Will Donnellan, M.D., TENNESSEE ONCOLOGY
As medical professionals, we all have a unique path that led us to our chosen field. While this path is often decades in the making, most oncologists can pinpoint a handful of transformative experiences that drew them to this specialty. For many, it was a specific interaction with a patient that sparked a desire to treat those affected by cancer. For others, it was a fascination with the science underlying cancer and the methods being developed to combat it. For me, it was both.
As a first year internal medicine resident at the University of Alabama in Birmingham (UAB), two thirds of the year was spent on the general medicine wards taking care of patients with medical problems ranging from infections to diabetes. The remainder of the year was spent working with subspecialists who had expertise in treating patients with more specific medical problems. Within internal medicine the number of subspecialties is vast. It was only by chance that one of the few subspecialty months to which I was assigned was oncology.
I clearly remember my first day on the oncology ward. It was the last month of my intern year, and after eleven months of regular thirty hour shifts I was ready to move on to the less exhausting lifestyle of a second year resident. I had already made the decision to pursue a fellowship in pulmonary/critical care medicine and planned to use this last month preparing my application. However, by the end of the month my career plans would change. This change started with “Blake”, a patient hospitalized on the oncology ward whom I had the privilege to care for.
Blake was in his early twenties and was enjoying his independence at a college out-of-state. He had been well until several days earlier when an urgent care visit for fatigue revealed that he was anemic. He returned home to Alabama, and was referred to our oncology clinic for evaluation. Additional bloodwork suggested leukemia, and he was admitted to the hospital. After a thorough work up including a bone marrow biopsy, Blake was found to have precursor B-cell acute lymphoblastic leukemia (ALL). We planned to begin treatment with an investigational protocol designed for pediatric patients with high-risk precursor B-cell ALL. As we started, I felt as if we were heading into uncharted waters. Would this investigational protocol work? Would Blake be able to tolerate the side effects? How would he deal with his new diagnosis of cancer?
It did not take long for me to realize the strength of Blake’s character. Despite painful procedures, constant invasions into his privacy, and an abrupt departure from his previously normal lifestyle, his positive attitude was unwavering. Checking in on Blake each morning before our team’s rounds was a bright spot in my day. He would always smile and say “Hey Doc, what’s new?” Not a single day did he show any sign of doubt, fear, or frustration.
Blake did well. Despite several setbacks, a follow up bone marrow biopsy showed that he was in complete remission. I was happy for Blake and hoped that he would be cured. I remember being humbled by the faith that he and his family had in our team and the trust they placed in our ability to treat his aggressive form of cancer.
Blake was not the only person I met that month who countered their cancer diagnosis with a positive and undefeatable attitude. During my short time on the oncology ward I met others whose resiliency and determination inspired me. Based on these experiences, by the end of the month I had firmly decided that oncology was the field for me. I had previously requested many of my rotations for the second year of residency to be in the pulmonary clinic and ICU, so somewhat frantically I contacted my internal medicine program director and notified him of my change in mind. With relief I was informed that the schedule was still flexible and I was able to sign up for rotations on the oncology consult service, bone marrow transplant unit, and outpatient oncology clinic. These rotations reinforced the feelings that I had experienced during my initial month on the oncology ward and assured me that my decision to change career paths was right.
As my second year of residency ended, I completed the oncology fellowship application, wrote my personal statement, and requested letters of recommendation from professors in my program. Anxiously, I submitted my application the same day the application website “went live”. After that it was a waiting game. With many more applicants than spots available, there was no guarantee of even being invited for an interview. Thankfully, after several weeks the interview invitations began to come. After scrambling to secure a personal loan and applying for an additional credit card, I was able to make travel arrangements and I began the interview process.
Ultimately, I decided that I wanted to stay at the University of Alabama for fellowship and after waiting a couple of seemingly long months I found out that I “matched” to the UAB oncology program. You would think that after all of that decision making I could relax a little and settle into learning about how to treat patients with cancer. However, I quickly found that my decision making was not over. Very shortly after starting fellowship, more questions about my long-term career plans began to arise. Did I want to focus on hematology (blood cancer), or solid tumor oncology (cancer involving certain organs)? Did I want to treat patients, conduct research, or do both? If I wanted to do research, did I want to do research in the lab or in the clinic? As one might expect, trying to make these decisions while at the same time trying to become proficient in oncology was a challenge.
