In many ways, defeating cancer is like assembling an exceedingly tricky jigsaw puzzle. We may have some ideas about the big picture, the contours, but we're left with a jumble of interior pieces to match up, little by little. Fortunately, Dr. Phil Greenberg likes puzzles.
"I like the idea of asking a question and finding an answer," he said, his trace Brooklyn accent exuding enthusiasm.
Greenberg and his colleagues focus on one major portion of this puzzle: the function of rare disease-fighting immune cells called T cells. During his more than three decades of research at the Fred Hutch, he has become a world expert in discovering how T cells can be manipulated to treat a range of cancers — and with milder side effects than traditional therapies.
Greenberg was part of a team in the early 1990s that first showed it's possible to extract T cells from the body, multiply them to the billions in the lab, and infuse them into a sick patient to seek and destroy particular diseased cells. This initial success, backed by many years of testing in model organisms, involved protecting immune-compromised patients from cytomegalovirus infection, an often-deadly complication common to people who have received bone marrow transplants.
Since then, Greenberg and his colleagues have found that the same approach can cure late-stage melanoma, a deadly form of skin cancer. It has also shown potential to treat other cancers, including prostate and pancreatic cancers, and aggressive leukemias, Greenberg’s primary concentration.
Despite this promise, T-cell therapy is still in its infancy, with many difficult questions unanswered. It remains a challenge, for instance, to identify precisely which of the thousands of components of a cancer cell both make it malignant and could actually be exploited — the Achilles' heel, if you will — by deploying an army of T cells appropriately matched for the task.
To that end, Greenberg and his lab have discovered a protein that appears to be a hallmark of leukemia cells. With that knowledge, they have developed a way to engineer supercharged T cells that are not only more adept at seeking out and destroying these cancer cells but also can be multiplied — and thus delivered to a patient — much more rapidly than current approaches allow.
"Within two weeks we can create billions of T cells that are better than the original ones," Greenberg said, whereas current T cells take months to clone and cannot be effectively generated for all patients. The promising new technique will soon be tested in acute leukemia patients whose cancer has relapsed.
Greenberg first began pondering how the immune system could be used to fight cancer after medical school, when he conducted postdoctoral research with a dynamic group of University of California scientists focused on immunology.
In 1976, Greenberg joined the faculty of the then-young Fred Hutch, which attracted him because of its rare combination of expertise in both cancers and the immune system. Back then, medical luminaries like Dr. E. Donnall Thomas were in the early days of developing bone marrow transplantation, which has now provided critical clues about the immune system's potential to fend off cancer.
Although the idea of patient interaction attracted the self-described "people person" to a medical career, Greenberg made the difficult decision in the mid-1990s to devote his attention to his ever-expanding laboratory research.
"Being a physician and taking care of patients is a very special opportunity," he said. "You get a gratification that you can get from nothing else in your life. When I gave that up, I felt a substantive loss."
Still, Greenberg finds peace in knowing that he is working "to develop something that will ultimately help patients and be a unique contribution."
And he's truly committed to the effort, right down to the car he drives: His license plate reads, "DRTCELL."