"We found that we can stop the tumor from growing outto 100 days, at which time we stopped measuring since this is a longtime for experiments of this type," says Paterson. "The tumors stoppedgrowing or went completely away." The researchers published theirfindings in the September 15 issue of The Journal of Immunology.
"Theproblem that we encounter is that often by the time a patient presentswith cancer, they've developed immune tolerance to the tumor antigen,particularly when the antigen is expressed at low levels on normaltissue as with Her2/Neu," explains Paterson. "So how is the body tomount a strong enough immune reaction?"
In general, bacteria aregood at inducing both innate and adaptive immune responses, activatingsuch immune cells as macrophages, dendritic cells, and T cells. Thishelps jump-start the immune response to break tolerance.
But, whyListeria over other bacteria as a vehicle to deliver a tumor-associatedantigen? Because of Listeria's unusual life style. Normally, whenbacteria get taken up into an antigen-presenting cell, they areengulfed by a phagocytic vacuole where they get killed-whereupon theirproteins get broken down into smaller pieces (peptides) and attached toMHC Class 2 molecules. These egress to the cell surface, where theyexpand and activate helper T cells, which are enlisted into the immuneresponse.
But Listeria has evolved to escape from this vacuoleand survive inside the cytosol of antigen-presenting cells, where itcan replicate and grow, unlike other bacteria. So, although some of thebacteria are destroyed in the vacuole that feeds the MHC class IIpathway of antigen presentation with the induction of helper T cells,others survive by escaping into the cytosol of the cell. This isimportant because the antigen-processing pathway that feeds antigenicpeptides to the surface of the cell for recognition by killer T cellsis generated in this cellular compartment. "We reasoned that if wecould get Listeria to secrete a foreign protein into the interior ofthe cell, it would target that pathway and would elicit a strong killerT cell response, and we have shown that," says Paterson. "Listeria isalmost unique in the bacterial kingdom in doing this."
In thismodel, pieces of the very large HER-2/Neu molecule are broken up intolittle fragments and bound to the MHC Class 1 molecule within theantigen-presenting cell. This is what the killer T cell "sees" at thecell surface. These killer T cells, which are being produced in thespleen, where Listeria usually colonizes, seek out and destroy thetumor. This system ensures an increase in the production of killer Tcells that can recognize the HER-2/Neu pieces on the surface of thetumor cell. In addition, the Penn team helped the immune system alongby fusing the tumor antigen to a bacterial protein that seems toactivate antigen-presenting cells. They have found that by doing thisthe immune system now recognizes regions of the HER-2/neu molecule thatare not immunogenic when presented by other vaccine approaches.
Patersonfirst hit on the idea of using Listeria as a cancer vaccine vector overten years ago. "It took a while to dissect what elements of an immuneresponse were best able to cause the rejection of established tumors,"she says. "But in the last couple of years it has paid off and we arevery excited to see the technology finally being tested in cancerpatients. The dream of the cancer immunotherapist is to provide analternative and more humane way of controlling metastatic disease thancurrent chemotherapies."
The Listeria vector is currently beingprepared for a clinical trial targeting a tumor antigen associated withcervical cancer by Advaxis Inc., a cancer vaccine biotech company thathas licensed Penn patents on the use of Listeria monocytogenes as avaccine vector. Paterson is the scientific founder of Advaxis and Chairof the Scientific Advisory Board. The successful demonstration that theListeria vector technology can also be used with the HER-2/neu moleculepaves the way for applying this promising cancer vaccine approach tobreast cancer.
This research was funded by the Department ofDefense and the National Cancer Institute. Co-authors are Reshma Singhand Mary E. Dominiecki, both from Penn, as well as Elizabeth M. Jaffeefrom the Johns Hopkins University School of Medicine.
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