Vaccine Cures Breast Cancer in Mice

Using a vaccine based on the bacterium Listeria monocytogenes, scientists have eradicated established breast tumors in mice.

A cancer vaccine works as an immunotherapy, boosting an immune response against tumor-associated antigens. The scientists delivered the tumor-associated antigen HER-2/Neu to immune cells, which eventually enlisted killer T cells to seek our and destroy the tumor cells that displayed the HER-2/Neu molecule. However, usually by the time a patient presents with cancer, the patient has developed immune tolerance to the tumor antigen, especially when the antigen is expressed at low levels on normal tissue such as HER2/Neu. Thus, the problem is how to mount a strong-enough immune reaction.

The investigators chose Listeria over other bacteria because it evolves to escape from a phagocytic vacuole and survives inside the cytosol of antigen-presenting cells, where it can replicate and grow, unlike other bacteria. The antigen-processing pathway that feeds antigenic peptides to the surface of the cells for recognition by killer T cells is generated in this cellular compartment.

"We reasoned that if we could get Listeria to secrete a foreign protein into the interior of the cell, it would target that pathway and would elicit a strong killer T cell response, and we have shown that,” said Yvonne Paterson, Ph.D., professor of microbiology at the University of Pennsylvania School of Medicine (Philadelphia, USA), who led the research.

In the study, pieces of the very large HER-2Neu molecule were broken up into little fragments and bound to the major histocompatibility complex (MHC) class 1 molecule within the antigen-presenting cell. This is what the killer T cell "sees” at the cell surface. These killer T cells, produced in the spleen where Listeria usually colonizes, seek out and destroy the tumor. To help the immune system, the research team fused the tumor antigen to a bacterial protein that seems to activate antigen-presenting cells, so that the immune system recognizes regions of the HER/2 Neu molecule that are not immunogenic when presented by other vaccine approaches. The Listeria vector is currently being prepared for a clinical trial targeting a tumor antigen associated with cervical cancer.

"We found that we can stop the tumor from growing out to 100 days, at which time we stopped measuring since this is a long time for experiments of this type,” added Dr. Paterson. "The tumors stopped growing or went completely away.” The findings were published in the September 15, 2005, issue of Immunology.