Responses by Walter Urba, M.D., Ph.D.
Last fall, the Oregon Historical Society shined a local light on pioneering research in immunotherapy when it recognized Providence Cancer Center's Walter Urba, M.D., Ph.D. as a "cancer warrior" and named him a 2014 Oregon History Maker.
We asked Dr. Urba to update us on immunotherapy today and the work being done to bring powerful new treatments to patients in Portland and all over the world.
Q: What is immunotherapy?
Immunotherapy is a treatment strategy that takes advantage of the body’s own immune system to fight cancer. Normally, the immune system is very good at hunting down and destroying harmful invaders, such as bacteria, viruses and even cancer cells. But cancer can be a master of disguise, and the immune system doesn’t always recognize it as something foreign. One approach to immunotherapy focuses on teaching the immune system to recognize cancer cells better. Another approach attempts to manipulate the immune system to boost its power to destroy cancer cells.
Q: What are the potential benefits of immunotherapy compared to standard cancer treatments?
That’s a much more interesting question to answer than it used to be. The hope has always been that immunotherapy can be much more targeted than chemotherapy and radiation. With those two standard treatments, the ability to selectively target tumor cells isn’t so great. Healthy cells get poisoned or irradiated along with cancer cells, which is why people experience hair loss, anemia, nausea and other toxic side effects. Immunotherapy can be toxic, too, but the advantage is that in some cases, we can selectively apply it to cancer cells and minimize damage to normal cells.
Another big advantage is that immunotherapy works by an entirely different mechanism than chemotherapy or radiation, so we can combine it with other therapies to get better results than either treatment could achieve alone.
But the biggest advantage that we have seen is that when a patient’s cancer responds to immunotherapy, the treatment appears to bring about a much longer, more sustained remission than the newer targeted therapies are achieving. Targeted therapies interfere with the growth of cancer cells by targeting and attacking abnormal proteins produced by genetic mutations in the cancer cells. These drugs can make tumors shrink quickly and dramatically. But over time – and unfortunately, time is measured in months rather than years – the tumors evolve and become resistant to the targeted treatment. Immunotherapy, at this point, may not cause tumor regression in as many patients, but when it does work, patients go into remission for years, and we believe that most of these people, who are now experiencing long remissions, are going to be cured.
Q: Is immunotherapy still investigational, or is it now considered a mainstream cancer treatment?
It’s mainstream now. When I joined Providence in 1993, I had been doing research in immunotherapy at the National Cancer Institute for 10 years, and that became our focus at the Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Center. In those early days, only a handful of centers in the world were investigating this approach. Most of the drug companies had no interest in it and thought it wouldn’t work. You rarely heard about it at scientific meetings.
Twenty years later, the journal Science declared cancer immunotherapy the 2013 “Breakthrough of the Year.” Now, just about every major research center has an immunotherapy program, and those that don’t are building them as fast as they can. Every drug company wants to have an immunotherapy “drug” in its pipeline, and every major oncology conference has immunotherapy at the top of its agenda. It’s an exciting time, and very gratifying that our program has been one of the major contributors, along with other groups around the world, who have hung in there and led the way.
Q: What have been some of the most exciting landmarks of Providence’s two decades of immunotherapy research?
There have been many, but two stand out: our progress with OX40 and our contributions to the development of ipilimumab.
The biggest highlight has to be our work with OX40, an immune-boosting antibody developed by our own scientists. Our team has been working hard for more than 10 years to translate OX40 from the laboratory to the clinic. The first human clinical trial, funded largely by local contributions and conducted here in Portland, found that the treatment significantly shrank tumors in 12 of 30 patients.
After that trial, MedImmune – a wholly owned subsidiary of the global pharmaceutical company AstraZeneca – expressed interested in the technology. So it was a very proud moment when we licensed it to a small biotech company, AgonOx, started here by our own scientist and OX40 originator, Andrew Weinberg, Ph.D., and his company then sublicensed it to MedImmune. The resulting research agreement allows us to continue working on OX40, while MedImmune invests the millions of dollars required to keep the work moving forward. OX40 reached a new milestone last year when a new clinical trial brought the treatment to people outside of Portland for the first time.
