Drawing Professional Inspiration From Personal Experience

Bradley Muller, MD

When Bradley Muller, MD, received a diagnosis of lymphoblastic leukemia (ALL), he started a journey that would undoubtedly alter his life forever. However, despite the hardship he had to overcome, it would eventually help put him in a position to help children with cancer and hopefully contribute to a future where no child would have to experience this again.

“My treatment course spanned over 2 and a half years, and over that time I had to figure out how I was going to cope with this horribly traumatic experience in a positive way,” said Muller, a pediatric hematology-oncology fellow at St Jude Children’s Research Hospital in Memphis, Tennessee. “My oncologists were the ones [who] helped me with that. I knew pretty early into my treatment that from the way that I was being treated by them and all the staff around them that I wanted to be part of this. So, I would say when I was 8 years old, I knew that I wanted to pursue this type of career.”

In an interview with Oncology Fellows, Muller detailed the journey that led him to pursue an academic career in pediatric oncology and discussed the focus of his research that he hopes will someday improve outcomes for pediatric patients with T-cell ALL.

Oncology Fellows: Could you provide some background on your story
as a pediatric patient with T-cell ALL?

Muller: When I was 7, I went to the pediatrician with worsening symptoms of fevers, headaches, and muscle aches. We just thought it was a virus for the first few weeks. But eventually, I started developing shortness of breath, especially when I was lying down, and had trouble waking up.

My parents rushed me back to the pediatrician; they did a complete blood count, and from there they noticed that my white [blood] cell count was beyond the quantification limit of the assay. Afterwards, a chest X-ray revealed a large mass in my chest. I was rushed to the emergency department and was diagnosed with T-cell ALL soon thereafter. I spent the next 2 to 3 weeks in the pediatric [intensive care unit], getting stabilized with multi-agent chemotherapy and many other interventions.

I then embarked on a treatment journey of about 2 and a half years, which is the treatment duration for this disease. This was back in 1998 to 2001, so the outcomes of this disease were not nearly as good as they are now. The approach to treating [patients with] this disease was more of a kitchen sink–type approach, where you throw everything at it that is known to be effective and worry less about the long-term effects, as survival is the primary goal. I had an intense chemotherapy regimen that included lumbar punctures with intrathecal chemo- therapy, along with craniospinal radiation [because of] leukemia in my cerebral spinal fluid and brain.

How did that experience translate to your journey as a medical student?

I [had] known since I was 8 years old that I wanted to take care of [pediatric patients], but not only that, I wanted to specialize in treating [pediatric patients] with T-cell ALL. I went to undergrad, majored in biochemistry, and went to medical school at East Tennessee State University in Johnson City.

While I was in medical school, I had a neat opportunity here at
St Jude where I took part in this National Institutes of Health–funded program called the Pediatric Oncology Education Program. St Jude has had this for decades, where they’ll take an undergrad student or medi- cal student and over the course of the summer you do research here. It’s a highly competitive program and I applied every year I was an undergrad and was never accepted into it.

But then when I was in medical school, I finally got in. [Starting
in] 2015, I worked with Brandon Triplett, MD, who is now deputy clinical director of the hospital, but at that point he was a clinical bone marrow transplant specialist. He showed me everything that St Jude is and helped push me [toward] this career path because he taught me immunology through bone marrow transplantation. He also gave me a lot of autonomy; I’m someone who likes to get up early, go exercise, get my work done early, and then be done. I would do that every morning; I’d get to work early, get all the research that we needed done by the midafternoon, and then the afternoons were all mine to shadow at all the different clinics and services here at St Jude.

Through that exposure, I met a lot of my current mentors [who] have been my mentors for now nearly a decade, which is crazy to think about. During that time is when I met Hiroto Inaba, MD, PhD, who’s now the program direc- tor for our fellowship, but also my main clinical mentor. He and Brandon have mentored me throughout medical school and all of [my] residency training.

I ended up doing my residency at Johns Hopkins [University] in Baltimore, [Maryland], and that was a cool experience to get training there. But I would always get these random messages from Brandon saying, “Don’t fall in love with that fancy place, because you’re coming back here for training.” So, at the end of my residency, I ended up coming back to St Jude, not only for training but with the goal of becoming faculty within our leukemia division, taking care of patients with and researching T-cell ALL.

The first year of fellowship is hard and that is the norm everywhere. It is clinically focused where you are immersed in practicing clinical medicine, taking care of patients with both hematological and oncological disorders.
I rotated through all of our services at St Jude including leukemia/lymphoma, solid tumor, neuro-oncology, bone marrow transplant, and hematology. Moreover, I was on- call overnight frequently, answering pages from our hos- pital and its catchment area, providing recommendations on how to appropriately take care of our patients. During this year, I learned the most, and became very comfortable with the clinical side of being a pediatric hematologist- oncologist. It was during this time that I started taking care of my own patients, which, to this day, brings me the most joy. But then after those 12 months, my role become more research focused, and in our fellowship you can do any type of research that you can think of. You can do basic science in the laboratory like I’m doing and study cancer or whatever else, or you can do clinical projects or global projects—whatever your interest is. Altogether, my research years are to teach me how to think like a scientist, so that later on in my career, I am able to understand the basic science and research that are foundational in run- ning clinical trials, and, particular to my interests, my goal is to run clinical trials for patients with T-cell ALL.

Could you describe your research focus within T-cell ALL and what makes it unique?

My principal investigator is Paul Thomas, PhD, and our lab focuses on T-cell receptors, which [are] the main protein that defines a T cell. These receptors typically bind to cells that are cancerous to kill them, or they bind to cells that express proteins that have come from a viral or bacterial infection. We’ve recognized that there are different types of malignancies, including T-cell ALL, with certain subtypes that will express the T-cell receptor.

My role in the lab here is understanding the biology of these T-cell receptors when they’re expressed on these malignant cells, with the idea of targeting them and de- veloping a therapeutic [agent] that interacts with them in a way that can be beneficial for our patients. My project is somewhat different than everyone else’s in the lab. Everyone wants to know what the T-cell receptor is bind- ing to and what those interactions mean, usually in the context of a normal and productive immune response. I want to find out what these T-cell receptors on cancer cells are binding to and understand the biology of these interac- tions, with the hypothesis that they provide an advantage to the cancer.

I’m the only pediatric oncologist in the Thomas lab, and we have multiple projects working on T cells targeting dif- ferent types of cancers. Paul has put me in [a] position to be a [sort of] consultant to these different projects, as I can provide a clinical perspective, while our graduate students, post-doctoral researchers, and staff scientists dive deep into the basic science. At the end of the day, I’m interested in, “Why does all that matter?” because I want to know how this fascinating science can be translated into helping our patients. Thus, I bring a unique perspective to many of the projects within the Thomas Lab.

My project focuses on a certain subtype of T-cell ALL called γδ T-cell ALL, where the malignant T cells express a γδ T-cell receptor on the cell surface. Previous studies at St Jude have shown that patients with this subtype of T-cell ALL have poorer outcomes compared with other types of T-cell ALL, and the defining characteristic of this subtype is expression of this receptor.

This difference is what brought me to this project so that I can understand why expression of this type of T-cell receptor correlates with poorer outcomes. It likely plays some biological role in the cancer, and my job is to dis- cover and describe its mechanism.

The project has taken multiple paths, because frequent- ly that is required to make novel discoveries. That makes the science a little more challenging, especially when I’ve only had a few years of lab experience. But it also makes me very thankful for all the graduate students, senior [postdoctoral researchers], and staff scientists who know how to do everything. I’m much more comfortable with the clinical side at this point in my career, but I’m getting much better at the bench side now.