over the viral "vectors" that have been used to deliver gene therapy, because these liposomes do not produce the kinds of immunologic response seen when disabled viruses are used to carry the payload. They also say that the nanoparticle is of a small uniform size and consistency, and has been proven to work in animals bearing tumor.
In preclinical research, Chang and long-term research colleague Kathleen Pirollo, Ph.D. have found that these nanoparticles substantially improve the tumor-fighting power of both chemotherapy and radiation therapy. These agents work synergistically with traditional therapies because the newly restored p53 protein helps push cancer cells that are now damaged to self-destruct.
"We believe this approach will make it difficult for the cancer cells to become resistant to therapy," Chang said. "As a result, cancers treated with these liposomal formulations should be less likely to recur after therapy is complete."
For example, use of these p53-loaded liposomes in combination with radiation therapy eliminated prostate and head and neck tumors in mice, which then survived cancer-free for more than 200 days - until they all died of old age. Similar promising results were seen when the nanoparticles were combined with chemotherapy to treat animal models of melanoma and aggressive breast cancer.
Among the solid tumors approved for testing in the clinical trial are head and neck, prostate, pancreatic, breast, bladder, colon, cervical, brain, melanoma, liver and lung cancers.
Georgetown University Medical Center
Once inside, the nanoparticle, which the researchers call a "immunolipoplex," will deliver its payload - the p53 gene whose protein helps to signal cells to self-destruct when they have the kind of genetic damage characterized by cancer and by cancer therapies.
More than half of all cancer patients have cancer cells that have lost normal functioning of the p53 gene, so-called "guardian of the genome," and the Georgetown researchers believe that restoring the gene will improve the tumor-killing ability of traditional treatments.
"We are excited about the promise this nanoparticle has shown in animal tumor models, and are anxious to offer it to patients," said Chang, Professor in the Department of Oncology and Co-director of the Molecular Targets & Developmental Therapeutics Program at Georgetown.
The federal Food and Drug Administration granted approval for the trial to begin in late July. The work is being sponsored by grants from the National Institutes of Health and private foundations. Additional support comes from SynerGene Therapeutics, a biotech research firm with which Chang collaborates.
John Marshall, M.D., Director of Developmental Therapeutics and GI Oncology at Georgetown, will serve as the trial's principal investigator.
The researchers believe that immunolipoplex represents an advance over the viral "vectors" that have been used to deliver gene therapy, because these liposomes do not produce the kinds of immunologic response seen when disabled viruses are used to carry the payload. They also say that the nanoparticle is of a small uniform size and consistency, and has been proven to work in animals bearing tumor.
In preclinical research, Chang and long-term research colleague Kathleen Pirollo, Ph.D. have found that these nanoparticles substantially improve the tumor-fighting power of both chemotherapy and radiation therapy. These agents work synergistically with traditional therapies because the newly restored p53 protein helps push cancer cells that are now damaged to self-destruct.
"We believe this approach will make it difficult for the cancer cells to become resistant to therapy," Chang said. "As a result, cancers treated with these liposomal formulations should be less likely to recur after therapy is complete."
For example, use of these p53-loaded liposomes in combination with radiation therapy eliminated prostate and head and neck tumors in mice, which then survived cancer-free for more than 200 days - until they all died of old age. Similar promising results were seen when the nanoparticles were combined with chemotherapy to treat animal models of melanoma and aggressive breast cancer.
Among the solid tumors approved for testing in the clinical trial are head and neck, prostate, pancreatic, breast, bladder, colon, cervical, brain, melanoma, liver and lung cancers.
Georgetown University Medical Center
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