Hope for pediatric transplant patients and their families
Dr. Emmanuel Katsanis talks about his two passions – improving the lives of sick children and running.
Treatment for patients with blood cancers like leukemia or lymphoma may include a bone marrow transplant to replace unhealthy tissue to increase odds of recovery and survival. Transplants can be lifesaving but are complex and challenging, especially for children. Physician-scientist Dr. Emmanuel Katsanis not only performs transplantation, but also actively researches tumor and transplant immunology. Dr. Katsanis is a professor of pediatrics, medicine, immunology, and cancer biology, and is a BIO5 member. He discusses his three decades of expertise in the lab and clinic as the Director of the Blood and Marrow Transplant Program and Division Chief of Pediatric Hematology/Oncology at the University of Arizona, as well as directing his own research lab.
As a physician-scientist, you provide care for children with cancer and blood disorders, and conduct research at the University of Arizona’s Steele Children's Research Center and Diamond Children's Medical Center at Banner University Medical Center. Tell us a little bit about your research and how your work at both the bench and bedside impact one another.
My research has always been driven by my clinical experience. I started as an MD, and then did my training in pediatrics in Canada, and then from there went to the University of Minnesota where I trained in pediatric hematology/oncology. The first year in my fellowship was clinical, but we were required to spend some time in the lab, which for me was like starting kindergarten again.
With time I got to enjoy what I was doing, and especially with projects that I found to be more clinically relevant and translational. I ended up doing three years in the laboratory there and then stayed at the University of Minnesota and had protected time, so my research experience improved significantly.
Coming to Arizona, I continued in this same area of tumor immunology back in the time where most oncologists were making fun of us. They thought that the immune system would never be able to have an effect against cancer, but as a bone marrow transplant physician, I had seen the effects of graft versus host disease in patients.
A lot of what my lab has done has moved into clinical trials, and most recently, if we get the funding, we’re looking at starting a multi-center Phase II clinical trial.
Being in Arizona and having large minority populations, we have a difficult time finding a matched unrelated donor. You would prefer that someone would have a matched sibling, but the chance of having a matched sibling is one in four, and with smaller families, we don't often have a sibling. We used to do transplants with unrelated donors and very young kids’ cord blood as donors.
If you're Hispanic of Mexican background, the chances of finding a matched related donor is only about 38%; if you're African American it's only 17%. Having minority patients, we often had to use unrelated donors that we're not fully matched. Haplo-identical bone marrow transplantation was done back in the years that I was in Minnesota, but it was problematic with a lot of complications.
With work that was done primarily at Johns Hopkins, they found that you can use a half-matched donor, called haplo-identical. In pediatrics, parents are always a half match with their kids, and siblings have a 25% chance of being a full match but also have a 50% chance of being a half match. Within the family, you pretty much always find a donor, so this was very important to implement here.
The protocol that we initially used was a little bit different than Johns Hopkins’ in terms of the conditioning of the transplant, which for pediatrics was more intensive. But the question that I asked at that point was, “Why are they using cyclophosphamide following transplantation?”
We knew it was because the allo-reactive cells from the half-matched donor proliferate once they're infused into the patient, and if those allo-reactive cells are not eliminated, the patient is likely going to die of graft versus host disease. They found that you can give chemotherapy following transplantation and that would eliminate most of the other reactive T cells, but would not kill the stem cells, so they had protection against graft versus host disease.
We thought another drug may be better, so we studied a variety of different agents and found that a medication that was used mainly for certain lymphomas and leukemias was equally effective in suppressing graft versus host disease and allowed better graft versus leukemia effect.
We then proceeded to a clinical trial - a Phase 1 study where we slowly decreased the amount of cyclophosphamide and replaced it with bendamustine. We found that just replacing one day had the best results - the patients that received that engrafted significantly earlier, tended to have less infections, and all three patients are alive and disease free more than two to three years after transplantation.
We now have moved to a Phase 1B where we're doing a larger cohort of patients on this dosing, and we're waiting to hear if our NIH submission will get funded which will expand this to a multicenter trial, which will be randomized between patients getting only cyclophosphamide versus cyclophosphamide and bendamustine.
What is the most challenging thing about your job, and what is the most rewarding?
A lot is challenging, but I think the most challenging is time.
I'm very committed to my patients. I pretty much attend almost every day. We're not a huge center, which has allowed me to be able to do so much clinical. My mornings start seeing the patients and then in the afternoon there is more research and, unfortunately, a lot of administration.
What I love doing is seeing the patients - seeing how they do, making sure I do a good job, making sure they're happy and especially their parents. It’s important knowing that me and my team have done everything that we can do. Fortunately, the results have significantly improved from the years that I’ve been doing this - 75 to 80% can be cured - so knowing that this was a lethal disease that now you have cured is obviously very, very rewarding.
