Defu Zeng, professor of diabetes immunology and hematopoietic cell transplantation
The use of donated healthy stem cells to fight cancer has increased long-term survival rates for patients diagnosed with leukemia, lymphoma and other blood disorders.
The process works by introducing healthy immune cells, or T cells, that eliminate tumor cells and prevent the cancer from relapsing.
But for blood cancer patients who receive donor hematopoietic stem cell transplants as part of their treatment, graft-versus-host disease (GVHD) often hampers their recovery.
It occurs when the donor T cells (the graft) don’t recognize other cells in the recipient’s body (the host) and attacks them as if they are foreign bodies.
While many cases of GVHD are mild, the disease can be severe or become chronic and causes side effects such as mouth ulcers, gastrointestinal distress and rashes.
Now, through experimental work, an international team of researchers led by City of Hope’s Defu Zeng
, professor of diabetes immunology and hematopoietic cell transplantation (HCT), believe they may have found a way to prevent GVHD following stem cell transplants without sacrificing the transplants’ ability to fight leukemia and lymphoma. The study results were published recently in the Journal of Clinical Investigation.
“Currently, immunosuppressive drugs have been used to prevent GVHD, but immune-suppressants also subdue the anti-cancer effects of the donor T cells, resulting in cancer relapse, in addition to other side effects such as an increased risk of infection,” explained Zeng. “Therefore, prevention of GVHD while preserving anti-cancer effects remains the holy grail of allogenic HCT.”
According to the researchers, when a specific type of donor T cell called CD4+ was purposefully depleted soon after infusion of donor bone marrow, GVHD was prevented, while strong graft-versus-leukemia (GVL) effects were preserved.
The depletion of CD4+ cells essentially caused another type of T cell (CD8+) to become exhausted in their quest to destroy normal tissue, but strengthened in their fight against cancer, meaning that the donor CD8+ T cells eliminated tumor cells without causing GVHD.
While the findings have only been seen in animals models so far, Zeng said that successful translation of the regimen into clinical application in humans may represent a novel approach that allows strong anti-cancer effects without causing GVHD.
He said this kind of add-on therapy will promote the wide-spread application of donor stem cell transplants as a curative therapy for hematological malignancies like leukemia and lymphoma, without the nasty side effects that often come along with transplantation.
Next, Zeng and his colleagues plan to work to do just that, translating the unique regimen into clinical application at City of Hope by carrying out a clinical trial in collaboration with Ryotaro Nakamura
, M.D., associate professor of hematology and hematopoietic cell transplantation, and Stephen J. Forman
, M.D., the Francis & Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation. Forman leads City of Hope’s Hematologic Malignancies and Stem Cell Transplantation Institute
, which is one of the largest and most successful bone marrow and blood stem cell transplant centers in the world.
“If we see promising results, we will extend this trial by working with our collaborators from this current study,” said Zeng.
At the same time, Zeng is also working with Arthur D. Riggs
, Ph.D., the Samuel Rahbar Chair in Diabetes & Drug Discovery, John Williams
, Ph.D., professor in the Department of Molecular Medicine, and David Horne
, Ph.D., vice provost and associate director of Beckman Research Institute of City of Hope, and chair of the Department of Molecular Medicine, to develop a CD4+ deleting antibody, using the unique meditope technology invented at City of Hope by Williams and colleagues.
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