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The small but mighty cell
A pioneering bone marrow transplant at the U of M 50 years ago has led to thousands of lives saved and launched a new generation of potent cell therapies
By Nicole Endres
David Camp was born with a hereditary disease that would certainly have cut his life short. A severe immune system deficiency prevented his body from forming enough antibodies to fight off the germs of everyday life.
That is, until August 24, 1968, when one of David's four older sisters, 9-year-old Doreen, donated her healthy bone marrow to save her baby brother's life in a first-of-its-kind transplant at University Hospitals.
David Camp became the recipient of the world's first successful bone marrow transplant from a matched, related donor, under the direction of famed University of Minnesota Medical School immunologist Robert A. Good, M.D. It was a monumental feat – and it pioneered an entirely new field of specialty care that would open the door to cures for dozens of other life-threatening diseases.
Since achieving this milestone 50 years ago, the University has continued to lead the field. U teams have performed nearly 8,000 blood and marrow transplants (BMTs), primarily for the treatment of leukemias, lymphomas, myelomas, and other blood-related cancers.
Today, the use of BMT has expanded beyond blood cancers and immune deficiencies to also include solid tumors, Fanconi anemia (FA), bone marrow failure disorders, and inherited metabolic diseases such as adrenoleukodystrophy (ALD) and Hurler and Hunter syndromes.
U experts are also exploring the use of BMT to treat the skin blistering disease epidermolysis bullosa (EB), HIV/AIDS, and autoimmune diseases such as scleroderma, multiple sclerosis, and inflammatory bowel diseases.
"BMT has evolved into the establishment of an entire cell therapeutics domain," says Veronika Bachanova, M.D., Ph.D., an associate professor in the Medical School and member of the Masonic Cancer Center. "It is not stagnant. It brings about so many new sprouts."
BMT, a type of cell therapy, works by replacing diseased or failing bone marrow with healthy stem cells that will eventually settle in the bone marrow and produce new blood cells. Healthy blood cells are critical to the body, as red blood cells carry oxygen to our tissues, platelets form clots after an injury, and white blood cells fight off infection.
Stem cells for a transplant can come from a donor's bone marrow, a donor's blood, donated umbilical cord blood (the blood left in a placenta after a baby is born), or even a patient's own body in some cases.
Before a transplant, a patient receives high doses of chemotherapy and sometimes radiation to both destroy the cancer or other disease-causing cells and prepare the body to receive the healthy cells. Then the healthy cells are infused intravenously, where they home to the bone marrow.
Over the following days, the transplanted stem cells start to grow, making new blood and marrow, as well as a new immune system for life.
Left: Renowned U immunologist Robert A. Good, M.D., led the world's first successful bone marrow transplant from a matched, related donor (Photo: Courtesy of University Archives). Right: (Photo: Scott Streble)
Some aspects of the process are quite similar to what they were 50 years ago, says Medical School professor Daniel Weisdorf, M.D., who served for five years as head of the Division of Hematology, Oncology, and Transplantation and 40 years as head of the University of Minnesota Health Adult Blood and Marrow Transplant Program.
"But many, many things have improved," he says, naming better donor-recipient matching techniques, conditioning processes, transfusion practices, antibiotics and antivirals, drugs to support immune recovery, symptom control, and long-term follow-up.
These improvements make BMT available to more people than ever before. Older adults were once deemed ineligible for the intense treatment regimen, as were people who were already very sick. Now, the process is much safer. Whereas many of his patients 25 years ago were in their 30s and 40s, Weisdorf says that now most of his patients are in their late 50s or early 60s.
"There's been improvement in everything," says his colleague Claudio Brunstein, M.D., Ph.D., an associate professor in the Medical School and current director of the M Health Adult Blood and Marrow Transplant Program. "More people survive transplant, and survive it longer."
Making the match
John Kersey, M.D., performed the first successful bone marrow transplant for treating lymphoma (Photo: Courtesy of University Archives).
David Camp's bone marrow transplant in 1968 worked because his U of M doctors made a careful donor selection based on human leukocyte antigen (HLA) tissue typing. The body uses HLA markers to recognize which cells are one's own and which are invaders, so a close match between the patient's and donor's HLA markers is critical to a successful transplant.
Following that success, the Medical School team continued to pioneer new frontiers in donor selection over the next several decades. They developed autologous marrow transplantation for chronic myelogenous leukemia in the 1980s and — for the approximately two-thirds of patients without an HLA-matched sibling donor — started a volunteer unrelated donor transplant program in 1985.
The year after that, the National Marrow Donor Program, which operates the now well-known Be The Match Registry, was created in Minneapolis.
In the 1990s, umbilical cord blood — saved after birth — came onto the transplant scene and changed the BMT landscape.