As you can imagine, it's hard to give up any of the things that I do because you see what's happening clinically. You know you can't cure everybody and that there are still issues, so you then have the drive to go back to the lab. Fortunately, I’m not alone. I work with other scientists, and I've had postdocs and junior faculty members in my laboratory of diverse backgrounds over the years.
Currently, I’m working very closely with Dr. Richard Simpson, who's an exercise immunologist. We have found both with our passion in running but also in immunology a lot of common areas, so our labs are collaborating very closely, and especially with the viral infections and viral reactivation because he has done a lot of work previously in that arena.
With the patients that I mentioned in the clinical trial, we are looking to see how their immune system reconstitutes compared to the controls following transplantation. Ultimately, we're learning how the immune system may be benefited by this approach.
We’ve had a few physician-scientists on the podcast already, and they always say their job isn’t easy. Do you have any words of wisdom for people thinking about pursuing this dual career?
Things have really changed from when I started my residency back in 1983. I've seen the field change, and I’ve been in different countries doing this. My biggest worry is that the physician scientist, especially with the funding situation, is becoming almost extinct.
We do have a lot of pressures where our salaries come from - I’ve been fortunate to be supported by an endowed chair that helps offset some of the clinical work, even though, as I mentioned, I see patients have virtually every day.
Back when I was starting, you wrote an NIH grant and you had a one in four chance of getting funded - that has really changed. Even though I know more, it's harder to get a grant now than it was 15 years ago.
I’m our department chair and on the Promotion and Tenure Committee, and we just had a meeting today discussing how we promote not necessarily tenured professors, but at least a track that people can be motivated to work with scientists, because what you don't want to happen is to have physicians just look after patients and not be interested in the science.
It's very important to have that phenotype that is interested in both, even though they may not be able to run their own lab. I think there needs to be a focus in being able to promote that so the scientists could have a partner that has an interest to see things move forward.
You were born in Canada, did your MD in Greece, came back to Canada, and then moved to the US. How do you think that global perspective shapes how you view science and medicine, and life in general?
My mom was seven months pregnant when she took the boat from Athens and landed in Halifax, Canada. I was born a couple months later in Quebec City, and I grew up in Montreal. My mom was the driving force pushing me in school.
I started off going to a Greek school in a church in Montreal, where it was half Greek, half English for the first three years, and then after three years, it was all English. After I finished the ninth grade in Canada, my parents said, “We're moving to Greece.”
It was initially a shock, but I feel that those were the best years of my life growing up there. I started running track and became the Greek champion at 800 meters when I was 16 for 16 and under.
The push was to get into medical school, which I wanted, and in Greece it's very difficult to get in. I managed to get in, and running then had to disappear from my life because it was too difficult to continue on.
Initially I thought I would do hematology because I saw a lot of kids that had a congenital blood disorder that required chronic transfusions. Finishing my studies in Greece, I came back to Canada and did my residency in Montreal and Ottawa. When I rotated through hematology/oncology dealing with the kids with cancer was where I found I needed to be. I had some patients that I looked after that I bonded with very closely, and it’s very difficult when you're young to see your patients die, so from there on that's what I wanted to do. I then moved to Minnesota mainly because it had a very strong bone marrow transplant program.
Seeing the different healthcare systems and the different problems have given me a different perspective. I see the pluses of Canada - the universal health care - especially when we're dealing with kids with cancer. Sometimes here you have to fight with insurance companies to even get a CT scan. There are some negatives, but when you're dealing with pediatrics, I don't think having universal health care has any negative.
I also have kids – one was born in Minnesota and the other in Tucson. I sent both my kids to study in Canada, and they ended up liking it, and they're going to stay in Canada. They saw the perspective that I had in life and being worldly in terms of how you see everything, so they adjusted very easily.
I’m glad that I was forced to move to Greece because it really impacted all avenues in my life.
You mentioned your passion for running, and I know you did eventually find your way back into the sport. Talk to us about how having hobbies and passions like running outside of a demanding job are really important to keeping you mentally and physically healthy.
I get up at four o'clock every morning to run. I started a running group when I first moved to Arizona, and we've named our group “The Interloopers.” Since 1998, we meet every Tuesday and Thursday at five o'clock in the morning at one of the tracks in town, and then on the weekends, we run a long run.
Most of us have aged and have gotten slower, and now we have quite a few younger members. As I’ve gotten older, I’ve gotten slower and the younger members that were slower are now passing me. I'm very much into data and graphics, so I make sure if I lose from them that I age grade that performance and I send them a graph to show that I’m still better, even though I was a mile behind.
What keeps me sane is having this group, and it's been a stable group that we've had, and everybody's welcome to join. We don't charge anything, and if you're looking for company to run early in the morning when it's dark in the winter and cool in the summer, then that's the place to be.
This group has been especially important with the pandemic, as that has been for a long period of time our only outing.
We like to end these podcasts with a light-hearted question. We think of our researchers as superheroes, so if you were a superhero, what would your superpower be?
Being able to touch a patient and kill every last cancer cell in their body, really, really fast, age graded or not.