Thomas A. Waldmann, M.D.

Making Discoveries in Immunology

BY CLAIRE MCCARTHY, NCI

Who would have thought that a mere $50 grant could launch a career in medical research? But that’s exactly what happened in 1954 when Harvard Medical School (Boston) gave a $50 grant to two medical students—Thomas Waldmann and Sherman Weissman—to study erythropoietin (a hormone that stimulates the production of red blood cells) in rabbits. After their medical residencies—Waldmann at Massachusetts General Hospital (Boston) and Weissman at Boston City Hospital (Boston)—both went on to be research fellows and clinical associates at the National Cancer Institute (NCI). And both have gone on to have distinguished research careers—Waldmann at NCI and Weismann at Yale (New Haven, Connecticut).

Waldmann’s fascination with immunology emerged during his internal medicine residency when he did a rotation in Mass General’s polio ward, which had 300 patients, 70 of whom could only breathe while encased in giant mechanical respirators called iron lungs. “That was the last polio epidemic in our country,” he said. Jonas Salk had developed the polio vaccine and by 1956 it had become widely available. “I was truly impressed with how effective a vaccine could be for preventing a very serious, acute, infectious disease.”

Coming to NIH. Waldmann applied to NIH for a research position in lieu of serving two years in the military. In the 1950s, between the Korean and Vietnam wars, the general military draft and the doctor draft were in effect. The doctor draft channeled physicians into two-year obligatory service in the Army, Navy, Air Force, or U.S. Public Health Service (which included NIH clinical associate positions). In 1956, Waldmann came to NIH as one of the “Yellow Berets” to learn science as a clinical associate in the NCI’s Metabolism Branch. (The term “Yellow Beret” came about because those who came to NIH to avoid the draft were initially perceived as cowards—the opposite of the brave U.S. Army Special Forces called the Green Berets. Later, however, most considered “Yellow Beret” to be a badge of pride.)

“I intended to be here for two years—that was 62 years ago,” said Waldmann. “My education has been in the corridors of the NIH [because] of the proximity of the Clinical Center to research labs and the ability to have patient-oriented clinical research.” The NIH Clinical Center was relatively new at the time, having opened in 1953.

As a trainee in NCI, Waldman began studying how the body metabolizes proteins, including immunoglobulins, in the blood. By 1959, he had become a senior investigator, and his research had expanded to include work with patients with primary immunodeficiency diseases and disorders of lymphatic channels. In the 1950s and 1960s, scientists had only a primitive understanding of the immune system. “There was no knowledge of B and T cells, retroviruses were not defined, receptors were unknown, etc.,” he recalled. There was “nothing approaching our understanding of HIV or retroviruses.”

At that time, scientists didn’t yet have the ability to use knockout or transgenic animals, so Waldmann and his colleagues studied patients with genetic immunodeficiency diseases to understand the immune system.

Discovery. In one project, Waldmann and his colleagues discovered that some patients who had unusually low concentrations of immunoglobulin in their blood were losing the protein through enlarged lymph vessels that supplied the lining of the small intestine. In 1961, he published a paper in Gastroenterology describing the discovery of this disease, which he called primary intestinal lymphangiectasia (Gastroenterology 41:197–207, 1961).

People with the disease were prone to infections, had severe abdominal discomfort, and were not likely to live to adulthood. In 1967, Waldmann and his colleagues published a comprehensive report about the disease in the Journal of Clinical Investigation (J Clin Invest 46:1643–1656, 1967). Later, the National Organization of Rare Diseases named the disease “Waldmann Disease.”

The genetic cause for this gastrointestinal disease was discovered in 2017 by someone Waldmann had recruited to NIH in 1989: Michael Lenardo, who’s now chief of the Molecular Development of the Immune System Section at the National Institute of Allergy and Infectious Diseases. Lenardo and his colleagues had encountered children in Turkey who had a similar disease and determined that it could be attributed to defects in the CD55 gene. The defect prevented the production of the cell-surface protein complement decay–accelerating factor (which is produced by CD55), which regulates proteins that help immune mediators clear pathogens from the body.

Serendipitous finding. In 1981, there was a serendipitous finding in Waldmann’s laboratory by the late Takashi Uchiyama. Uchiyama was trying to make antibodies that would bind to the marker CD4 (extracellular cluster of differentiation–4), which is expressed by a specific helper T cell. However, the antibody he made targeted what turned out to be the receptor for interleukin-2 (IL-2), a cytokine involved in the activation of T cells.

This discovery was important because it showed that the IL-2 receptor was expressed on abnormal T cells—in patients with leukemia, graft-versus-host disease (when transplanted tissue is rejected by the immune system), and autoimmune conditions—but not on most T cells of healthy individuals. In 1997, after years of research and clinical trials, the FDA approved the IL-2 receptor as a treatment to prevent transplant rejection. Later IL-2 and similar IL-2 receptor antibodies were approved as therapies for immune-related disorders, cancer, and multiple sclerosis.

IL-15 plays a role. While Waldmann was studying IL-2 and its receptor, he co-discovered a new cytokine, IL-15, which is key to the maintenance and development of two types of immune cells that attack and kill tumors.

“We showed that IL-15 played an enormous role in the maintenance and development of natural killer [NK] cells and memory CD8 T cells,” he said. Intravenous infusions of IL-15 in cancer patients, “showed a 30-fold increase in the number of NK cells and a 350-fold increase an NK-cell subset.”