For me, a single paper published in the New England Journal of Medicine (NEJM) on August 10, 2011 clarified my plans. It was only my second month of oncology fellowship, and I remember the looming fear of being a new, unseasoned oncology fellow who was responsible for the care of cancer patients. I recall sitting down in the fellows’ on-call room, opening that week’s issue of the NEJM, and seeing the title: “Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia”. I thought, “Chimeric Antigen Receptor T cells”, what is that? As I began to read the article I became completely intrigued. The authors described a patient with chronic lymphoid leukemia (CLL), who relapsed despite being treated with multiple chemotherapy regimens over the course of many years. His leukemia was now resistant to the standard treatments and giving more chemotherapy was unlikely to work.
After considering his options, the patient decided to enroll in a phase 1 clinical trial in which his research doctors were evaluating a new form of therapy known as chimeric antigen receptor modified T-cells, AKA CAR T-cells. In the article, the doctors described how they removed the patient’s white blood cells and separated out the T-cells, a specific type of immune cell. They then purposely infected the T-cells with a virus analogous to HIV. The virus had been manipulated beforehand such that once it infected the T-cells it re-programmed them in a way that they could now recognize and kill leukemia cells. The CAR T-cells were then infused back into the patient where they could circulate, find the leukemia cells, and launch an all-out attack that, in theory, would obliterate his leukemia.
As I was reading, I remember thinking that this sounded like something out of a science fiction movie. A patient with relapsed cancer gets his immune cells removed and infected with a modified form of HIV. This in turn transforms his immune system into something akin to The Terminator, which could then completely demolish his cancer. Yeah right, like that was going to work. Despite my skepticism, I was impressed with the fact that someone even figured out how to attempt this complicated process in the first place. Kudos to these doctors for trying, even if their cancer-killing CAR T-cells didn’t work. I assumed that it was the audacity of their attempt alone that made the article worthy of being published in the prestigious NEJM. I was wrong. As I continued reading, I realized that the article was being published because their audacious, science fiction attempt at curing this patient’s relapsed cancer actually worked.
Fourteen days after infusion of the CAR T-cells the patient began having chills and low-grade fevers. Over the next 5 days, his symptoms worsened. He became so sick that he was admitted to the hospital. What his initial blood work showed was astounding. The cancer cells were dying, and they were dying so quickly that his body couldn’t clear them fast enough. The toxic substances that are released when cancer cells die began to build up in his system and were making him sick. The doctors recognized this complication immediately, and they gave him intravenous fluids and medicines to treat it. His condition improved and he was discharged home. By one month after the infusion, his enlarged lymph nodes could no longer be felt. A bone marrow biopsy was done and where the leukemia had once been, it was gone. This person who found himself in a dire circumstance, with leukemia that had relapsed on all standard treatments, was now in a complete remission.
I finished the article and remember feeling exhilarated and triumphant, even though I hadn’t done anything but read about what these brilliant researchers had accomplished. Sitting there in the on-call room that day, the goals for my career began to crystallize. I wanted to take care of people with blood cancers. I wanted to do clinical research. I wanted to be involved in bringing CAR T-cells and other forms of immune therapy to those who needed them.
On April 6, 2016 the first patient at Tennessee Oncology’s Sarah Cannon Center for Blood Cancers was treated with CAR T-cells. The patient had relapsed lymphoma, and was in a situation analogous to the patient in the NEJM article. Similarly, he too responded almost immediately and went into remission. Standing at his bedside as the CAR T-cells were being infused, I recall thinking that I had come full circle. Just 5 years earlier I was a new oncology fellow who knew very little about taking care of people with cancer. Now I was an oncologist at a world-class cancer program, taking part in a clinical trial that offered a life-saving treatment to a person in need.
Within a year more than a dozen patients were treated at the Center for Blood Cancers with CAR T-cells. The vast majority went into remission immediately. We now have over ten clinical trials that are evaluating various types of T-cell therapy in cancer, and not just blood cancer. This past month the first patient at Sarah Cannon with metastatic lung cancer was treated with T-cell therapy. The pace at which the field is moving is rapid and it is a testament to the patients participating in the research trials that are propelling these treatments along. In fact, on October 18th the first CAR T-cell for the treatment of adults with relapsed lymphoma was FDA approved. The approval was based on a clinical trial in which Tennessee Oncology and Sarah Cannon participated.
Every provider at Tennessee Oncology can probably tell you a story about the series of events that led them to the field they are in today. This has been mine. While the exact paths that led us here are different, we are all here because we believe that caring for cancer patients is a privilege. It is our obligation to deliver the most advanced cancer care available to those who need it. This is our commitment. This is our calling. This is why oncology is our chosen field.
References: Porter, et al. Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia. NEJM 2011;365:725-33