Novel Biologic Therapies for GVHD

点击翻译按钮获取中文摘要

Novel Biologic Therapies for GVHD Abstract: For patients with high-risk malignant and non-malignant hematologic diseases, hematopoietic stem cell transplant (HCT) often represents the only option for cure. However, HCT is fraught with complications, leading to high rates of toxicity and patient death. The principal cause of early non-relapse mortality is acute graft-versus-host disease (AGVHD), with death from infection a close second. These two are interrelated, as intensifying global immune suppression to control AGVHD increases infection risk. Moreover, augmented immunosuppression can also increase the risk of malignant relapse. To move the field forward, we must develop targeted, evidence-based prevention and treatment strategies, designed to specifically control alloreactivity while preserving anti-tumor and anti-viral protective immunity. Perhaps the greatest need for these targeted therapeutics is in GI AGVHD, the leading cause of AGVHD- related death. Two issues predominate, which significantly impede progress: (1) We do not adequately understand the distinct mechanisms controlling GI T cell infiltration versus tissue residency or damage, which inhibits development of specific therapies. (2) We do not understand the mechanisms driving steroid-refractory GI AGVHD, significantly slowing treatment development for this most deadly type of AGVHD. The goal of this proposal is to address these unmet needs, and thereby discover the next generation of therapeutics for GI AGVHD. We will do so by completing the following three Specific Aims: (1): Prioritize and validate next-generation GI-targeted therapeutics with a novel translational pipeline. We will test the hypothesis that a pipeline from patient/NHP-derived therapeutic candidates → mouse → NHP AGVHD models can prioritize new AGVHD therapeutics. (2) Determine the impact of Notch ligand blockade on the blood and GI immune landscape in NHP and transplant patients. We will test the hypothesis that Notch ligand blockade with the anti-DLL4 mAb REGN421 protects against GI AGVHD, and that it does so by inhibiting effector T cell infiltration into the GI tract. (3) Identify predictors of steroid responsive and resistant GI AGVHD in patients. We will test the hypothesis that unifying mechanisms of steroid response and resistance can be identified in patients by comprehensive linked immune studies of the blood and GI tract at AGVHD diagnosis. By completing these aims, we will discern the mechanisms driving GI AGVHD, and thus fundamentally advance our ability to care for patients undergoing HCT.