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MICROBIOLOGY
Combo Vector Delivers Blow Against Melanoma
For decades, researchers have poked and prodded the bacteria
Listeria monocytogenes to discover how it interacts with the immune system, eventually shutting down key bodily functions.
Darren Higgins and colleagues have created a vaccine vector system that exploits the best features of live and killed bacterial vaccines. The vector, loaded with a model tumor antigen, prevented the development of melanoma in mice. (Photo by Pam Murray)
Now, investigators from HMS and London's Hammersmith Hospital have found a way to use Listeria to fight disease. In the November
Gene Therapy, Darren Higgins, HMS assistant professor of microbiology, and co-authors report that by modifying
Escherichia coli to express a
Listeria protein, they have created a vaccine that protects mice against melanoma.
The image at left shows a macrophage with a fluorescent protein delivery vector inside its phagosome. With the background light removed (middle), the phagosome is clearly illuminated. At right, the phagosome is lysed and its fluorescent contents pour into the macrophage cytosol. (Image courtesy of Darren Higgins)
Higgins's group showed in 1999 they could deliver the
Listeria protein listeriolysin O (LLO) to the cytosol of macrophages using an
E. coli vector. LLO lyses phagosomes in infected cells, allowing the bacterium to enter the cytosol. To create the vector, they stripped out the virulence components from killed
E. coli, leaving a framework that remains attractive to the macrophages and dendritic cells at the front lines of the immune system.
In the new study, prior to injecting the killed bacteria into mice, they added two proteins to the E. coli shell: LLO to lyse the phagosome and ovalbumin, a model tumor antigen. Then they injected the mice with ovalbumin-tagged melanoma cells. In the mouse, the Trojan horse E. coli enters the immune cells and its LLO lyses the cells' phagosomes, spilling their contents into the cytosol. Ovalbumin then travels to the cell surface, where it tells T cells what to search for and destroy--in this case, the tagged melanoma cells.
The vaccination resulted in complete protection in six of eight mice, which remained tumor-free for more than 90 days, and delayed tumor growth in the other two.
"The results of this study are very positive," said Higgins. "They suggest we could utilize this killed bacterial formulation to prime the immune system against diseases like cancer or viral and bacterial pathogens."
--John Lacey and Tom Reynolds
Copyright 2002 by the President and Fellows of Harvard College
