An experimental antibody treatment largely prevented a bone marrow transplant complication called graft versus host disease (GVHD) within the intestines, without causing broad immune suppression, in a preclinical study led by researchers from Penn Medicine and Dana-Farber/Boston Kid’s Cancer and Blood Disorders Center and published today in Science Translational Medicine.

Even when a bone marrow transplant cures leukemia or lymphoma, GVHD-;wherein T cells within the donor graft attack the recipient’s own tissues-;can still be fatal. The condition is among the many leading causes of death and long-term hostile health consequences related to bone marrow transplants.

Senior co-corresponding authors Ivan Maillard, MD, PhD, a professor of Medicine and vice chief for research in Hematology-Oncology on the Perelman School of Medicine on the University of Pennsylvania, and Leslie S. Kean, MD, PhD, a professor of Pediatrics at Harvard Medical School and director of Pediatric Stem Cell Transplant at Dana-Farber/Boston Kid’s Cancer and Blood Disorders Center, together with lead creator Victor Tkachev PhD, an assistant professor of Surgery at Mass General Brigham, have long sought to stop this fatal complication. Their study helps pave the way in which for human clinical trials of the brand new treatment.

We found that only a single dose of antibodies to dam the Notch signaling pathway, given immediately before the transplant, was in a position to prevent gastrointestinal GVHD, without impairing immune function in the remaining of the body. The timing was critical. Intervening before any symptoms of GVHD appear made the long-term protection possible.”

Ivan Maillard, MD, PhD, Professor of Medicine and vice chief for research in Hematology-Oncology on the Perelman School of Medicine on the University of Pennsylvania

Maillard and colleagues present in prior studies that the GVHD-causing activity of donor immune cells-;especially T cells-;requires a signaling pathway called the Notch pathway. In experiments with mouse models of GVHD, the researchers found that blocking a specific Notch activator-;generally known as DLL4-;was very effective at stopping GVHD when administered inside the first days after transplantation: It stopped donor T cells from infiltrating and attacking the intestines, a significant site of severe GVHD, yet didn’t block the T cells’ infection- and cancer-fighting capabilities.

On this study, Maillard and his lab teamed up with Tkachev, Kean, and colleagues, to check the anti-DLL4 strategy in a big animal model of GVHD, which the Boston researchers developed to raised simulate the human immune system and the consequences of GVHD treatment.

They confirmed that the Notch pathway involvement in GVHD was conserved across species, and that only a single dose of the DLL4-blocking antibody given immediately before transplant greatly increased survival and prevented signs of GVHD within 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.

The successful test in multiple preclinical models opens the way in which for initial clinical trials, now being planned at Penn Medicine and Dana Farber/Boston Childrens, the researchers said.

“If this latest, more targeted strategy for stopping GVHD is successful in clinical trials, it’d allow us to increase the usage of bone marrow transplants to higher risk patients who aren’t currently eligible for a standard transplant,” said Kean. “This unique approach could allow us to string the needle between efficacy and the downsides of world immunosuppression brought on by other GVHD treatments.”

Perelman School of Medicine student Ashley Vanderbeck and University of Michigan student Eric Perkey were co-first authors on the paper, with Tkachev.

The study was supported by Regeneron, Inc., the Leukemia & Lymphoma Society (TRP-6583-20), the National Institutes of Health (R01-HL095791, P01-HL158504, U19-AI051731, R01-AI091627, R37-AI34495, R01-HL56067, R01-HL11879, R01-HL-115114, T32-AI070077, T32-GM007863, F30-AI161873, F30-AI136325), and Be the Match Foundation/CIBMTR Amy Strelzer Manasevit Research Program.

Source:

University of Pennsylvania School of Medicine

Journal reference:

Tkachev, V., et al. (2023) Notch signaling drives intestinal graft-versus-host disease in mice and nonhuman primates. Science Translational Medicine. doi.org/10.1126/scitranslmed.add1175.