In a newly reported study, an experimental antibody treatment largely prevented gastrointestinal acute graft versus host disease (GI-aGVHD) in the intestines of mice and non-human primates (NHPs) given a bone marrow transplant—allogeneic hematopoietic cell transplant (allo-HCT)—but without causing broad immune suppression. The study, headed by researchers at Penn Medicine and Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, demonstrated that antibody blockade of the Notch signaling pathway improved post-transplant survival and protected against gastrointestinal GVHD in particular. The study builds on previous work in mice that highlight the treatment’s translational potential and demystify some of the mechanisms behind its effects. The results could help pave the way for human clinical trials.
“We found that just a single dose of antibodies to block the Notch signaling pathway, given immediately before the transplant, was able to prevent gastrointestinal GVHD, without impairing immune function in the rest of the body,” said Ivan Maillard, MD, PhD, a professor of Medicine and vice chief for research in hematology-oncology at the Perelman School of Medicine at the University of Pennsylvania. “The timing was critical. Intervening before any symptoms of GVHD appear made the long-term protection possible.”
Maillard is co-senior and co-corresponding author of the team’s published paper in Science Translational Medicine, which is titled “Notch signalling drives intestinal graft-versus-host disease in mice and nonhuman primates.”
Allogeneic hematopoietic cell transplantation (allo-HCT) has lifesaving potential for patients with hematological malignancies and bone marrow disorders, the authors wrote. However, acute graft-versus-host disease (aGVHD) can be potentially fatal in recipients. “Among aGVHD manifestations, gastrointestinal involvement (GI-aGVHD) is most challenging, with nearly all cases of severe aGVHD prominently involving the gastrointestinal (GI) tract,” the team noted. And even when a bone marrow transplant is curative for leukemia or lymphoma, GVHD—in which T cells in the donor graft attack the recipient’s own tissues—can still be fatal. “The condition is among the leading causes of death and long-term adverse health consequences associated with bone marrow transplants.”
Maillard, together with co-senior and co-corresponding author Leslie S. Kean, MD, PhD, a professor of pediatrics at Harvard Medical School and director of pediatric stem cell transplant at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and lead author Victor Tkachev PhD, an assistant professor of surgery at Mass General Brigham, have long sought to prevent this fatal complication.
In prior studies, Maillard and colleagues found that the GVHD-causing activity of donor immune cells—especially T cells—requires the Notch signaling pathway. In experiments with mouse models of GVHD, the researchers showed that blocking a particular Notch activator known as DLL4 effectively prevented GVHD when administered within the first days after transplantation. This strategy stopped donor T cells from infiltrating and attacking the intestines, a major site of severe GVHD, but did not block the T cells’ infection- and cancer-fighting capabilities.
To date, preclinical studies have relied heavily on mouse allo-HCT models, but these are not always ideal and, as the team pointed out, “… mouse allo-HCT differs from human allo-HCT in terms of transplant conditioning, supportive care, and complications.” For their newly reported study Maillard and his lab teamed up with Tkachev, Kean, and colleagues to test the anti-DLL4 strategy using an antibody called REGN421 in a large animal model of GVHD, which the Boston researchers developed to better simulate the human immune system and the effects of GVHD treatment, and allowing them to test the effects of targeting a single pathway.
“… we developed a T cell–replete haploidentical allo-HCT model of aGVHD in nonhuman primates,” they wrote. “In this model, treatments can be evaluated initially as single agents for their activity in GVHD prophylaxis, unlike in human patients, where new interventions must be combined with drugs used for routine GVHD prevention.”
The team confirmed that the Notch pathway involvement in GVHD was conserved across species, and demonstrated in their animal models that just a single dose of the DLL4-blocking antibody given immediately before stem cell transplantation greatly increased survival and prevented signs of GVHD in the intestines, but without causing global immunosuppression.
The research team also observed that the antibody shrank the number of conventional T cells in the intestines, leading to a higher ratio of suppressive T regulatory cells to conventional T cells. They 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.
Importantly, DLL4/Notch inhibition protected mice and NHPs from GI-aGVHD through “unique mechanisms” that differed from those of other more global inhibitors of T cell activation, the investigators pointed out. “Instead of global immunosuppression, DLL4/Notch inhibition provided specific protection from GI-aGVHD, an effect not observed with other single agents tested for aGVHD prevention in NHPs.”
The successful test in multiple preclinical models opens the way for initial clinical trials, now being planned at Penn Medicine and Dana Farber/Boston Children’s, the researchers 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,” commented Kean. “This unique approach could allow us to thread the needle between efficacy and the downsides of global immunosuppression caused by other GVHD treatments.”
Noting limitations of the preclinical study in their report, the team concluded, “Practically, the unique single-agent activity of REGN421 in NHPs nominates DLL4 blockade as a worthwhile strategy to develop for the prevention of GI-aGVHD in patients, especially because it is predicted to have activity on a pathogenic gut homing program that other interventions do not neutralize. Possible future strategies include combination of DLL4 inhibitors with other agents to blunt aGVHD at nonintestinal sites.”