"It made stem cell transplants available to nearly everyone. That was the big breakthrough," says pediatrics professor John E. Wagner Jr., M.D., who holds the Children's Cancer Research Fund/Hageboeck Family Endowed Chair in Pediatric Oncology and McKnight Presidential Chair in Childhood Cancer Research. "No longer were we limited by matching. We could do mismatched transplants successfully with cord blood."
In the last 10 years, therapeutic advances have made stem cell donations from a half-matched donor such as a parent or child a viable option, too.
"So we've gone from having donors for about half of our patients who needed transplant to having donors for almost everyone who comes through the door," Brunstein says. "Finding a donor is no longer a problem, despite the fact that donor selection became more strict because of our better understanding of the HLA system."
While most BMTs across the country are performed to treat people who have cancer, U of M physician-scientists have been leaders in developing BMT to treat other diseases as well.
"Here at Minnesota, we do a lot of things for these very niche diseases," says Paul Orchard, M.D., a professor of pediatrics and medical director of the U's inherited metabolic and storage disease BMT program. "And people come to us from all over."
In 1978, a Medical School team was the first in the United States to perform a BMT to treat the genetic bone disorder osteopetrosis.
Based on early success with an inherited enzyme deficiency condition called Hurler syndrome, researchers in the early 1980s then pioneered the use of BMT for other inherited metabolic diseases, including leukodystrophies such as ALD. "Now we transplant more patients with ALD than anywhere else in the world," Orchard says.
The U's expertise in Fanconi anemia (FA), a rare, inherited disease that leads to bone marrow failure, also has made it a sought-out treatment center. Today this program, under the direction of Margaret MacMillan, M.D., treats more FA patients than any other center in the nation.
More recent research has led to an experimental treatment for epidermolysis bullosa (EB), a devastating skin blistering disorder. U of M physician-scientists were the first to use cells from one organ, the bone marrow, to heal a totally different organ, the skin.
"It's important to see this new application as a continuation of what this place is about," says Medical School Dean Jakub Tolar, M.D., Ph.D., who leads the EB research program and holds the Edmund Wallace Tulloch and Anna Marie Tulloch Chair in Stem Cell Biology, Genetics, and Genomics, "and how deep our tradition
is in BMT."
Left: Molly and Adam Nash (Photo: Courtesy of Lisa Nash). Right: (Photo: Scott Streble)
Despite the improvements in BMT, there's still work to do.
Key to a better BMT process today is keeping both relapse rates and graft-versus-host disease (GVHD) in check. And that requires striking a delicate balance.
A patient needs enough immune suppression to ward off GVHD, a complication affecting some 50 percent of transplant patients receiving donor-derived cells, in which the donor cells see the recipient's organs as invaders and attack them. There can't be too much immune suppression, though, because the recovering immune system is what keeps the cancer away. And although BMT is curative for many, 20 to 30 percent of patients still relapse.
"BMT preconditioning is still too toxic," Weisdorf says. "I'm so proud of how it works and how many people we can make better. But I'm sure it feels to patients like, 'You step off this bridge, and we promise we'll catch you.' … It's safer than it used to be, and it works better than it used to. But we need a bigger safety net at the bottom."
A half century of BMT expertise at the University has paved the way for precision medicine — using cell-based therapies that target disease and leave normal cells unharmed. Safer and less toxic, these approaches stand to improve long- term outcomes for patients.
One experimental cell therapy being developed at the Medical School employs the power of the immune system's own natural killer (NK) cells, white blood cells that kill viruses and detect and eliminate early signs of cancer. The Masonic Cancer Center's Jeff Miller, M.D., holder of the Roger L. and Lynn C. Headrick Chair in Cancer Therapeutics, has studied and refined the use of these cells over the last 20 years. Clinical trials continue to progress.
"We have shown for the first time that this therapy can bring about remission in a patient with the most refractory [difficult-to-treat] acute myeloid leukemia," Bachanova says. Although this NK cell therapy is not yet considered curative on its own, remission could make a patient eligible for a BMT.
The team is expanding the use of NK cell therapies to treat not only leukemia but also lymphoma and solid tumors such as ovarian and lung cancers.
University of Minnesota Medical Center and Masonic Children's Hospital are among the 30 centers in the nation certified to offer another treatment, CAR T-cell therapy, to children and young adults with treatment-resistant or relapsed acute B-cell lymphoblastic leukemia (ALL). Like the NK approach, CAR T-cell therapy redirects a patient's own immune system to fight cancer.
Because the therapy is so new, doctors don't really know how the modified T cells will function long term — whether they'll know when to back down after the initial cancer threat is resolved or whether they'll keep fighting, potentially attacking healthy cells in the body when the cancer is gone.
