Preclinical Notch inhibition to prevent graft-versus-host disease in mice and non-human primates
Ivan MaillardPhD, MD
The Trustees of the University of Pennsylvania, Medical Center
Project Term: July 1, 2019 - June 30, 2022
We have identified peri-transplant blockade of individual Notch ligands as a new therapeutic strategy to prevent graft-versus-host disease (GVHD) in mice. In a non-human primate model, a single dose of an antibody targeting the Notch ligand DLL4 markedly increased GVHD-free survival as a single agent. Building on the highly conserved role of Notch signaling in GVHD, we propose to identify and characterize the most promising combination therapeutic strategies for clinical translation to patients.
Graft-versus-host disease (GVHD) remains one of the most dangerous complications of bone marrow transplantation in patients with leukemia, lymphoma and other blood cancers. GVHD arises because donor immune cells recognize foreign antigens in the recipient, causing damage to multiple target organs. Despite use of preventive treatments, many patients still experience acute GVHD, which can be life-threatening, and/or chronic GVHD, which can trigger long-term complications and decrease the quality of life. Better therapies for the prevention and treatment of GVHD could lower the risks and toxicity of bone marrow transplantation, while allowing more patients to benefit from its life-saving potential. Using mouse models of bone marrow transplantation, we discovered a new therapeutic strategy to prevent acute and chronic GVHD by blocking signals delivered to immune cells early after transplantation by the Notch pathway. Inhibiting Notch signaling prevented GVHD through mechanisms that differed from all other treatments tested so far and preserved beneficial aspects of bone marrow transplantation, including anti-tumor effects. Remarkably, a single dose of an antibody blocking Delta-like Notch ligands, when given immediately prior to transplantation, was sufficient to provide potent long-term protection from GVHD in mice. To evaluate how best to develop this new strategy for patients, we have started studying the effects of Notch ligand blockade in a non-human primate model that mimics many aspects of human bone marrow transplantation. This model provides essential translational information to guide the development of new treatments that can be tested directly in patients. Our preliminary data show that a single dose of an antibody targeting the Notch ligand Delta-like4 (anti-DLL4) markedly increased the GVHD-free survival of transplantation recipients in non-human primates. Anti-DLL4 was particularly potent at controlling intestinal GVHD, the most dangerous manifestation of acute GVHD. Our results show that the function of individual Notch ligands in GVHD is preserved from mice to non-human primates, and thus likely in humans. Building on these results and on our collective expertise, we propose to determine key mechanisms of GVHD protection from Notch inhibition and identify the most promising therapeutic strategies for clinical translation. Specifically, we will study the impact of Notch blockade on immune cells that trigger GVHD in the gut and other target organs in mice and non-human primates. Using newly developed anti-DLL1 antibodies, we will explore whether combined inhibition of DLL1 and DLL4 provides superior GVHD control in non-human primates, as observed in mice. Finally, we will administer Notch ligand blockade with other existing treatments in search of combinations that are well tolerated and have optimal efficacy. Our ultimate goal is to develop new clinical trials to better control GVHD in patients.