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 Toward a 'smart' patch that automatically delivers insulin when needed
18.01.2017 | American Chemical Society

nachricht 127 at one blow...
18.01.2017 | Stiftung Zoologisches Forschungsmuseum Alexander Koenig, Leibniz-Institut für Biodiversität der Tiere

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

Im Focus: How to inflate a hardened concrete shell with a weight of 80 t

At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).

Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

Nothing will happen without batteries making it happen!

05.01.2017 | Event News

 
Latest News

A big nano boost for solar cells

18.01.2017 | Power and Electrical Engineering

Glass's off-kilter harmonies

18.01.2017 | Materials Sciences

Toward a 'smart' patch that automatically delivers insulin when needed

18.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>