In his off hours, Dr. Michael Smylie — a medical oncologist and clinical research veteran at the Cross Cancer Institute in Edmonton — gravitates to activities that will push his physical boundaries, such as long cycling trips or scaling Mount Kilimanjaro (currently the number one item on his bucket list).
Back at the office, he is pushing boundaries related to cancer treatment — and with significant success. Smylie specializes in late-stage melanoma, which has the nasty distinction of being the deadliest of skin cancers, but is finally meeting its match with the introduction of immunotherapies. For the first time, due to promising clinical trial results and research initiatives, he can now offer patients hope for their future.
“Treatment for melanoma has experienced a revolution,” says Smylie, who took his medical training, residency and fellowship at the universities of Leicester, Saskatchewan and Ottawa, respectively. “Now, there is a relatively good chance we can cure this cancer.”
For more than five decades, treatment for late-stage melanoma involved chemotherapy, the hormone drug tamoxifen and/or interleukin-2/interferon. Cocktails had such devastating side effects that they were nicknamed “toxic placebos.”
“Rarely would you get a patient who did well,” says Smylie, who is 62 years old and a father of five. “It was depressing.” Indeed, median life expectancy for stage 4 melanoma was seven months, and only one patient in 20 lived longer than five years.
Then, in 2007, Smylie attended a National Cancer Institute meeting in the United States where stakeholders — including pharmaceutical companies, biotech firms and melanoma experts — gathered together and committed collectively to finding more effective drug therapies for melanoma. This critical event prompted the exploration and development of immunotherapies (also known as biological therapies), which are treatments designed specifically to help the immune system attack cancer cells.
Normally, our immune systems are efficient and robust, switching on and off as necessary to fight germs or infection. “But cancer cells are master manipulators,” says Smylie. They can create an environment where they engage the “off” switches, called checkpoints, shutting down the immune system’s restorative capacity and giving cancer cells the ability to grow wildly. Immunotherapy agents do not treat cancer directly, Smylie explains. Instead, they release the “brakes,” reactivating the immune system so it can attack the rabid cancer cells.
“Immunotherapy is now one of the pillars of cancer treatment,” he says.
For the last decade, Smylie has been in charge of conducting international immunotherapy clinical trials (spearheaded and funded by global pharmaceutical companies or cancer research groups from the U.S. and Europe) at the Cross Cancer Institute. His duties include assessing a trial’s viability in Alberta, reviewing protocols, getting approval from the ethics committee, overseeing the ordering and delivery of medications, tracking and treating side effects, collecting and reporting measurement data, and discussing results with organizers.
The first major immunotherapy trial for late-stage melanoma took place in 2007 and was designed by an American pharmaceutical group called Medarex. It involved 600 patients and took three years to complete. The treatment group, which included two individuals in their 30s from Alberta, received an intravenous infusion of ipilimumab every three weeks for three months. Data showed that 20 per cent of participants remained alive at the five-year mark — the Alberta patients remain cancer-free today — and noted that the immunotherapy was “a potentially curative treatment for metastatic melanoma.”
A subsequent trial, conducted eight years later, added a PD1 inhibitor (PD1 is a cancer protein responsible for putting on those “brakes”) to ipilimumab. That combo treatment resulted in 58 per cent of trial participants being alive after three years.
A more recent trial, which began in the fall of 2017, involves 2,000 patients (20 from northern Alberta, under Smylie’s purview) with stage 3 melanoma. Patients in the trial are receiving treatment — either a single product (ipilimumab or nivolumab) or in combination — for one year. Though preliminary findings won’t be available until the summer of 2019, it is anticipated that the combination treatment will provide something called a “dual blockade,” restoring the immune-system function of participants and stopping cancer cells from being able to turn it off in the first place.
In addition to working on international clinical trials, Smylie is involved in several other research ventures around immunotherapy. He has recently helped design a protocol in conjunction with Dr. Philip Halloran to examine “inflammatory signatures” of cancer cells (the hypothesis is that cancers with higher inflammation signatures will respond more favourably to immunotherapy treatments). In conjunction with medical colleagues at the University of Alberta, he is conducting biopsies on the melanoma lesions of 35 participants to measure these inflammation rates and track immunotherapy success.
He is also working with another U of A group studying small molecule inhibitors of immune checkpoints.
There are challenges with such research: it takes time to conduct trials, collaborate with stakeholders, create awareness and educate staff. And, in some cases, patients simply do not respond to immunotherapy. But Smylie is proud of the Cross Cancer Institute’s research program for making critical inroads into melanoma treatment, much of which has been supported by Alberta Cancer Foundation donors along the way.
“The amount of knowledge is exploding,” he says. “We are learning more about the science every day.”
And that learning is clearly a team effort. Smylie’s colleague, Dr. John Walker, is appreciative of how Smylie leads and inspires by example. “[He] has helped hundreds of melanoma patients by bringing practice-changing clinical trials to the CCI, but I also credit Mike with helping me develop my own practice style,” says Walker. “He is an excellent communicator and a true gentleman in clinic. The science of medicine may be learned in a classroom, but the art of practice can only be taught by a gifted practitioner.”
Smylie is grateful for such collegial support, and for the patients who have taken this brave, road-less-travelled with him. “My clinics are populated with people living longer and having a better quality of life,” he says. “It is absolutely stunning.”
Questions with Dr. Smylie
Describe what you do in 10 words or less.
Make a difference in cancer patients’ lives.
What’s the biggest misperception about what you do?
Some people still think immunotherapy is a form of chemotherapy. We still have to get over that hump. Immunotherapy, although given intravenously like chemotherapy, is not chemo.
Where do you get your best ideas?
From reading. I enjoy science fiction — I loved the Foundation series by Isaac Asimov. I also love history and books about historic figures.
What’s the best lesson you’ve learned?
Manipulating the immune system actually works.
What motivates you?
Seeing patients do well.
What do you do to recharge?
I cycle with two other doctors. One is very competitive and my goal is to beat him. Sadly, he usually comes out on top.
Why does your research matter?
Because we are making such a huge impact on patients’ lives