How a common chemo drug thwarts graft rejection in bone marrow transplants
The chemotherapy drug cyclophosphamide prevents graft-versus-host (GVHD) disease in people who receive bone marrow transplants through an immune system cell that evades the toxic effects of cyclophosphamide and protects patients from a lethal form of GVHD. These findings could pave the way for improvements in preventing GVHD and rejection of transplanted bone marrow and new therapies to prevent or treat a relapse of the underlying cancer after a transplant.
“Finding the optimal conditions to avoid interfering with immune cells working to eradicate cancer while preventing graft rejection and GVHD is the holy grail of bone marrow transplant,” said Leo Luznik, MD, associate professor of oncology at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. “We've known for some time that giving cyclophosphamide after a transplant helps prevent GVHD, and our study provides an important piece of the puzzle for why it works.”
GVHD occurs when newly transplanted immune cells from donor bone marrow attack the patient's body. Commonly used immunosuppressant drugs prevent rapid-onset, acute GVHD but not persistent, long-lasting, chronic GVHD, which may lead to severe disability and death.
In the early 2000s, Johns Hopkins scientists Leo Luznik and Ephraim Fuchs found that giving patients high doses of cyclophosphamide—a drug derived from nitrogen mustard and used to treat blood cancers—3 days after bone marrow transplant successfully thwarts acute and chronic GVHD. Posttransplant cyclophosphamide was found to enable safe administration of new, half-matched bone marrow transplants in addition to traditional, fully matched ones. Medical centers around the world now use the Johns Hopkins protocol of posttransplant cyclophosphamide, and Luznik said the inexpensive drug is becoming increasingly mainstream in bone marrow transplant regimens.
Luznik and his team inventoried types of immune cells present in the blood of bone marrow transplant patients treated with posttransplant cyclophosphamide. The scientists zeroed in on a type of immune cell called regulatory T cells, which were known to suppress autoimmune responses. They found high levels of the regulatory T cells in patients treated with posttransplant cyclophosphamide, and lab-cultured cells survived cyclophosphamide treatment.
Using polymerase chain reaction methods that amplify DNA and Jones' assay that detects by-products of ALDH, the Johns Hopkins team found that regulatory T cells express high levels of the enzyme aldehyde dehydrogenase (ALDH).
“These regulatory T cells are resistant to posttransplant cyclophosphamide and likely subdue the autoimmune-like response of the donor's bone marrow, preventing GVHD,” said first author Christopher Kanakry, MD, clinical fellow at the Johns Hopkins. He added that patients receiving standard immunosuppressive drugs after transplant, as opposed to high-dose cyclophosphamide, have slower recovery of regulatory T cells in their blood.
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.