Rewriting Immunity's Rules: New Strategies Against Cancer
Watch 68-year-old Albert Yu's vigorous swing of a tennis racket and it's hard to imagine that he is the veteran of some tough years of chemotherapy and radiation, the kind often prescribed to beat back cancer. He plays with determined control and balance, keeping up even when he's challenged by a steady stream of machine-fed balls.
Just two years ago, Yu could barely get up out of a chair. He was at the end of an exhausting eight years of battle against lymphoma. That's a cancer that hits white blood cells and distorts their ability to protect the body from bacteria and disease. His physicians at Stanford Hospital had used the most advanced therapies available, even enrolling Yu in clinical trials of experimental treatments. The cancer would go away for a little bit, Yu said, then it would come back. It became more and more obvious, said his wife, Mary Bechmann Yu, "that the remissions were getting shorter and shorter and that we needed to rethink our strategy."
Replacing Yu's exhausted immune system with a transplant was the avenue his Stanford physicians suggested, a version of a whole system do-over first accomplished in 1956 by replacing a patient's diseased bone marrow with healthy marrow from his identical twin. The bone marrow is where the body generates cells for the immune system. Over the decades, the transplant technique has been improved to make transplants possible between unrelated people. But the underlying challenge has remained the same: to provide a new immune system that recognizes the abnormality of cancer cells and destroys them while accepting the cells in its new body, just if they were original equipment.
Tricking immune cells
His Stanford physicians offered Yu a new treatment called, for short, TLI/ATG. The letters represent a two-part approach to manipulating the behavior of the immune system. The regimen is based on a discovery made by Stanford immunologist Samuel Strober, MD.
The TLI/ATG strategy, initially developed through animal studies, relies on the impact of radiation on certain cells in the immune system. Strober observed that those cells could be manipulated with radiation to increase in number and to do a better job of attacking cancer cells. The other trick in the strategy is to reduce the reaction of the transplanted immune cells to their new environment. Typically, they would attack, in a behavior called graft versus host disease, but the TLI/ATG protocol suppresses that response.
"It's a wonderful example of bench to bedside research," said Robert Lowsky, MD, who worked with Strober, Judy Shizuru, MD, PhD, and other Stanford physicians to perfect the treatment they first saw work with mice in 2001. Yu read about the technique in 2005 and was intrigued because it offered someone like him, then beyond the standard age for transplant, a chance for a more sustained remission. "It was a higher risk," he said, "but a higher return."
Cellular transplants began at Stanford in 1986, with a bone marrow transplant for a child with leukemia. Since then, more than 3,800 adults and children have been treated. The program, with a 22-bed adult inpatient unit at the Hospital and 56-bed/chair outpatient infusion area, is recognized by the National Cancer Institute for its excellence in care and research.
Scientific advances pushed a change in the program's name from "Bone Marrow" to "Blood and Marrow." The staff now includes a cadre of more than 50 nurses specially certified in oncology and chemotherapy. Some have been with the program since its inception. The program also includes collaborative care rooms so patients with cardiac issues can receive that extra layer of required attention.
"You get to know everybody there," Yu said, "and after a while, they're like family."
As it does with every patient, the BMT program creates a team of physicians who coordinated Yu's care. His group included his original oncologist, Ron Levy, MD; his chief transplant physician, Wen-Kai Weng, MD; and radiation oncologist Rich Hoppe, MD.
Preparing at home
Yu's treatment protocol allowed him to be physically conditioned and then transplanted almost completely without hospitalization, in comparison to the weeks of isolation behind double doors that some transplant patients must endure. But the treatment still requires juggling a complex set of interconnected events designed to push his immune system down to zero while keeping him from becoming infected. He was vulnerable to even one stray germ, his wife said. "It was a little bit like walking a tightrope and he was so fragile."
Yu said his wife made an extraordinary effort to make their home a totally clean place. They also asked to consult with someone who'd gone through the same procedure. Stanford made that introduction. Hearing about the experience first-hand, said Mary Bechmann Yu, "turned out to be a tremendous resource, medically and emotionally."
When, finally, Yu sat in a reclining chair at Stanford's Cancer Center so the transplant cells could flow through an IV into his arm, it was almost a non-event, Yu said. "They just bring in a bag and injected it into my vein. But it was very emotional for me. I felt somebody gave me life."
The BMT program found Yu a donor who was a perfect match. Future patients will benefit from work that continues to modulate treatment even further so those immune system cells can be even more precisely controlled, said Robert Negrin, MD, Chief of the Division of Blood and Marrow Transplantation. "There's a lot going on now to try to understand and figure out what controls the induction of an immune response—how these cell populations talk to each other." Then comes the issue of how to use that knowledge to predict an individual's unique interaction to chemotherapy, radiation and transplanted donor cells.
The hope, Lowsky said, is to be able to manipulate the immune system to accept any donated cell or tissue, enabling any patient to have a transplant that would not trigger rejection.
Over the next nine months, as his new immune system built its ability to function at full strength, Yu took life slowly. Every day, he went to the Cancer Center where nurses would draw his blood, test it and give him additional treatments. "Then I'd receive whatever was needed that day to try to normalize my blood chemistry," Yu said, "and keep me going while I healed and until I could make immune cells on my own."
The TLI/ATG protocol produces such a long-lasting impact on the immune system that Yu does not need additional daily medication to suppress his immune system. He has also worked to regain his muscle tone and cardiovascular stamina, enrolling in an exercise class and working out with weights. In addition to tennis, he's also swimming and playing golf.
"I feel that once you've had cancer, I don't think you want to say you can be cured for sure. On the other hand, there's no point in thinking about it," Yu said. "We're way more conscious about how we spend our time," said his wife. "We have a very different yardstick to our calendar."
What to know about blood and marrow transplantation
Bone marrow, the liquid center of our bones, produces red blood cells that carry oxygen, platelets that control bleeding and white blood cells, the vital part of our infection-fighting immune system. Inserting donated bone marrow builds a new immune system able to eliminate various kinds of cancers, including leukemia and lymphoma.
Bone marrow can be withdrawn under regional or general anesthesia from the hip bones, but most donations of immune system-generating blood cells can be taken directly from the blood stream.
After donation, a person's marrow is replenished within four to six weeks.
To join the national registry, donors must be between 18 and 60 years old.
The closer the match between donor tissue and patient, the better. Genetics determine tissue type, so the more complex someone's ethnic makeup, the more difficult it is to find a donor.
The non-profit National Marrow Donor Program has been registering and connecting donors with patients since 1987. It now includes 7 million donors and works with a group of almost 500 hospitals, blood centers and laboratories. It is also part of a worldwide network that works cooperatively with service organizations, student groups and corporations to build the registry.
For more information about the registry, visit bethematch.org .