Anti-inflammatory Therapy to Improve Outcomes After TPIAT

Overview

Patients with severe chronic pancreatitis may be candidates to have their pancreas removed and their islets transplanted into the liver to reduce the risk of diabetes mellitus, a procedure called total pancreatectomy with islet autotransplant (TPIAT). However, over half of patients who have a TPIAT will need to remain on some supplemental insulin life-long after the procedure. We will study therapies that may reduce damage to transplanted islets, and thereby improve long-term outcomes. Two promising anti-inflammatory therapies are available to protect islets from damage at the time of transplant: (1) the Tumor Necrosis Factor (TNF)-alpha inhibitor etanercept and (2) the serine protease inhibitor alpha-1 antitrypsin. Both agents are commercially available for clinical trials. Proof-of-principle for etanercept has been demonstrated in type 1 diabetic allotransplant recipients, in whom a 10 day course of etanercept early post-transplant significantly improved long-term insulin independence, due to better survival of the transplanted beta cell mass in the engraftment period. Alpha-1 antitrypsin (A1AT) reduces inflammatory cytokines, protects against cytokine-induced beta cell apoptosis, and prolongs islet graft survival in mice and intraportal IAT non-human primates. This initial 3-arm drug-treatment clinical trial will investigate the use of Etanercept and A1AT to improve IAT function at 90 days and 1 and 2 years post-TPIAT compared to standard care. Forty-five patients undergoing TPIAT will be randomized 1:1:1 to receive either: 1) etanercept (50 mg on day 0; 25 mg on days 3, 7, 10, 14, and 21), 2) alpha-1 antitrypsin (90 mg/kg IV days -1, +3, 7, 14, 21, 28) or 3) standard care. Patients will have mechanistic assessments drawn in the early post-operative period including inflammatory cytokines and chemokines and measures of beta cell loss. Metabolic testing will occur at 90, 365, and 730 days post-TPIAT, including mixed meal tolerance testing, IV glucose tolerance testing, and glucose-potentiated arginine-induced insulin secretion (GPAIS).

For patients with severe pancreatitis refractory to medical and endoscopic therapy, total pancreatectomy (TP) with islet autotransplantation (IAT) may be considered. While 90% of TPIAT recipients have some function of the transplanted islet graft, only about 1/3rd come completely off insulin. The long-term goal of the proposed research is to develop new therapies that will increase the number of patients who are non-diabetic following islet autotransplant. Such therapies may also benefit recipients of islet allotransplant for type 1 diabetes. Following islet transplantation, the islets must acutely survive the stress of the procedure, and then they must engraft in the liver and establish a vascular supply. The greater the functional islet mass engrafted, the lower the risk of post-operative diabetes. It has been estimated that more than half of the islet mass may be lost in the early post-transplant period in islet transplant recipients. Beta cell apoptosis is common during the first month post-transplant and is upregulated in the presence of inflammatory cytokines such as TNF-alpha. Thus, a major contributor to islet loss is the inflammatory damage sustained by the transplanted islets in the early post-transplant period; we propose to directly target this destructive process. Two promising anti-inflammatory therapies are available to address this problem: (1) the TNF-alpha inhibitor etanercept and (2) the serine protease inhibitor alpha-1 antitrypsin. Both agents are commercially available for clinical trials. Proof-of-principle for etanercept has been demonstrated in type 1 diabetic allotransplant recipients, in whom a 10 day course of etanercept early post-transplant significantly improved long-term insulin independence, due to better survival of the transplanted beta cell mass in the engraftment period. Alpha-1 antitrypsin (A1AT) reduces inflammatory cytokines, protects against cytokine-induced beta cell apoptosis, and prolongs islet graft survival in mice and intraportal IAT non-human primates. This initial 3-arm drug-treatment clinical trial will investigate the use of Etanercept and A1AT to improve IAT function at 90 days and 1 and 2 years post-TPIAT compared to standard care. Forty-five patients undergoing TPIAT will be randomized 1:1:1 to receive either: 1) etanercept (50 mg on day 0; 25 mg on days 3, 7, 10, 14, and 21), 2) alpha-1 antitrypsin (90 mg/kg IV days -1, +3, 7, 14, 21, 28) or 3) standard care. Patients will have mechanistic assessments drawn in the early post-operative period including inflammatory cytokines and chemokines and measures of beta cell loss. Metabolic testing will occur at 90, 365, and 730 days post-TPIAT, including mixed meal tolerance testing, IV glucose tolerance testing, and glucose-potentiated arginine-induced insulin secretion (GPAIS). The latter measures the maximally stimulated acute C-peptide response (ACRmax) as the best estimate of islet mass and the primary endpoint (at day 90) for this study. Results will be used to select the most promising agent for future study in a randomized, blinded multi-center clinical trial.