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Immunotherapy

Engineering a vaccine to thwart cancer

The first things you notice in Dr. Jean Gariépy’s office are the giant yucca plants perched on his filing cabinets and windowsill. Their lush, shiny green leaves stand out in the soft-spoken scientist’s cozy office, which overlooks Sunnybrook’s Bayview campus.

Outside his office, there’s a flurry of activity. Voices and the whirring of machines can be heard as the 10 members of his lab work on their projects. Under Gariépy’s direction, they are engineering biomolecules like proteins, peptides and nucleic acids for imaging and targeted treatment of cancer.

The research in Gariépy’s lab is basic and applied. Ultimately, it is translational. His recent work on the protein carcinoembryonic antigen (CEA) in particular is pushing its way to the fore of clinical realization.

Gariépy, a senior scientist in the Odette Cancer Research Program at Sunnybrook Research Institute, and his postdoctoral fellow, Dr. Aws Abdul-Wahid, are studying the molecular biology of CEA and its role in metastasis, the spread of cancer from its original site to elsewhere in the body. In metastasis, cancer cells most often migrate to the liver, lung and bone.

Discovered in 1965 by Drs. Phil Gold and Samuel Freedman, CEA is an established tumour marker that is associated with cancers of the colon, rectum, pancreas, stomach, breast, lung, thyroid and ovaries. “It’s typically present in humans at birth, but after that it disappears and it’s only weakly expressed along the gastrointestinal tract. After you’re born, that marker is very rare. That’s why it’s a useful [tumour] marker,” says Gariépy, who is also a professor of medical biophysics and pharmaceutical sciences at the University of Toronto.

Cancer cells teem with CEA. So much of the molecule is expressed on cancer cells that some of it is shed in the blood, which is how it is measured clinically. Oncologists check CEA levels in the blood to assess a patient’s response to therapy and likelihood of disease recurrence, rather than to detect cancer.

For years researchers have suspected that CEA plays a role in metastasis, but they had yet to nail down the precise mechanisms by which it did so—until recently.

Dr. Jean Gariépy (right) and postdoctoral fellow Dr. Aws Abdul-Wahid are trying to harness the power of the body’s immune system to fight cancer.

In a study published in Molecular Oncology in 2014, Abdul-Wahid and Gariépy showed that one piece of the CEA molecule on the surface of tumour cells—called the N domain—bound to its counterpart on nearby cancer cells. “We found it actually made cancer cells ‘stickier.’ They tended to clump with each other. When cancer cells clump, they aggregate [and] expand [just] as seeds sprout,” Abdul-Wahid explains.

The researchers are the first to show that this particular region of CEA also binds to fibronectin, a protein that is part of the extracellular matrix, which provides structural and biochemical support to the cells it surrounds. This interaction allows cancer cells floating in the bloodstream to attach themselves to secondary sites in the body; disrupting this interaction, therefore, could well be the key to blocking metastasis, Gariépy surmised, correctly as it turned out.

What’s more, they were surprised by the strength of these interactions. “If you have a cancer cell that’s covered with this molecule, you don’t just have an affinity of this binding to that and forming these ‘zippers.’ It’s more like an avidity of having thousands, if not more, of these molecules trying to strap [themselves] to this thing and that with pretty good affinity for each individual interaction.

“So these cells have this propensity to want to stick together, to stick to the matrix. We don’t see this on normal cells because they don’t express CEA,” says Gariépy.


Marshalling one’s natural defenses

Armed with these discoveries, Gariépy and Abdul-Wahid set out to develop a vaccine to interfere with these interactions to block the implantation of cancer cells, thereby preventing metastasis.

Cancer vaccines fall into two categories: preventive and therapeutic. Preventive vaccines are given to healthy people to protect against infections associated with cancer. Examples are vaccines against the human papillomavirus to ward off cervical cancer, and vaccines against the hepatitis B virus to prevent liver cancer.

Preventive vaccines are similar to traditional vaccines that protect against polio or chicken pox, for example, in that they are based on antigens—substances that induce an immune response, like the production of antibodies. The immune system recognizes the antigens as foreign and “remembers” them to prevent future infections.

Therapeutic cancer vaccines, on the other hand, are given to people who have the disease, with the aim of preventing recurrence, destroying residual cancer cells after another type of treatment, or stopping a tumour from growing or spreading. They are a type of immunotherapy designed to enlist the body’s natural defenses to fight cancer.

Most therapeutic vaccines have failed mainly because cancer cells elude the immune system’s natural ability to spot and destroy that which is foreign, says Gariépy. “Most cancer cells express ‘self’ antigens—molecules that are normally found in humans. So your immune system does not want to raise an immune response against that. Your body basically rejects the idea of mounting a significant immune response.”

