Study Explains Cyclophosphamide’s Role in Preventing Graft-vs-Host Disease
Results of a Johns Hopkins study may explain why cyclophosphamide prevents graft-vs-host disease in people who receive bone marrow transplants. The experiments point to an immune system cell that evades the toxic effects of cyclophosphamide and protects patients from a lethal form of graft-vs-host disease.
The findings, published online today in Science Translational Medicine, could pave the way for improvements in preventing graft-vs-host disease and rejection of transplanted bone marrow and for new therapies to prevent or treat a relapse of the underlying cancer after a transplant.
Post-Transplant Cyclophosphamide in Graft-vs-Host Disease
"Finding the optimal conditions to avoid interfering with immune cells working to eradicate cancer while preventing graft rejection and graft-vs-host disease is the holy grail of bone marrow transplant," said Leo Luznik, MD, Associate Professor of Oncology at the Johns Hopkins Kimmel Cancer Center. "We've known for some time that giving cyclophosphamide after a transplant helps prevent graft-vs-host disease, and our study provides an important piece of the puzzle for why it works."
In the early 2000s, Dr. Luznik and his colleague Ephraim Fuchs, MD, found that giving patients high doses of cyclophosphamide 3 days after bone marrow transplant successfully thwarts acute and chronic graft-vs-host disease. Post-transplant cyclophosphamide also enabled safe administration of new, half-matched bone marrow transplants in addition to traditional, fully matched ones. Today, the protocol of post-transplant cyclophosphamide is becoming increasingly mainstream in bone marrow transplant regimens, according to Dr. Luznik.
However, scientists lacked an explanation for why post-transplant cyclophosphamide effectively curtailed acute and chronic graft-vs-host disease.
Study Details
Previous studies at Johns Hopkins found that cyclophosphamide kills all of the donor's transplanted bone marrow cells except for stem cells containing high levels of an enzyme called aldehyde dehydrogenase (ALDH), which help stem cells evade the toxic effects of cyclophosphamide and rebuild the patient's immune system.
In the current study, Dr. Luznik and his team inventoried types of immune cells present in the blood of bone marrow transplant patients treated with post-transplant cyclophosphamide. They found high levels of the regulatory T cells, which are known to suppress autoimmune responses, in patients treated with post-transplant cyclophosphamide, and lab-cultured cells survived cyclophosphamide treatment. Using polymerase chain reaction methods that amplify DNA and an assay that detects byproducts of ALDH, the researchers found that regulatory T cells express high levels of ALDH.
"These regulatory T cells are resistant to post-transplant cyclophosphamide and likely subdue the autoimmune-like response of the donor's bone marrow, preventing graft-vs-host disease," said Christopher Kanakry, MD, first author of the study and clinical fellow at the Johns Hopkins Kimmel Cancer Center. Patients receiving standard immunosuppressive drugs after transplant, as opposed to high-dose cyclophosphamide, have slower recovery of regulatory T cells in their blood, he added.
The scientists also showed, in lab-cultured human cells, that an ALDH-blocking drug strips regulatory T cells of their ability to grow and protect themselves from cyclophosphamide. Dr. Luznik said that his team is continuing to study methods to improve post-transplant cyclophosphamide, and it may be possible to use these findings to add other relapse-fighting therapies early after transplant.
"Our findings may also lead to even wider acceptance of post-transplant cyclophosphamide," he said.
Funding for the study was provided by the National Institutes of Health, National Cancer Institute, National Heart, Lung, and Blood Institute, the Conquer Cancer Foundation of the American Society of Clinical Oncology, and Otsuka Pharmaceutical.
The assay used in this research was developed and patented by Richard Jones, MD, of Johns Hopkins.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