Further, Waldmann showed that using a combination therapy of IL-15 and tumor-specific antibodies was an effective cancer treatment in mouse models. Similarly, in ongoing clinical trials, this combination treatment has shown encouraging results in cancer patients.

Waldmann hypothesized that IL-15 could also improve the effectiveness of an immunotherapy called checkpoint blockade. The immune system produces molecules that keep immune responses in “check” to prevent uncontrolled inflammation and damage. Some cancer cells have figured out a way to exploit these checkpoints to avoid being attacked by the immune system.

Treating a patient with checkpoint-blockade therapy is like “removing the brakes of the immune system that were preventing immune cells from responding to a cancer,” Waldmann said. “IL-15 treatment would be an accelerator to enhance the CD8 T-cell response to cancer cells. So, combining these treatments would significantly enhance tumor immunity.” His hypothesis was proven correct and was supported in experimental studies. Now this combination therapy is being investigated in clinical trials.

Throughout his career, Waldmann has noted a pattern. “We would make a discovery, see a disorder in a human disease, make a new agent [such as a new antibody or cytokine], test that in [animal models], and finally test it in patients with leukemia, immunodeficiency diseases, or autoimmunity.”

New investigations. This cycle continues with Waldmann’s ongoing translational research, which builds on his previous studies of IL-2 and IL-15 receptor signaling. Now, he is investigating downstream mediators of the IL-2 and lL-15 pathways. He is studying the role of the JAK-STAT (Janus kinase–signal transducer and activation of transcription protein) signaling pathway in cancers and immune disorders. Disruptions in JAK-STAT interactions contribute to increased cell division, cell survival, and tumor formation.

Waldmann is testing the effectiveness of JAK-STAT inhibitors as cancer treatments in experimental models. He wants to watch as this research at the NIH grows, matures, and eventually produces clinical therapies.

Yet, along with looking forward, Waldmann reflected back on studies that helped immunology advance. “Science builds on what goes on in the past,” he said. “Certainly, the field of immunology has changed [thanks to the] science of the past and the huge number of people that contributed to the field.”

MORE ABOUT THOMAS A. WALDMANN, M.D.

Co-Chief of the Lymphoid Malignancies Branch, NIH Distinguished Investigator, Head of the Cytokine Immunology and Immunotherapy Section, National Cancer Institute (NCI)

Website: https://irp.nih.gov/pi/thomas-waldmann

Born: New York City

Grew up: In New York and Washington, D.C.

Research interests: Understanding how the dysregulation of the human immune response leads to autoimmune disorders, immunodeficiency, and malignant diseases. A major area of my work focuses on the role of interleukin (IL)-2 and IL-15 on the development and function of immune cells, as well as on how their pathways can be therapeutically targeted to treat cancer.

Education: University of Chicago, Chicago (A.B. in philosophy) and Harvard Medical School, Boston (M.D.)

Training: Residency in internal medicine at Massachusetts General Hospital (Boston)

Came to NIH: In 1956, as a clinical associate; in 1958 became a fellow; appointed senior investigator in 1959; head of NCI’s Immunophysiology Section 1968–1973; in 1971, became chief of the Metabolism Branch (renamed the Lymphoid Malignancies Branch in 2014); became an NIH Distinguished Investigator in 2007

Honors: National Academy of Sciences, American Academy of Arts and Sciences, National Academy of Medicine, and the recipient of many awards

What excites him about research: Developing new approaches to treat leukemias, lymphomas, and rare diseases

Views on trainees and technicians in his lab: I cannot emphasize too strongly how important the people in the lab are. It is through their hands that the research gets done. They also bring new interpretations, ideas, and insights to studies.

Outside interests: My hobby is photography. When I was very young, my father bought me a $15 camera, and I took pictures at an apple blossom festival in Virginia. My local camera dealer was so impressed that he gave me $1.15 in exchange for a picture. When I came to NIH, I joined the camera club. I was interested in nature photography as well as experimental photography, in which I used special effects to make posters. I was the color-slide photographer of the year in 19 or 20 camera club competitions. I still do photography now, but it’s focused on close-up portraits of my grandchildren.

Little known fact: When I was in medical school in the 1950s, it was the era of investigations by Senator Joseph McCarthy and the House Un-American Activities Committee (HUAC). The HUAC came to Harvard to search for communists in academia. In rebellion, someone at Vanderbilt Hall (the dormitory for medical students) painted all the toilet seats red. I woke in the night and went to the bathroom and ticked my tennis shoe in the red paint. The next thing I knew, I was in the dean’s office and the people were saying, “Thomas Waldmann, we hold you morally and financially responsible for this reprehensible act.” However, I was too much of a [nose-to-the grindstone sort of person] to be punished, and so I was exonerated. Although I didn’t get in trouble, my friend Sherman Weissman [who later came to NIH as a clinical associate with Waldmann] put a red jelly bean in my mailbox every day during that period.

What about you would surprise most people: I have become a cook. Until a few months ago, I had not cooked. No one, not even my kids, would know me as a cook.

Interesting fact about his family: The demographics during my residency at Harvard’s Mass General were different in 1956. The one woman on the housestaff was Kathy Spreng. She was my boss when I was an intern. Now, she is my wife, Kathy Waldmann.