Pancreatic cancer is currently considered an “orphan” disease. Unfortunately this term means that there are no current therapies that are considered curative of the disease. However, an unlikely ally in the production of an effective treatment has been found in the form of Listeria bacteria, specifically the species Listeria monocytogenes.

An Unlikely Ally

Listeria monocytogenes (L.monocytogenes) is the leading cause of mortality in food borne pathogens, causing death in 20-30% of anyone subject to a listeriosis infection. Even the more well-known food borne pathogens (e.g. Salmonella) pail in comparison to the deadly effects of L.monocytogenes. Its use in the fight against cancer therefore is rather unexpected and referencing it as an unlikely ally is a considerable understatement.

Constructing a “Radioimmunoconjugate”

So how is it actually helping treating cancer? A group of scientists at the Albert Einstein College of Medicine in New York have coupled the bacterial cells with a radioisotope with the aid of antibodies. The resulting construction is referred to as a radioimmunoconjugate. In this case, Claudia Gravekamp and company combined the radioisotope 188-Rhenium to their antibody structure. 188-Rhenium is a beta-emitting radioisotope, meaning it emits radiation across a relatively large distance as it decays. The radioimmunoconjugate was then attached to the surface of the Listeria cells.

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Numerous means of attaching treatments to antibodies have been demonstrated over the years. Claudia Gravekamp and co. have attached their antibodies to the surface of L.monocytogenes. “mAb” refers to Monoclonal AntiBody.

The Clever Bit

A few years ago it was discovered that Listeria bacteria had the unique attribute of infiltrating tumours without affecting normal tissues. The reason behind this was soon discovered to be due to the immunosuppressed microenvironment that is often found in tumours. The Listeria bacteria is cleared from normal tissue rapidly as the immune system is at full force, however in the immunosuppressed environment of a tumour, the immune system is virtually non-existent meaning the Listeria bacteria can happily survive in and around the tumour tissue.

Because of this feature of Listeria bacteria, the addition of a radioimmunoconjugate  to the bacterial cells can ensure a targeted therapy straight to – and only – the tumour tissue. The issue of “bystander killing” of healthy tissue (as demonstrated in the image below) therefore occurs at a much lower level, definitely low enough to no longer be considered a problem. Furthermore, the radiation emitted by the radioisotope is thought to actually damage the DNA of tumour cells more than that of healthy tissue as tumour cells grow much more rapidly, exposing their chromosomes in the process. Pretty clever isn’t it?

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As radiation emitted by radioisotopes is not “aimed” towards tumour tissue but rather affects all tissue surrounding it, healthy tissue in close proximity to the isotope can be affected – this is referred to as “bystander killing”.

The Experiment

Mice models inoculated with highly metastatic pancreatic tumour cells were treated with an attenuated (safe) version of the bacterial strain in multiple, low doses. After daily doses for one week, the mice were then given a week off before receiving four further daily doses. The percentage decrease in metastases was approximately 90% than those in untreated mice. As well as this remarkable decrease in metastases, the Listeria bacteria were found to have been completely cleared from the livers and kidneys of all mice models without damaging either organ.

Future Potential

Producing a treatment against pancreatic tumour cells is incredible in itself but to produce an effective treatment against metastatic pancreatic cancer is even more remarkable. The disease is incredibly lethal due to the early metastatic behaviour of the cancer cells involved, quite often having infiltrated and damaged vital organs before it has even been diagnosed.

A development such as this therefore is a true breakthrough. If the therapy can prove its worth in later phase trials (where it is used in human volunteers) then this could well be a revolutionary cancer treatment. And whose to say it can only be used against metastatic pancreatic cancer? Perhaps it can be extended into treating further cancers with high mortality rates such as brain tumours that have spread throughout the body. This truly is an exciting development and may well pave the way for the harnessing of bacteria in the scene of oncological treatment.

References

Images:  Litvak-Greenfeld D. and Benhar I., “Risks and untoward toxicities of antibody-based immunoconjugates” Advanced Drug Delivery Reviews, 64(15): p.1782-1799, 2012.

Original paper: http://www.pnas.org/content/early/2013/04/17/1211287110

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