A novel therapeutic to fight colon cancer by using the bacteria primarily responsible for causing strep throat is being explored in the labs of John McCormick of the Schulich School of Medicine & Dentistry at the University of Western Ontario, London, Ontario, Canada.
McCormick’s team has bioengineered a streptococcal bacterial toxin to attach itself to tumor cells. By doing this, they force the immune system to recognize and attack the cancer.
In an exclusive interview, McCormick said that while the work is still at the preclinical stage it “demonstrates that the streptococcal pyogenic exotoxins from Streptococcus pyrogenes could potentially be used as therapeutics for the treatment of colon cancer. We hope that this work will help to further develop these types of cancer therapeutics with the goal of using these proteins to target metastatic tumor cells,” he told Bioscience Technology and Drug Discovery & Development.
McCormick’s team outlined their work in the paper, “Control of established colon cancer xenographs using a novel humanized single chain antibody-streptococcal superantigen fusion protein targeting the 5T4 oncofetal antigen,” in the journal PLOS One.
Kelcey Patterson, a doctoral candidate at Western and the lead author on the PLOS One article, showed that the engineered bacterial toxin could significantly reduce the size of human colon cancer tumors in mice, with a drastic reduction in the instances of metastasis. By using mouse models that are stripped of their immune system, they were able to create a “humanized mouse” – one that would not only grow human colon cancer cells, but would also support a human immune system, to test the anti-cancer immunotherapy.
“Our team has been studying these bacterial toxins, called ‘superantigens,’ for their role in bacterial infections,” McCormick said. “We are now utilizing the power of these toxins to re-direct the immune system to go after cancer cells.”
In the work, McCormick’s research team used molecular techniques to link the streptococcal pyrogenic exotoxin C (SpeC) toxin to an antibody that recognizes and binds to a protein expressed on the tumor cell. This protein, a tumor-associated antigen, is expressed on cancer cells but not (or have limited) expressed on normal cells.
“The initial engineering of this was quite difficult and took a long time to figure out,” McCormick said. “Although not trivial, we now know how to do it.”
McCormick said the team focused on the strep bacteria because it brings with it several advantages.
“Streptococcus pyogenes, the bacteria that causes strep throat, produces these toxins as part of their life cycle but only a few types of bacteria make these particular toxins,” he explained. “Staphylococcus aureus also makes similar toxins although the ones from S. aureus can also cause foodborne illness and we think the streptococcal ones would likely have less side effects.”
“We have also done a lot of work previously with these toxins studying their structure and function so we can specifically alter (mutate) them to modulate their activity,” he added.
McCormick explained that the streptococcal toxin works by binding to receptors on white blood cells (T lymphocytes) and forces them to activate. During an infection, these toxins can activate very large numbers of T lymphocytes.
“This therapeutic basically sticks the toxin onto the cancer cells, and then the toxin forces the immune system to activate on top of the tumor,” he said. “We have introduced a mutation into the toxin so that it doesn't work until it binds to the tumor.”
McCormick said the next steps of the project include developing additional therapeutics that target different tumor antigens and to start testing them in combination. The work reported in the PLOS One article was funded by the Canadian Institutes of Health Research. A new grant from the Cancer Research Society will allow the team to develop different toxin and antibody combinations to fight other types of cancer (see Inspired by Life).
The cancer grant “is really to build additional therapeutics and test their function,” McCormick said. The idea is to “personalize this therapy depending on what tumor associated antigens were expressed by a patient's tumor.”
Inspired by Life
Life sometimes throws us for a loop and sometimes it can inspire us.
For John McCormick, associate professor at the University of Western Ontario’s Schulich School of Medicine and Dentistry, this happened in 2002 when he was an assistant professor and hard at work studying the role of toxins in infectious disease. That year a good friend of his, Alison Look, unexpectedly was diagnosed with colon cancer.
Look and McCormick were close. They had gone through graduate school together in Alberta. Her colon cancer had metastasized to her liver, and Look died in 2005 at the age of 36. The experience left an indelible mark on McCormick.
“I felt that we should apply some of our knowledge of these toxins to try to develop new treatments with the goal of targeting the metastatic cells and hopefully help someone one day,” he said. “Our previous work had not focused at all on cancer therapy, but I felt we should try to use some of the basic science of these toxins to try to develop a therapeutic that may be able to target metastatic cells.”
McCormick’s previous work focused on the toxins produced from bacteria that can cause toxic shock syndrome through systemic immune system activation.
“This is a relatively rare disease, but it can be devastating,” McCormick said. “So we had been studying the structure and function of these toxins in the context of toxic shock syndrome. The cancer therapeutics have been modified however, so they won’t cause systemic effects.”
“We didn’t have much funding for the project over the years, but thankfully the Canadian Cancer Research Society is now funding the work with an operating grant,” he added.
McCormick continues to view Look as an inspiration. “I dedicated the PLoS One paper to her memory,” he said.