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 disease-fighting immune cells called T cells. During his four decades of immunotherapy research at Fred Hutch, he has become a world expert in discovering how T cells can be manipulated to treat a range of cancers — with milder side effects than traditional therapies.
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, a small but diverse and talented group led by Dr. E. Donnall Thomas was in the early days of developing bone marrow transplantation as a cure for patients with blood cancers. Their work has since provided critical clues about the immune system's potential to eliminate cancer.
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 laboratory testing, involved protecting immune-compromised patients from cytomegalovirus infection, an often-deadly complication common to people who have received bone marrow transplants.
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 aggressive leukemias, Greenberg’s primary concentration.
His group has since learned how to re-engineer T cells’ DNA to transform the cells into better cancer fighters. In an ongoing clinical trial, Dr. Greenberg and Hutch colleague Dr. Aude Chapuis are using this technique to train patients’ T cells to recognize and kill cells bearing a leukemia marker called WT1 by engineering the cells with a WT1-specific receptor. Working with acute myeloid leukemia patients who have relapsed after transplant, or are at high risk of relapse, the team is seeing very encouraging responses.
"I like the idea of asking a question and finding an answer."
“It’s incredibly gratifying to treat a patient and they get better, and when it’s an experimental therapy that you’ve developed ― that’s a pretty wonderful thing,” he said.
Now, Greenberg and his colleagues are extending their successes with this strategy, called T-cell receptor (TCR) therapy, beyond leukemia. TCR therapy is being tested in a trial for patients with certain advanced lung cancers that bear the WT1 marker, and versions targeting other cancer markers are moving toward clinical trials in ovarian cancer and in pancreatic cancer ― the disease that took the life of Greenberg’s father in 2001.
Greenberg remembers when doctors told his father that there was nothing that could be done for his cancer.
“He always had this idea that he could fight and overcome anything … that message was very difficult for him to accept, and yet it was the reality,” the researcher said.
Greenberg is excited by T-cell therapy’s potential for treating this disease that has impacted his family and so many others.
Dr. Phil Greenberg is the Head of Immunology at Fred Hutchinson Cancer Research Center. He says we can make Tcells see tumors better, kill tumors better, and then persist and eradicate tumors better.
“As best we can tell, this would be a better therapy than anything that exists for pancreatic cancer right now,” Greenberg said. “It’s hard to be this optimistic without ever having treated a pancreatic cancer patient with this [experimental therapy], but the biology of what we’re doing looks so good.”
As much as Greenberg’s immunotherapy research has advanced since he joined the Hutch, he sees much more progress coming down the pike.
“This is just the tip of the iceberg,” Greenberg said. “Now we can change T cells to make them function better, make them survive better, make them target the cancer better. The things we’re doing now, we couldn’t even have dreamed about back when I started.”
And he's truly committed to the effort, right down to the car he drives: His license plate reads, "DRTCELL."