The finding — and following — of a killer (T-cell)
To really appreciate this story, we have to start at the end—simply put, there are people alive today because of a discovery made by an oncology fellow in the mid 1980s. And not just alive-these people are doing well, living healthy and full lives, sometimes symptom-free, because one doctor, Thomas P. Loughran Jr., M.D., professor of medicine and director, Penn State Hershey Cancer Institute, noticed something that no one else did.
“He’s a super doctor,” says George Graham of Bryn Athyn, Pennsylvania, one of Loughran’s patients who was unable to find appropriate treatment for large granular lymphocyte (LGL) leukemia at other facilities.
Loughran came to discovering LGL through what might be considered standard detective work—he reviewed patient labs and blood smears and kept looking. During a rotation at the University of Washington, Loughran saw a patient who was referred to the chief resident with an unknown illness and a history of recurrent fevers and infections. Upon reviewing the patient’s blood smear, Loughran was the first to notice that the patient’s white cells were granular lymphocytes that were larger than they should be. After reviewing the previous five years of records of the hematopathology laboratory directed by Marshall Kadin, M.D., he realized that other patients with similar histories also had the unusual white cell appearance. Loughran and Kadin went on to publish their discovery and subsequent research in the Annals of Internal Medicine.
“I was doing what you are supposed to do as a good doctor,” Loughran recalls of his time as a fellow at the Fred Hutchinson Cancer Research Center in Washington. “At that point, I didn’t have any real research background, but I was interested in it.” Loughran and his team next discovered that the LGL cells were clonal, copying themselves as they proliferated throughout the blood. “We were lucky because the next twenty patients actually didn’t have the clonal chromosomal abnormality.”
Hide and Seek with LGL
Patients with LGL leukemia are difficult to treat because the disease is difficult to diagnose. Unlike typical cancers that present with a large tumor or a decrease in organ function, LGL leukemia masks itself like several other illnesses. Because doctors don’t usually find it unless they are specifically looking for it, patients are often treated for something else, like rheumatoid arthritis (RA), anemia, and Felty’s syndrome.
“Before it was found, a lot of patients were diagnosed with chronic neutropenia, maybe anemia with unknown etiology, or unspecified leukemia. Others were simply undiagnosed with anything,” Loughran says. “Of the first twenty patients I found, none of them had an actual diagnosis or they were diagnosed with something like red cell aplasia.”
The basic hypothesis is that these cells are antigen-driven killer T cells. They are part of the immune system and are normally resting. When a virus is detected, the cells become activated and kill off the virus, and then they go back to resting. But in some cases, the cells remain active and clone, eventually developing into LGL leukemia. The exact cause for this remains unclear, but Loughran suggests that it may be triggered by a specific virus or a chronic infection.
“LGL leukemia causes inflammation that is very similar to rheumatoid arthritis,” Loughran says. “About a third of patients with LGL leukemia also have RA and another subset of patients has Felty’s. One study in England found that one-third of patients with Felty’s also has LGL leukemia. RA, Felty’s, and LGL are probably a continuation of the same cell process.” The tendency for patients with LGL to be misdiagnosed and mistreated allows the disease to progress, sometimes for years. Often, a patient’s symptoms are even vaguer, making them simply sick in general.
Finding the Right Treatment
“I was out of it for about a year,” Graham recalls. “I was just very weak, then spent a week in the hospital after a heart attack, but wasn’t feeling better.”
After seeing his regular doctor and being referred to an oncologist in the Philadelphia-area, Graham was finally diagnosed with leukemia. But the news that followed was even worse than the diagnosis.
“They told me to go home and get your things in order because you have three to four weeks to live,” Graham says. Unwilling to accept the scenario, Graham sought out second opinions and searched for treatment options at NIH and Penn, but came up empty. One of his physicians, however, was familiar with Loughran’s work and encouraged Graham to get in touch with him.
“He did the blood tests and said ‘you’re not going to die, we’re going to make a formula and you will start it next week,’” Graham remembers. “I started to feel better almost immediately, finding out that I’m not going to die. But then taking the medicine did wonders. Dr. Loughran told me ‘we can control this,’ and he did.”
Loughran says the treatment for LGL leukemia is primarily immunosuppressive. Since the cells are always active, medications are needed that will turn off or kill the LGL cells. Loughran generally treats patients with either low doses of methotrexate or cyclophospharmide, sometimes in combination with prednisone. “Chemotherapy doesn’t work in this disease as the cells are resistant to it,” Loughran says. After treatment, Graham went into complete remission and has been doing well for two years.
Tracking the Disease
The team at the Cancer Institute, including colleagues at University Park, is determined to find new ways to treat LGL leukemia. One recent project partnered Loughran with Réka Albert, professor of physics and biology at Penn State, and Ph.D. candidate Ranran Zhang as they developed a computer model to demonstrate the signaling of proteins and molecules in T-cells that develop into LGL leukemia. By identifying the structures behind the ongoing life of a T-cell, researchers hope to target that cause with medications and treatments that will eradicate them. Results of the study, which were published in Proceedings of the National Academy of Sciences, may have uncovered the two proteins that keep these cells alive. “Now, instead of testing all 500 proteins, we can test these two to give us an individualized approach to treatment,” Loughran says.
At the same time, Loughran has also established a registry for patients with LGL leukemia. The goals of the registry are to capture clinical information about patients, offer clinical studies, and provide treatment advice. The registry includes history from close to 500 patients throughout the world and tracks their treatment and prognosis.
As Loughran and his team continue to look for a cure by studying LGL leukemia’s infancy, some patients have been able to move past their treatments altogether. A case study in successful treatment, Graham now has six month follow-ups but no symptoms. He splits his time between Pennsylvania and Florida with occasional side trips to Italy to teach photography.
“I am well and feeling great,” he says.
by Holly Swanson