A number of significant advances have been made recently by researchers within the Gene and Virus Therapy Program. Some of the most notable advances have been made in the area of virus research:
Oncolytic measles viruses
Stephen Russell, M.D., Ph.D., is studying viruses that kill cells. And each virus has its preferred target. Hepatitis B virus kills liver cells, HIV kills T cells, and poliovirus kills nerve cells. Hence the dream of creating ‘oncolytic’ viruses that will selectively kill cancer cells without harming the patient. Several viruses are being studied in this regard, but research into using measles virus as an anticancer agent is unique to Mayo Clinic.
The measles virus in the MMR (measles, mumps, rubella) vaccine was originally isolated in 1954 from the throat washings of a measles patient named David Edmonston and was weakened (attenuated) by teaching it to grow in cells that it would not normally infect. As the virus adapted to its new environment in the tissue culture dish, it acquired mutations that destroyed its ability to cause disease in humans. At the same time it acquired a capacity for selective destruction of cancer cells. This remarkable cancer-destroying activity of attenuated measles viruses was discovered in Dr. Russell's laboratory and appears to result from its ability to target CD46, a receptor that is over-expressed on many human cancers where it protects them against the damaging effects of natural host defense proteins.
Our discovery that measles virus is a powerful oncolytic agent has led to a major and concerted translational research effort involving Gene and Virus Therapy Program researchers interacting closely with other Programs of the Cancer Center, including the Women’s Cancer Program, the Hematologic Malignancies Program, the Gastrointestinal Malignancies Program and the Imaging Program.
These investigators engineered measles virus to change its genetic makeup in ways that will make it a more ‘user-friendly’ agent for cancer therapy. They have developed technology for targeting the virus to specific sites in the body by displaying monoclonal antibodies on the viral coat, and they have inserted additional genes that make it easier to monitor virus spread and elimination in treated patients. They have tested both unmodified and genetically engineered viruses.
The measles virus has been tested against a variety of tumors in animal models where it shows a broad spectrum of activity against lymphoma, multiple myeloma, ovarian cancer, glioma and pancreatic cancer. Ovarian cancer was one of the first cancers where activity was shown. Kah Whye Peng, PhD., and her colleagues grew ovarian cancer cells in the peritoneal cavity of mice. When they administered a measles virus expressing a soluble marker into the peritoneal cavity to treat these tumors, mice that got the control (non-active) virus died, while mice receiving the therapeutic virus lived much longer than the control-treated animals.
Drs. Russell and Morris collaborated to demonstrate that PET imaging can be used to track the propagation of NIS expressing measles viruses by using Iodine-124 as tracer. By using a combination of measles viruses for therapy, Dr. Russell, Mark J. Federspiel, Ph.D., and Kah W. Peng, Ph.D., have collaborated to show that expression monitoring by NIS expression can be combined with expression monitoring by CEA release. This work was published in Clinical Cancer Research (12(6):1868-75, 2006), while a second paper from these investigators in Cancer Gene Therapy (13(8):732-8, 2006), demonstrated how a virally encoded soluble marker peptide can be used to probe the pharmacokinetics of an oncolytic measles virus.
Eric Poeschla, M.D., and Yasuhiro Ikeda, Ph.D., have made great progress with their studies of the basic biology of HIV, which often leads to development of cancer. For example, Dr. Poeschla has determined that the cellular factor LEDGF plays an essential part in HIV integration by tethering the pre-integration complex to cellular chromatin. This work provides the basis for a new approach that will now be attempted to direct the integration of HIV vectors to specific target sites in the cellular genome.
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