Some of the early research at Kimmel Cancer Center was in bone marrow transplants. In fact, the first human bone marrow transplant at Johns Hopkins took place in his 1968, five years before the cancer center was officially approved in 1973.
at that time George Santos Joined the cancer center as the first recruitment of center director, albert owensAs a naval officer, he conducted bone marrow transplant research at the U.S. Naval Radiological Defense Laboratory.
While studying the effects of nuclear explosions in research models, Dr. Santos found that high doses of radiation destroyed the bone marrow of mice, but when they received bone marrow transplants from healthy mice, the donor bone marrow took over and the mice observed that they can survive.
This led to the idea of bone marrow transplants in humans, which kills the cancer-filled bone marrow and replaces it with donor bone marrow.
Conventional wisdom said it wouldn’t work, but as it turned out, researchers at Santos’ cancer center weren’t daunted.
“I remember his tenacity. He was able to inspire people, both staff and patients, to have faith and belief that little by little we could make progress.” georgia vogelsangprofessor emeritus of oncology and former trainee of Santos.
Santos, director of the cancer center’s bone marrow transplant program from 1968 to 1994, was a true pioneer. His early animal research became the blueprint for advances in bone marrow transplantation and other cancer treatments.
bone marrow
Bone marrow (the spongy material deep within bones) is the factory for all blood and immune cells. Without it, we cannot live. Diseases such as leukemia and lymphoma represent production failures in the bone marrow factory, where an excess of abnormal cells overwhelms and crowds out healthy blood and immune cells.
“The only way to kill a patient’s cancer is to kill the patient’s own bone marrow,” Dr. Santos explained.
The first person to receive a bone marrow transplant at Johns Hopkins University was a leukemia patient. For Santos, it was personal. The walls of his office were decorated with photos of the many patients he treated throughout his career. These photos tell the story of a translational researcher whose pioneering research was driven by a desire to help patients desperately trying to survive.
GVHD attack
In the early days, it was commonly said that bone marrow transplants were just as bad, if not worse, than the disease. The reason for this characterization was Santos’ biggest enemy: a complication known as graft-versus-host disease (GVHD).
In GVHD, immune cells in a donor’s bone marrow do not recognize their new host and launch a vicious attack on vital tissues and organs that can be as deadly as cancer.
In fact, it was a rotation in the bone marrow transplant unit where he witnessed firsthand the power of the immune response and Drew Pardollwill focus on cancer immunology research as director of the Kimmel Cancer Center’s Bloomberg-Kimmel Cancer Immunotherapy Institute.
GVHD often had devastating consequences. Patients were hospitalized for several months and many died. The risk of graft rejection, in which bone marrow no longer regenerates within the patient’s body, and her GVHD made bone marrow transplantation one of the most intensive and riskiest medical treatments at the time. Still, the patient who was a candidate for a bone marrow transplant had a blood cancer that was certain to kill him. The bone marrow transplant may not be successful, but it at least gives her some chance of survival.
Overcoming GVHD
Some of the first major advances by cancer center bone marrow transplant researchers were learning how to manage and even manipulate GVHD to fight cancer. Also, a type of drug therapy has emerged that can reset the bone marrow factory and take the teeth out of GVHD.
jonesThis important advance uses high doses of the drugs busulfan and cyclophosphamide to replace whole body radiation and its dangerous toxicity as a way to kill a patient’s diseased bone marrow before transplanting healthy donor bone marrow. Born from pioneering advances by Santos in combination.
Related research by cancer center researchers john hilton and michael colvin He deciphered how cyclophosphamide acts against cancer, paving the way for its drug therapy to become the global standard.
As is common with cancer center researchers, they took a gamble in pursuit of better outcomes for patients. Researchers at other cancer centers were following similar paths of discovery, but Johns Hopkins experts were inspired by Santos to explore unconventional approaches to advance treatments. There were a lot.
