Experience with a Novel Efalizumab‐Based Immunosuppressive Regimen to Facilitate Single Donor Islet Cell Transplantation

Abstract

Islet transplantation is an experimental therapy for selected patients with type 1-diabetes (T1DM). It remains limited by immunosuppressive drug toxicity, progressive loss of insulin independence, allosensitization, and the need for multiple islet donors. We describe our experience with an efalizumab-based immunosuppressive regimen as compared to the prevailing standard regimen, the Edmonton protocol. Twelve patients with T1DM received islet transplants: 8 were treated with the Edmonton protocol; 4 were treated with daclizumab induction, a 6-month course of tacrolimus, and maintenance with efalizumab and mycophenolate mofetil. The primary endpoint was insulin independence after one islet infusion. Only 2 Edmonton protocol treated patients achieved the primary endpoint; 6 required islets from multiple donors, and all experienced leukopenia, mouth ulcers, anemia, diarrhea, and hypertransaminasemia. Four became allosensitized. All patients treated with the efalizumab-based regimen achieved insulin independence with normal hemoglobin A1c after a single islet cell infusion and remained insulin independent while on efalizumab. These patients experienced significantly fewer side effects and none became allosensitized. Trial continuation was terminated by withdrawal of efalizumab from the market. These data suggest that this efalizumab-based regimen prevents islet rejection, is well tolerated, and allows for single donor islet transplantation.

Porcine Islet Xenotransplantation for the Treatment of Type 1 Diabetes

“…In one trial, all 8 patients who received an islet transplant and were treated with an Efalizumab-based regimen achieved insulin independence; 4 of these patients achieved independence after a single islet transplant (Posselt et al, 2010). In the second study, the 4 patients that were treated with an Efalizumab based regimen achieved insulin independence after a single islet transplant (Turgeon et al, 2010). Efalizumab was ultimately removed from the market in 2009 due to 4 cases of progressive multifocal leukoencephalopathy (PML), however, none of the recipients in either of these studies demonstrated evidence of this disease (Posselt et al, 2010;Turgeon et al, 2010).…”

“…Clinically, the humanized form, Efalizumab, has been used to treat another autoimmune disorder, plaque psoriasis, with few acute side effects (Lebwohl et al, 2003). There have been 2 trials to date in clinical islet allotransplantation that have reported its efficacy (Posselt et al, 2010;Turgeon et al, 2010). In one trial, all 8 patients who received an islet transplant and were treated with an Efalizumab-based regimen achieved insulin independence; 4 of these patients achieved independence after a single islet transplant (Posselt et al, 2010).…”

Clinical Islet Cell Transplantation – Recent Advances

“…They represent plausible future directions in immunosuppression for allogeneic islet transplantation 44,45 . …”

“…The islet-enriched proteins, namely glutamate decarboxylase-65, doublecortin, protein phosphatase 1, regulatory (inhibitor) subunit 1A (PPP1R1A), ubiquitin C-terminal hydrolase-L1 and the high-mobility group box-1 protein (HMGB1) were widely studied to predict the islet damage. However, the short half-life of these proteins restricts them to become reliable biomarker to predict the islet damage 45,[48][49][50] . In recent years, experiments on nucleic acid biomarkers such as miRNAs, circulating cell-free DNA (cfDNA), and unmethylated/methylated insulin DNA ratio have increased drastically.…”

Tolerance--Is It Worth It?

“…Although graft and patient survival was excellent (95% and 97% at 6 months), there was an 11% rejection risk and an 8% PTLD incidence. Other groups have used efalizumab as adjunct therapy in islet transplant trials (Posselt et al 2010;Turgeon et al 2010) as part of a maintenance immunosuppression regimen. The use of this agent was halted because of an association with progressive multifocal leukoencephalopathy (PML), a serious and usually fatal central nervous system infection caused by JC polyoma virus (Carson et al 2009).…”