Another exciting landmark for us was the positive study of an antibody called ipilimumab, which led to a new treatment for patients with advanced melanoma. We got involved early on in small pilot studies with the company that developed the antibody, which appeared to activate the immune system’s T cells to kill cancer cells. When the results looked promising, the company asked me to be the principal investigator of its worldwide phase 3 study. We led the international study, and in the clinical trial performed in 125 centers in 13 countries, ipilimumab doubled patient survival. The New England Journal of Medicine published the results, which led the Food and Drug Administration to approve the treatment, now called Yervoy, in 2011.
This was the first time that a drug had been shown to improve survival in people with advanced melanoma, and it was an immunotherapy. To be one of the leading teams associated with that advancement – and with the recognition that it brought to the entire field of immunotherapy – was personally satisfying and gratifying for everyone on our team, after so many years of work. It just felt great. We all do this because we want to make a difference, and you can make a difference by publishing papers and doing cool experiments, but there’s nothing like being a part of bringing a new therapy to people all around the world.
Q: What newer research is showing promise?
We are excited about a new vaccine technology being developed by our scientists Bernard Fox, Ph.D., and Hong Ming Hu, Ph.D., which shows promise for making cancer vaccines more effective. They have started a biotechnology research and development company, UbiVac, to further this work.
We also are optimistic about the work of Keith Bahjat, Ph.D., and Marka Crittenden, M.D., Ph.D. Dr. Bahjat has combined cancer-specific genes with a common bacterium, called Listeria monocytogenes, to create a vaccine that changes the bacterium into a potential cancer killer. He and Dr. Crittenden are using the modified bacteria to vaccinate patients with brain tumors who have completed their surgery, radiation and chemotherapy, in hopes of killing any tumor cells that may have escaped standard treatment.
As part of our next phase of research, Providence has embarked on a large genomics initiative that should integrate well with immunotherapy. Many mutations that we find in patients’ cancers after sequencing their tumor cell DNA cannot be attacked through targeted therapies that are currently available. However, those mutations lead to the production of abnormal proteins that can, potentially, be targeted with the immune system. We look forward to using what we learn from the genomics work to find better ways to target patients’ cancers with immunotherapy.
Q: Some analysts predict that in the next 10 years, 60 percent of people with advanced cancer will receive immunotherapy as part of their treatment. Do you agree?
There is no question that immunotherapy will represent a part of therapy for most patients with advanced cancer in the next 10 years – I agree 100 percent. We’re on the crest of a wave right now, and soon, instead of an occasional patient benefiting here or there, we’re going to see large numbers of patients benefiting. One of the treatments currently under investigation is going to be approved for lung cancer, and that alone affects some 200,000 patients a year. So if anything, the prediction is a minimum.
Q: A few months ago, the Oregon Historical Society honored you as a 2014 Oregon History Maker, referring to you as a “cancer warrior.” Who are Providence’s other cancer warriors?
There are too many to name, but if I have to name a few, I would start on the clinical side with Brendan Curti, M.D., a great doctor who has led the entire OX40 clinical program, among many other programs; and Dr. Crittenden, a radiation oncologist and tumor immunologist who is determining how best to integrate immunotherapy and radiation therapy to make treatment more effective.
On the lab side, the two who have led the charge from day one are Drs. Fox and Weinberg. Many of the scientists and physicians who’ve joined Providence are here because of their strong laboratory work and their commitment to getting laboratory results translated into more effective therapies for our patients.
Of course, we couldn’t do the work without the unsung heroes in our clinical trials office, our nursing team, our administration and our foundation – every one of them is engaged in the war on cancer. And we certainly could not have accomplished the progress that we’ve made without our patients, who are truly the heroes in all this, and without all of the philanthropists who have supported our work for so many years. That’s a story that really deserves to be told. OX40 is being developed by one of the largest pharmaceutical companies in the world now, and it would not be there if not for the local patients, business people and regular folks in the community who believed in it and were willing to pitch in a few dollars to get our work started and to keep it going. I talk about that a lot with colleagues all over the country, and they’re always amazed, because that just doesn't happen anywhere else.
Walter Urba, M.D., Ph.D., is a medical oncologist and director of cancer research at the Robert W. Franz Cancer Research Center at the Earle A. Chiles Research Institute at Providence Cancer Center.