An experimental antibody treatment could help to prevent graft versus host disease in the intestines, an early US study has shown – paving the way for human clinical trials.
Researchers from Penn Medicine and Dana-Farber/Boston Children’s Cancer and Blood Disorders Center found giving a single dose of antibodies to block the Notch signalling pathway immediately before the transplant stopped gastrointestinal graft versus host disease (GvHD). Crucially, the treatment did not impair immune function in the rest of the body.
Professor Ivan Maillard from University of Pennsylvania said: “The timing was critical. Intervening before any symptoms of GvHD appear made the long-term protection possible.”
Prof Maillard and colleagues found in prior studies that the GvHD-causing activity of donor immune cells, especially T cells, requires the activation of an internal messaging system called the Notch pathway. Using mouse models with GvHD, they found that blocking the DLL4 – an activator of Notch – was effective at preventing GvHD when administered within the first days after transplantation.
In this study, published in Science Translational Medicine, Professor Maillard and his lab teamed up with Professor Leslie Kean, professor of paediatrics at Harvard Medical School, and Dr Victor Tkachev, assistant professor of surgery at Mass General Brigham, to test the anti-DLL4 strategy in a non-human primate model of GvHD.
They confirmed the Notch pathway involvement in GvHD was conserved across species. A single dose of the DLL4-blocking antibody given immediately before transplant greatly increased survival and prevented signs of GvHD in the intestines without causing global immunosuppression.
The researchers traced the anti-DLL4 antibodies’ specific protection against gastrointestinal GvHD to the reduction of an adhesion molecule that normally promotes T-cell migration to the intestines.
Professor Kean said: “If this new, more targeted strategy for preventing GvHD is successful in clinical trials, it might allow us to extend the use of bone marrow transplants to higher risk patients who are not currently eligible for a traditional transplant.
“This unique approach could allow us to thread the needle between efficacy and the downsides of global immunosuppression caused by other GvHD treatments.”
Tkachev V, Vanderbeck A, Perkey E, Furlan SN, McGuckin C, Gómez Atria D, Gerdemann U, Rui X, Lane J, Hunt DJ, Zheng H, Colonna L, Hoffman M, Yu A, Outen R, Kelly S, Allman A, Koch U, Radtke F, Ludewig B, Burbach B, Shimizu Y, Panoskaltsis-Mortari A, Chen G, Carpenter SM, Harari O, Kuhnert F, Thurston G, Blazar BR, Kean LS, Maillard I. (2023) “Notch signaling drives intestinal graft-versus-host disease in mice and nonhuman primates.” Science Translational Medicine, doi: 10.1126/scitranslmed.add1175
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