“An entire generation of translational researchers trained at Hopkins looked to George as an intellectual and spiritual leader,” says Santos, who pioneered translational research ahead of other scientists. Rick Jones, current bone marrow transplant director, said he accepted the concept. “George was teaching the Hopkins community how to do this long before it was fashionable,” he says.
This important study also suggested the utility of using cyclophosphamide after bone marrow transplantation to control the severity of GVHD.
Until the early 2000s, researchers believed that donor bone marrow had to be an “exact match,” meaning it had to come from a family member with identical immune system components. At the time, this appeared to be the only way to force the immune cells in the donated bone marrow to recognize the new patient host as themselves and prevent severe cases of GVHD. However, such compatibility is found in only about half of patients, a limiting factor that limits bone marrow transplantation from becoming a treatment option for many patients who could benefit, especially the small number of underserved patients. It had become. The National Bone Marrow Donor Program was established in 1986 to match unrelated donors to patients who could not find a donor in their families, but many patients were left without a donor.
half match
FuchsThe expansion and combination of research portfolios has led to a paradigm shift. This overcomes the need for perfectly matched donors and makes bone marrow transplantation possible for all patients in need of treatment.
For decades, GVHD precluded bone marrow transplants for patients without a perfectly matched donor.
Pioneering discovery led by Jones and colleagues at Kimmel Cancer Center Ephraim Fuchs and Leo Ruznik It changed everything and, contrary to prevailing belief in the field, made it possible for almost all patients to undergo transplantation.
RuznikClinical studies have shown that when immune cells called T cells are removed from a transplant, the cancer may return, although the patient did not develop GVHD. This was one of his first observations of the immune system’s ability to kill cancer cells. The challenge was to remove the exact amount of her T cells. T cells are small enough to avoid the most severe cases of GVHD and needed in sufficient numbers for the immune system to prevent the cancer from coming back.
It turns out that cyclophosphamide, the same drug used to treat patients before bone marrow transplants, can limit GVHD when given after transplantation without interfering with the ability of T cells to eliminate surviving cancer cells. did. This discovery led Kimmel Cancer Center experts to develop a new type of bone marrow transplant known as a haploidentical or semi-identical transplant.
brodskySome of the first clues about how cyclophosphamide works were obtained in the 1980s by Michael Colvin and alan hesslater extended by Fuchs, Rzunik, and Jones. robert brodsky and Javier Bolaños Mead. They found that cyclophosphamide killed all transplanted donor bone marrow cells except stem cells, which contain high levels of an enzyme called aldehyde dehydrogenase (ALDH). Stem cells containing ALDH circumvent the toxic effects of cyclophosphamide and rebuild the patient’s immune system.
Further progress
This breakthrough approach meant that almost any parent, sibling, or child of a patient, as well as uncles and aunts, nieces and nephews, half-siblings, grandparents and grandchildren, could safely act as donors.
Since developing this treatment more than 20 years ago, Kimmel Cancer Center experts have performed more than 2,000 half-matched transplants for leukemia and lymphoma in adults and children.
These clinical studies have proven to be highly successful, with safety and toxicity comparable to matched transplants, and this treatment is now being used in adults with conditions such as sickle cell anemia and severe autoimmune diseases. and to treat chronic but debilitating non-cancerous blood disorders in children.
More recently, innovative research using semi-compatible grafts has begun to improve the efficacy and safety of solid organ transplantation with living donors. Kimmel Cancer Center researchers are working with transplant surgeons to begin transplanting kidneys with semi-identical bone marrow. Because the patient and donor have the same immune system, organ rejection and lifelong use of anti-rejection drugs can essentially be eliminated.
“Previously, GVHD limited the ability to perform incompatible transplants, but now it is very well managed, mainly due to cyclophosphamide, with almost 95% of patients surviving the transplant; “It all started with Al Owens and George Santos 50 years ago,” said Jones, director of the bone marrow transplant program at Kimmel Cancer Center.
