Listeria monocytogenes' main medical claim to fame is that it causes food poisoning. But by combining a weakened strain of the bacterium with a radioactive payload, scientists have used Listeria to kill metastases from pancreatic cancer.

The bacteria were less effective at taking out the primary tumors. But, corresponding author Claudia Gravekamp told BioWorld Today, "we are quite successful" at dealing with the primary tumors – "primary tumors can be removed by surgery or radiation."

The reason that pancreatic cancer's five-year survival rate has not budged for decades from a dismal 5 percent is that usually the tumor is not diagnosed until it already has metastasized, so that removal of the primary tumor gives patients only a brief reprieve.

Gravekamp, who is at the Albert Einstein College of Medicine, and her team discovered that weakened Listeria can kill cancer cells working on immunotherapies for pancreatic cancer. Listeria can deliver antigens to antigen-presenting cells of the immune system, and are being used by a number of groups to develop tumor immunotherapies. Advaxis Inc. is in the clinic with attenuated Listeria-based immunotherapies for cervical, head and neck and anal cancer, while Aduro BioTech Inc. is testing the approach clinically for pancreatic cancer and mesothelioma. (See BioWorld Today, June 6, 2012, and April 21, 2011.)

But "when we started testing them, we saw, to our surprise, that the Listeria alone was as effective as the Listeria with the antigen," Gravekamp said, suggesting that the bacteria were killing tumors through mechanisms other than revving up antigen-presenting cells.

For their current experiments, which were published in the April 22, 2013, online issue of the Proceedings of the National Academy of Sciences, Gravekamp teamed up with co-corresponding author Ekaterina Dadachova – also at the Albert Einstein College of Medicine – to add a cytotoxic payload in the form of radioactive antibodies to the Listeria, further enhancing their ability to kill tumor cells. They then repeatedly treated mice with metastatic pancreatic cancer with their compound, and looked at its effects on the primary tumor, its metastases to the liver and kidney, and healthy tissues.

Gravekamp termed the results "spectacular." Treatment with radioactive Listeria killed 90 percent of metastatic cells and reduced the size of the primary tumor by about two-thirds, while having minimal effect on normal tissues. Listeria that were not radioactive also killed both metastases and primary tumor cells, but to a lesser degree.

The bacterium's specificity for metastases is due to a combination of two factors. For one, the weakened strain that was used by Gravekamp, Dadachova and their colleagues can only survive in the immunosuppressed microenvironment of the tumor. "Our Listeria cannot survive in vivo in normal tissues," Gravekamp stressed.

In addition, the bacterium targets rapidly dividing tissues – the likely reason it is less effective in the primary tumor, which has the same immunosuppressed microenvironment as the metastases, but is "more dormant" than the still-growing metastases.

Gravekamp said, "I think, though we have to prove that of course, that you can use this for many tumor types." So far, the team has also tested the radioactive Listeria in triple-negative breast cancer, where "we see similar results" to the ones in the pancreatic cancer model. In other cell lines, where efficacy levels have differed, whether due to the cell lines or the bacteria.

To move ahead with translation of the findings, Dadachova told BioWorld Today, the team hopes to simplify the way in which the radioactivity is incorporated into the bacteria. Specifically, for clinical translation "it would be easier to avoid antibodies" which the team currently uses to tag the Listeria. The researchers are testing different radioactive isotopes to see which could be incorporated directly into the bacteria.

The team also wants to test the Listeria in a way, Dadachova said, that "emulates the clinical situation," removing the primary tumor completely before treating the metastases through surgery or combination therapies. Getting rid of the primary tumor completely, Gravekamp added, will be critical to the approaches for long-term success. "If there is a little bit of the primary tumor left, it is a source for new metastases."