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Graft-versus-host disease successfully prevented



An international team of researchers believe they may have found a way to prevent graft-versus-host disease after stem cell transplants, while retaining the transplants' positive effects on fighting leukemia and lymphoma.

The preclinical study results were published in the Journal of Clinical Investigation.

Allogeneic (meaning from a donor) hematopoietic cell transplantation (HCT) is a curative therapy for cancers of the blood and lymph system, including leukemia and lymphoma. It works by introducing healthy immune cells, or T cells, that eliminate tumor cells and prevent the cancer from relapsing.

Unfortunately, the same donor T cells can also attack the healthy tissue of the recipient's body, leading to induction of graft- (T cell) versus-host disease, or GVHD. Symptoms can be mild to severe and often include mouth ulcers, gastrointestinal distress and rashes.

"Currently, immunosuppressive drugs have been used to prevent GVHD, but immune-suppressants also subdue the anti-cancer effects of the donor T cells, potentially resulting in cancer relapse, in addition to other side effects such as an increased risk of infection," explained Defu Zeng, M.D., City of Hope’s professor of diabetes immunology and hematopoietic cell transplantation and the leader of the research team. "Therefore, prevention of GVHD while preserving anti-cancer effects remains the 'holy grail' of allogenic HCT."

According to the paper, titled "PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells," the research team, which included graduate students (first authors are Qingxiao Song and Xiong Ni) and scientists from City of Hope, Mayo Clinic, Fred Hutchinson Cancer Research Center and three Chinese medical schools, observed that temporary in vivo depletion of a specific type of donor T cells (CD4+) soon after infusion of donor stem cell transplants prevented GVHD while preserving strong graft-versus-leukemia (GVL) effects.

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.

"If successfully translated into clinical application, this regimen may represent one of the novel approaches that allow strong GVL effects without causing GVHD," Dr. Zeng said. "This kind of regimen has the potential to promote wide-spread application of allogenic HCT as a curative therapy for hematological malignancies."

Going forward, Dr. Zeng plans to translate this novel 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., F.A.C.P, leader of City of Hope's Hematologic Malignancies and Stem Cell Transplantation Institute.

"If we see promising results, we will extend this trial by working with our collaborators from this current study," Dr. Zeng said.

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DOI: 10.1172/JCI91138