Ottawa researchers pilot combination treatment for cancer

A team of researchers at CHEO, lead by Dr. Robert Korneluk, have discovered a new combined cancer treatment.

The therapy involves a live virus treatment as well as SMAC mimetics, both of which are currently being tested individually in clinical trials. By themselves, the treatments have not shown any substantial results, however when the scientists from CHEO combined the two, the results were surprising.

“They work much better than we could have thought of originally,” says Dr. Eric Lacasse, a research scientist on the team.

The research was published on Jan. 27 in Nature Biotechnology, covering the results from their lab tests.

This new combined therapy works with the body’s natural defences to be more effective at killing cancer cells in tumors.

The first treatment involves a live virus, or oncolytics. The virus is injected into a tumor where it specifically targets the cancer cells.  It infects the cancer cells and then bursts them open. This triggers an immune response in the body to fight off the virus as well as the cancer cells, working with the body’s immune system to combat the cancer.

The second treatment, used in conjunction with live virus treatment, is second mitochondriaderived activator of caspase (SMAC) mimetics. The role of this drug is, at a basic level, to induce cell death. Every cell has a preprogrammed death, however cancer cells in particular are extremely resistant to cell death. This drug works by targeting the proteins made by the inhibitor of apoptosis proteins (IAP) gene family.

These proteins, coded by the IAP gene, play a normal role in the body’s healthy cells to keep them alive. In cancer cells, however, the IAP gene is overactive and codes too many proteins, causing the cancer cells to resist death. The SMAC mimetics kill cancer cells by attacking the IAP proteins that are keeping the cancer cells alive.

Both treatments are currently being tested individually in human clinical trials; SMAC mimetics is in phase two of clinical trials, and the type of live virus treatment used in this research is in phase one.

Neither drug has been individually approved for therapeutic use. Scientists testing these drugs have not found significant results in treating the cancer patients in the trials. This is largely because the treatments alone have major limitations.

Like any other virus, the live virus treatment will be fought off by the body’s immune system, killing it off after a couple days. The live virus will not have enough time to infect the cancer cells fully before human antibodies attack it.

When the SMAC mimetics were used in clinical trials, scientists found that they were also ineffective when used individually. The SMAC mimetics need cytokines to be able to target the IAP gene and cause the cancer cells to die. Cytokines are cells produced in the body as a part of the immune system’s response to viruses.

The live virus treatment causes the production of cytokines in the body, and by doing so allows the SMAC mimetics to kill off cancer cells. Meanwhile, the live virus treatment is also contributing to fighting off the cancer by attacking the cancerous cells.

Dr. Lacasse says it became clear to the research team that two would be better than one.

Researchers have found a way to combine SMAC mimetics and live virus therapy to create an effective cancer treatment for mice

As of now, the team has not tested the treatment on humans. Their goal is to begin clinical trials within a year, but before that the team must have the drug made and tested for toxicity, tested on animals and then approved by an ethics board for human testing.

When the team gets past these steps, the climb isn’t over yet. Dr. Lacasse admits that tests on mice in labs do not always translate as easily into humans.

However, the current test results are hard to ignore.

“There is a synergy— an amplification of effects happening here when you put the two together. So in some cases depending on what kind of tumor cell line we use, we can see the virus killing ten thousand times better when the SMAC mimetic is present,” says Dr. Lacasse.

The research team has been receiving very positive feedback from their colleagues about their results.

Dr. Sivan Bevan, from the Canadian Cancer Society says, “the results so far are encouraging, and the next important step is to test this new combination in patients.”

Should this therapy prove to be successful in clinical trials, it could be very promising to cancer patients.

Current cancer treatments like chemotherapy and radiation can be toxic not only to the cancer cells but also to the healthy cells in the body. These treatments are very harsh and can mutate DNA, causing other health-related problems for patients in the future.

The combination of live virus treatment and SMAC mimetics would have fewer detrimental health effects for patients. After the patient is injected with the live virus, they would experience flu-like symptoms, but like any virus this would pass within days.

Dr. Lacasse says this gentler therapy would be particularly applicable to children who develop or are born with cancer.

“There are always greater detrimental side effects from chemo or radiation in children. So if they survive their cancer, these side effects will carry with them for the rest of their life.”

The combination therapy would be much less damaging to the patients’ DNA, allowing them to make a more long-lasting recovery.

The research team at CHEO anxiously awaits the approval of human trials to test this new treatment.

Front page photo © Senofi Pasteur.

Thumbnail photos © Jeremy Wilburn and © Julia Pichler.