That's why Masonic Cancer Center scientists Bruce Blazar, M.D., and Chris Pennell, Ph.D., are exploring ways to "turn off" the superpowered T cells when they're not needed anymore and turn them on again if needed.
Blazar's lab is also investigating the use of regulatory T cells to reboot the immune system after a BMT — with very promising results.
"Through a series of studies, we have been able to show that these cells are very potent suppressors of the graft-versus-host disease response," says Blazar, a Regents Professor and holder of the Andersen Chair in Transplantation Immunology.
Mark Osborn, Ph.D., an assistant professor of pediatrics in the Medical School, is taking a related research tack. He and his collaborators are using state-of-the-art gene-editing technologies to engineer T cells that are better able to direct their potent effects toward tumor cells while leaving normal tissue unharmed.
"These are next-generation therapies that are progressing at a pace that we hope will be applicable to the current generation of patients," Osborn says.
Left: (Photo: Jim Bovin). Right: Four-year-old Taytem White is one of the many patients who has gone through a bone marrow transplant for a disease other than cancer. Taytem had a BMT for Hurler syndrome, a rare genetic disease, in 2014. Read more of Taytem's story. (Photo: Courtesy of Chamonix White)
Survivors, no longer patients
One of the best parts of Weisdorf's job, he says, is when BMT survivors come back to the clinics for very long-term follow-up visits. This is one of the perks of working at an institution that has offered BMTs for 50 years.
"I always make a lot of noise in the waiting room," Weisdorf says. "Somebody transplanted in 1981 showed up, so I brought him out and introduced him to a lot of people and said, 'Here's 30-plus years later, and look at how healthy he's been.' It is obviously motivating for people going through the scary early parts of the transplantation process to see someone well many decades later.
"Then they're no longer patients, actually. That's the important part."
Philanthropy—from Children's Cancer Research Fund, Minnesota Masonic Charities, and many other benefactors—has been critical to the successes of the U's BMT program. Make a gift today to support BMT research and patient care, or learn more about how your gift can make a difference by contacting Bridgette Haley of the University of Minnesota Foundation at 612-625-6922 or bhaley@umn.edu.
Web extra
Learn about the child who received the world's first successful bone marrow transplant at the U and learn how BMT works.
(Photo: Scott Streble)
First successful BMT for lymphoma
David Stahl's future looked grim. It was 1975, and the 16-year-old had just been diagnosed with Burkitt's lymphoma.
"Back then, with the word 'cancer,' you thought 'death,'" he recalls.
Stahl was given a 5 percent chance of survival. But there was one last hope — to try an experimental bone marrow transplant. "The doctors said, 'If you don't, you're not going to make it,'" Stahl recalls. "So we said OK."
Under the direction of the University of Minnesota's John Kersey, M.D., a pioneer in his field and founding director of the Masonic Cancer Center, Stahl received the first-ever bone marrow transplant for treating lymphoma. The marrow came from his younger brother Kim. David Stahl still remembers seeing his brother wheeled by on a stretcher after the donation and giving him a thumbs-up.
The family remained optimistic.
"Dr. Kersey was very positive about it," Stahl says. "Maybe he had to be."
Or maybe it was because he was confident. Today Stahl is a technical illustrator, a husband, and a father to a college student — who attends the U, of course. He enjoys bowling, fishing, and spending time by the lake.
"It's nice to know that, because of the University, kids who had cancer like I did are living [long lives] now," he says. "I think about how lucky I am every day."
(Photo: Courtesy of University Archives)
First 'savior sibling'
Molly Nash was born in 1994 with Fanconi anemia (FA), a severe, inherited blood disorder that would likely cause bone marrow failure by age 6 and myelodysplastic syndrome or leukemia by age 8.
The only proven treatment was a blood or marrow transplant. Molly's parents, Lisa and Jack Nash, desperately searched for help in the 1990s, when very few children with FA survived without a matched brother or sister marrow donor. Unfortunately, Molly had no siblings.
After much ethical debate, the University of Minnesota's John Wagner Jr., M.D., offered a new option to the Nashes called embryo selection. Newly available technologies allowed for rapid genetic testing on a single cell after in vitro fertilization, letting couples select embryos that were unaffected by FA. After birth, these children can serve as HLA-matched donors for their ailing siblings.
The Nash family jumped at the idea, knowing their choice would be highly controversial — and that it was ultimately Molly's best chance to live.
On August 29, 2000, Adam Nash was born, and his umbilical cord blood was saved. Several weeks later, Molly received the stem cells from that cord blood via transplant.
Nearly 18 years later, both Molly and Adam are happy young adults who with their parents and sister, Delaney, are helping to raise money for FA research and care.
– Krystle Barbour
A patient-turned-researcher has teamed up with her doctor to advance the U of M's pioneering microbiota transplant program.
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