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Hootie Warren, immunotherapy researcher and oncologist

Leveraging the mechanisms of successful treatments

The day that Dr. Hootie Warren's future fell into place is etched in his mind. A Harvard Medical School student at the time, he was perusing the Boston Globe on October 8, 1990, when he came upon an article about Dr. E. Donnall Thomas' Nobel Prize win that day for pioneering bone marrow transplantation — and suddenly, Warren felt his siren call.

"I read about the development of bone marrow transplantation and decided that day I wanted to come to Seattle," Warren said. "Putting someone's immune system inside someone else's body is an incredibly profound thing. It's mind-boggling. And it's the clearest example of successful immunotherapy we have in medicine."

Since he came to Fred Hutch, Warren has aimed to understand how and why complex immunotherapies like transplantation work — and how they can fail. His research encompasses the broad landscape of treatments that harness the immune system’s power to fight cancer, from blood stem cell transplantation to immune-boosting drugs.

"If we could only understand what's happening in those individuals [for whom an immunotherapy is successful] and extract the principles, then perhaps we could understand why it's not working in the majority of people,” Warren said. “We could either tailor the therapy or perhaps combine it with other approaches so more people benefit."

One of Warren’s first areas of research at the Hutch was to study the way some of the newly transplanted cells — immune cells called T cells — attack leukemia cells. This phenomenon, called the graft-vs.-leukemia effect, is what makes transplantation a potentially cancer-curing immunotherapy, but it doesn't happen for all patients. He discovered a way to isolate just the T cells that zero in on leukemia cells, multiply them in the lab and give them back to the patient — taking advantage of the tremendous specificity of the immune system to target the patient's leukemia without harming normal tissue.

This technique is known as adoptive T-cell therapy. When done as part of a transplant, it can lessen a sometime serious side effect of transplantation called graft-vs.-host disease in which the transplanted immune-system cells see the patient's cells as foreign. In the years since, Warren has built on this success to work toward novel adoptive T-cell therapies to treat cancers outside of the transplant arena, such as kidney cancer.

Aiding him in his quest to understand and improve immunotherapy is a powerful, high throughput technology he co-invented with Fred Hutch colleagues Drs. Harlan Robins and Chris Carlson. Sparked by a conversation the three had one day in the Hutch’s cafeteria, the next-generation sequencing technology allows researchers to see how the millions of different T cells in each individual are programmed to target diseases, providing an unprecedented, deep look into what was until recently mostly a black box.

With this high-tech resource at his fingertips, Warren has turned his attention to helping people in a distinctly low-tech setting: sub-Saharan Africa. Children in this region have a remarkably high rate of a cancer called Burkitt lymphoma that is rare in North America and Europe. Treatment for this disease hasn’t changed in half a century, and African children diagnosed with Burkitt’s survive, on average, for less than a year ― an “unacceptable” outcome, Warren said.

Evidence suggests that an immune response to a pathogen ― the disease is linked to both malaria and Epstein-Barr virus ― somehow plays a role in the development of this immune-cell cancer. And Warren is working to find out how, by using the technology he co-invented to tease apart the cancer cells’ biology.

Understanding the root of sub-Saharan Africa’s Burkitt lymphoma scourge will have global repercussions. Cancers linked to infections, such as HPV, are a huge threat worldwide.

This “will have profoundly important implications for all of cancer biology and will provide us with enormously valuable insights into why cells become cancerous,” Warren said.

In this, as in all his research, Warren is motivated to help patients. As an oncologist, he spends a quarter of his time each year caring for people with cancer.

"I'm very lucky. I have not just one, but two great jobs," he said. "I really love doing science and I love taking care of patients.

"There are a lot of scientists who work hard just because they love science, but I think the ability to understand the human dimension of cancer very much gives meaning to what I'm doing in the lab,” he said.

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