Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Breast Tumors in Mice Eradicated Using Cancer Vaccine

15.09.2005


Listeria inside a macrophage, an immune cell enlisted in the immune response. Credit: Paul Neeson, PhD, University of Pennsylvania School of Medicine


When bacteria such as Listeria and Salmonella are taken up into a phagocytic cell of the immune system, they are engulfed into a phagocytic vacuole in the interior of the cell. Here they may be destroyed and fragments of antigens they carry will eventually egress to the cell surface to activate CD4 immune cells, which are important in assisting in the immune response. Listeria, unlike other bacteria, has evolved to break out of the vacuole and survive inside the immune cell. This way antigens that Listeria carries are targeted to a pathway in the cytoplasm where they are broken into peptides and taken to the cell surface for recognition by killer T cells. These killer T cells seek out and destroy tumor cells displaying tumor-specific antigens. Credit: Yvonne Paterson, PhD, University of Pennsylvania School of Medicine


Findings Could Lead To New Immune Therapy for Breast Cancer

A team from the University of Pennsylvania School of Medicine has shown that by using a cancer vaccine based on the bacterium Listeria monocytogenes, they can cure mice with established breast tumors. Cancer vaccines, which are more properly described as immunotherapy, work by boosting an immune response against tumor-associated antigens. Using Listeria, the researchers, led by Yvonne Paterson, PhD, Professor of Microbiology, delivered the tumor-associated antigen HER-2/Neu to immune cells. HER-2/Neu is overexpressed in 20 to 40 percent of all breast cancers and also present in many cancers of the ovaries, lung, pancreas, and gastrointestinal tract. These cells eventually enlist killer T cells to seek out and destroy the tumor cells that display the HER-2/Neu molecule.

"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," says Paterson. "The tumors stopped growing or went completely away." The researchers published their findings in the September 15 issue of The Journal of Immunology.



"The problem that we encounter is that often by the time a patient presents with cancer, they’ve developed immune tolerance to the tumor antigen, particularly when the antigen is expressed at low levels on normal tissue as with Her2/Neu," explains Paterson. "So how is the body to mount a strong enough immune reaction?"

In general, bacteria are good at inducing both innate and adaptive immune responses, activating such immune cells as macrophages, dendritic cells, and T cells. This helps jump-start the immune response to break tolerance.

But, why Listeria over other bacteria as a vehicle to deliver a tumor-associated antigen? Because of Listeria’s unusual life style. Normally, when bacteria get taken up into an antigen-presenting cell, they are engulfed by a phagocytic vacuole where they get killed-whereupon their proteins get broken down into smaller pieces (peptides) and attached to MHC Class 2 molecules. These egress to the cell surface, where they expand and activate helper T cells, which are enlisted into the immune response.

But Listeria has evolved to escape from this vacuole and survive inside the cytosol of antigen-presenting cells, where it can replicate and grow, unlike other bacteria. So, although some of the bacteria are destroyed in the vacuole that feeds the MHC class II pathway of antigen presentation with the induction of helper T cells, others survive by escaping into the cytosol of the cell. This is important because the antigen-processing pathway that feeds antigenic peptides to the surface of the cell 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," says Paterson. "Listeria is almost unique in the bacterial kingdom in doing this."

In this model, pieces of the very large HER-2/Neu molecule are broken up into little fragments and bound to the 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, which are being produced in the spleen, where Listeria usually colonizes, seek out and destroy the tumor. This system ensures an increase in the production of killer T cells that can recognize the HER-2/Neu pieces on the surface of the tumor cell. In addition, the Penn team helped the immune system along by fusing the tumor antigen to a bacterial protein that seems to activate antigen-presenting cells. They have found that by doing this the immune system now recognizes regions of the HER-2/neu molecule that are not immunogenic when presented by other vaccine approaches.

Paterson first hit on the idea of using Listeria as a cancer vaccine vector over ten years ago. "It took a while to dissect what elements of an immune response 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 are very excited to see the technology finally being tested in cancer patients. The dream of the cancer immunotherapist is to provide an alternative and more humane way of controlling metastatic disease than current chemotherapies."

The Listeria vector is currently being prepared for a clinical trial targeting a tumor antigen associated with cervical cancer by Advaxis Inc., a cancer vaccine biotech company that has licensed Penn patents on the use of Listeria monocytogenes as a vaccine vector. Paterson is the scientific founder of Advaxis and Chair of the Scientific Advisory Board. The successful demonstration that the Listeria vector technology can also be used with the HER-2/neu molecule paves the way for applying this promising cancer vaccine approach to breast cancer.

This research was funded by the Department of Defense and the National Cancer Institute. Co-authors are Reshma Singh and Mary E. Dominiecki, both from Penn, as well as Elizabeth M. Jaffee from the Johns Hopkins University School of Medicine.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

More articles from Life Sciences:

nachricht The “TRiC” to folding actin
10.08.2018 | Max-Planck-Institut für Biochemie

nachricht SERSitive: New substrates make it possible to routinely detect one molecule in a million
10.08.2018 | Institute of Physical Chemistry of the Polish Academy of Sciences

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The “TRiC” to folding actin

Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.

Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...

Im Focus: Lining up surprising behaviors of superconductor with one of the world's strongest magnets

Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur

What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...

Im Focus: World record: Fastest 3-D tomographic images at BESSY II

The quality of materials often depends on the manufacturing process. In casting and welding, for example, the rate at which melts solidify and the resulting microstructure of the alloy is important. With metallic foams as well, it depends on exactly how the foaming process takes place. To understand these processes fully requires fast sensing capability. The fastest 3D tomographic images to date have now been achieved at the BESSY II X-ray source operated by the Helmholtz-Zentrum Berlin.

Dr. Francisco Garcia-Moreno and his team have designed a turntable that rotates ultra-stably about its axis at a constant rotational speed. This really depends...

Im Focus: A molecular switch may serve as new target point for cancer and diabetes therapies

If certain signaling cascades are misregulated, diseases like cancer, obesity and diabetes may occur. A mechanism recently discovered by scientists at the Leibniz- Forschungsinstitut für Molekulare Pharmakologie (FMP) in Berlin and at the University of Geneva has a crucial influence on such signaling cascades and may be an important key for the future development of therapies against these diseases. The results of the study have just been published in the prestigious scientific journal 'Molecular Cell'.

Cell growth and cell differentiation as well as the release and efficacy of hormones such as insulin depend on the presence of lipids. Lipids are small...

Im Focus: Touring IPP’s fusion devices per virtual-reality viewer

ASDEX Upgrade and Wendelstein 7-X – as if you were there / 360° view of fusion research

You seem to be standing in the plasma vessel looking around: Where otherwise plasmas with temperatures of several million degrees are being investigated, with...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

2018 Work Research Conference

25.07.2018 | Event News

 
Latest News

Ph.D. student develops spinning heat shield for future spacecraft

10.08.2018 | Physics and Astronomy

Investigating global air pollution

10.08.2018 | Life Sciences

The “TRiC” to folding actin

10.08.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>