It’s almost like we’re teaching the immune system to reject the cancer from ever implanting.

To get around the problem of cancer cells not “looking” harmful to the immune system, Gariépy and Abdul-Wahid created a vaccine that targets CEA’s pro-metastatic properties, but disguised the molecule to trigger an immune response.

“We’ve focused on the tiny N domain of CEA that is involved in cell-cell adhesion with the view that it’s going to kind of look foreign. We’re making it look like an ‘altered self’ so that the immune system says, ‘That’s probably not something that’s in my body so I will raise an immune response against it,’” says Gariépy.

Making effective treatment vaccines has proven much more difficult than developing preventive vaccines. A major obstacle has been the lack of understanding of how the immune system will respond to a therapeutic vaccine. To be effective, a vaccine must prompt a specific immune response against the right target.

By focusing the vaccine-elicited immune response to the CEA N domain, the researchers have shown they can thwart cancer cells’ ability to settle elsewhere. “It’s almost like we’re teaching the immune system to reject the cancer from ever implanting,” says Abdul-Wahid.

They tested their vaccine in mice that were genetically modified to express CEA. Animals treated with their vaccine showed delayed onset of metastasis and limited tumour growth. The tumour volume of vaccinated animals was about one-half that of unvaccinated animals 24 days after implantation of cancer cells.

“We were able to protect animals from developing cancer in the peritoneum and the lung. In vaccinated animals, we were able to stabilize tumour growth. The tumour cells, once injected in unvaccinated animals, would grow out of control. The vaccinated animals, on the other hand, were able to control their tumour burden much better. That highlighted that vaccination is feasible as a strategy.

“Other people have attempted this kind of a vaccine for over 20-something years with very modest results—practically no successes. They were targeting the whole [CEA] molecule, not the ‘business’ end of it,” says Abdul-Wahid with a smile.


Next stop: patients

Having proved in principle that their strategy can prevent metastasis, the researchers are now developing a formulation for patients. They are working with pharmaceutical companies to obtain clinically approved adjuvants, which are substances that help activate the immune system, to use along with their vaccine. These adjuvants stimulate activity by B cells and T cells, which allow the body to remember and recognize invaders, and eliminate them.

One of the difficulties in evaluating whether the vaccine works in patients is the time needed to complete a clinical trial. Choosing patients with aggressive disease is one way around the problem, notes Gariépy.

Left: Expression of CEA on cancer cells renders them more aggressive and prone to metastasizing. Presence of CEA helps cancer cells aggregate with themselves as well as adhering to fibronectin present on target tissue (represented as brown filaments). Right: Giving the metastasis-preventing vaccine to patients helps the patient’s immune system recognize metastasizing cancer cells and limits their ability to spread to other parts of the body. On one level, antibody molecules tackle cancer cells, thus preventing their “clumping” and ability to implant (1). On a second level, cells of the immune system attack cancer cells that manage to escape the first wave of defenses (2), ultimately leading to the killing of the cancer cells by the patient’s immune system (3).

Illustration: Dr. Aws Abdul-Wahid

“This sort of vaccine faces more challenges than other types of treatment because you’re looking at an event that occurs fairly far in the future, so you have to pick your group of patients such that the disease tends to progress more rapidly than others in terms of metastasis,” says Gariépy. “That is why triple-negative breast cancer and ovarian cancer are interesting candidates for us to test the vaccine, because the outcome of metastasis would be quicker in these patients. This way, within a reasonable timescale of a trial—it may be three to five years—we’d start to see curves changing between vaccinated and unvaccinated [patients].”

Triple-negative breast cancer is hard to treat because it lacks the three receptors known to promote tumour growth—estrogen, progesterone and HER-2. Thus, therapies that target these receptors don’t work. It occurs in 10% to 20% of diagnosed breast cancers, and is more likely to spread and return.

It could be a year or two, or even longer, before clinical trials of the vaccine begin. Abdul-Wahid says if they can prove that it works, then the vaccine could be a viable strategy because it doesn’t require elaborate infrastructure and can be given by nurses. “My wish is that I would see patients—soon after diagnosis—immunized and then put into whatever first-line treatment that is needed. Then just like we do with the flu shot every year, these patients would be ‘boosted’ periodically, so that we can prevent or delay the onset of metastasis. Wouldn’t that be great?”

Would it ever.

This research is supported by the Canada Foundation for Innovation, Canadian Breast Cancer Foundation, Canadian Cancer Society, Canadian Institutes of Health Research, Federal Economic Development Agency for Southern Ontario, and Ontario Ministry of Research and Innovation.

Dr. Victor Yang illustration
Dr. Victor Yang