Pilot experience with opebacan/rBPI 21 in myeloablative hematopoietic cell transplantation.

Eva Guinan,Ilana Bergelson,David E Avigan,Robert J Soiffer,Spencer Brightman,Patrick J Scannon,Nancy J Bunin,Al Ozonoff,Ofer Levy,Lisa L Brennan

doi:10.12688/f1000research.7558.1

Abstract

Bacterial infection and inflammation contribute significantly to the morbidity and mortality of myeloablative allogeneic hematopoietic cell transplantation (HCT). Endotoxin, a component of the outer membrane of Gram-negative bacteria, is a potent inflammatory stimulus in humans. Bactericidal/permeability increasing protein (BPI), a constituent of human neutrophil granules, binds endotoxin thereby precluding endotoxin-induced inflammation and also has direct anti-infective properties against bacteria. As a consequence of myeloablative therapy used in preparation for hematopoietic cell infusion, patients experience gastrointestinal leak of bacteria and bacterial toxins into the systemic circulation and a period of inflammatory cytokine elevation associated with subsequent regimen-related toxicities. Patients frequently become endotoxemic and febrile as well as BPI-deficient due to sustained neutropenia. To examine whether enhancing endotoxin-neutralizing and anti-infective activity by exogenous administration of a recombinant N-terminal fragment of BPI (rBPI 21, generic name opebacan) might ameliorate regimen-related toxicities including infection, we recruited patients scheduled to undergo myeloablative HCT to participate in a proof-of-concept prospective phase I/II trial. After the HCT preparative regimen was completed, opebacan was initiated 18-36 hours prior to administration of allogeneic hematopoietic stem cells (defined as Day 0) and continued for 72 hours. The trial was to have included escalation of rBPI 21 dose and duration but was stopped prematurely due to lack of further drug availability. Therefore, to better understand the clinical course of opebacan-treated patients (n=6), we compared their outcomes with a comparable cohort meeting the same eligibility criteria and enrolled in a non-interventional myeloablative HCT observational study (n = 35). Opebacan-treated participants had earlier platelet engraftment (p=0.005), mirroring beneficial effects of rBPI 21 previously observed in irradiated mice, fewer documented infections (p=0.03) and appeared less likely to experience significant regimen-related toxicities (p=0.05). This small pilot experience supports the potential utility of rBPI 21 in ameliorating HCT-related morbidity and merits further exploration.

Highlights

Regimen-related toxicities, including infection, organ damage, and acute graft-versus-host disease, remain significant barriers to successful allogeneic hematopoietic cell transplantation (HCT)
Administration of a synthetic LPS antagonist for 6 days starting from the day of transplantation reduced TNFα production, intestinal damage, acute graft-versus-host disease (aGvHD) and mortality after murine myeloablative HCT while preserving the graft vs. leukemia (GvL) effect[7,9]
Upon entry into the systemic circulation, LPS is recognized by proteins that enhance its activity by shepherding LPS to its major tripartite pro-inflammatory cell surface receptor composed of Toll-like receptor 4 (TLR4), CD14 and MD-210–13

Summary

Introduction

Regimen-related toxicities, including infection, organ damage, and acute graft-versus-host disease (aGvHD), remain significant barriers to successful allogeneic hematopoietic cell transplantation (HCT). The “cytokine storm” hypothesis - that regimen-related injury to host cells creates a pro-inflammatory environment contributing to aGVHD and other toxicities – has been well substantiated in various experimental models[1,2] One consequence of such host cell injury, gastrointestinal (GI) damage from myeloablative therapy, results in leakage of bacterial lipopolysaccharide (LPS), referred to as endotoxin, into the systemic circulation in both mice and humans undergoing HCT3,4. Upon entry into the systemic circulation, LPS is recognized by proteins that enhance its activity by shepherding LPS to its major tripartite pro-inflammatory cell surface receptor composed of Toll-like receptor 4 (TLR4), CD14 and MD-210–13. This multi-step delivery system amplifies the effect of small amounts of LPS. Binding of BPI to LPS precludes LPS binding to both lipopolysaccharide-binding protein (LBP) and LPS receptors such as TLR4, inhibiting LPS-induced inflammation, including TNFα production[18]

Methods

Results

Conclusion