Bilateral administration of autologous CD133+ cells in ambulatory patients with refractory critical limb ischemia: lessons learned from a pilot randomized, double-blind, placebo-controlled trial

Abstract

Introduction CD133+ cells confer angiogenic potential and may be beneficial for the treatment of critical limb ischemia (CLI). However, patient selection, blinding methods and endpoints for clinical trials is challenging. We hypothesized that bilateral intramuscular administration of cytokine mobilized CD133+ cells in ambulatory patients with refractory CLI would be feasible and safe. Methods In this double-blind, randomized, sham-controlled trial, subjects received subcutaneous injections of granulocyte colony stimulating factor (10 mcg/kg/d) for 5 days, followed by leukapheresis, and intramuscular administration of 50-400 million sorted CD133+ cells delivered into both legs. Control subjects received normal saline injections, sham leukapheresis and intramuscular injection of placebo buffered solution. Subjects were followed for 1 year. An aliquot of CD133+ cells was collected from each subject to test for genes associated with cell senescence. Results 70 subjects were screened, of whom 10 were eligible. Subject enrollment was suspended due to a high rate of mobilization failure in subjects randomized to treatment. Of 10 subjects enrolled (7 randomized to treatment, 3 randomized to control), there were no differences in serious adverse events at 12 months and blinding was preserved. There were non-significant trends toward improved amputation free survival, 6 minute walk distance, walking impairment questionnaire and quality of life in subjects randomized to treatment. Successful CD133+ mobilizers expressed fewer senescence associated genes compared to poor mobilizers. Conclusion Bilateral administration of autologous CD133+ cell in ambulatory CLI subjects was safe and blinding was preserved. However, poor mobilization efficiency combined with high CD133+ senescence suggests futility in this approach.

Bone Marrow derived Cell Therapy in Critical Limb Ischemia: A Meta-analysis of Randomized Placebo Controlled Trials

“…Five of 10 studies used BM derived mononuclear cells (BMMNC), 3,4,8,11,33 one used BM derived mesenchymal stem cells (BMMSC), 9 one RCT used Ixmyelocel-T, a commercial pre-expanded cell product obtained from BM, 34 one study used CD34 þ cells, 12 and one used CD133 þ cells. 10 One study had a three-armed trial design with a BMMNC, a BMMSC, and a placebo group. 35 Patients with bilateral CLI were randomized to BMMNC or BMMSC in one leg and placebo in the other; hence, the contralateral leg served as an internal control.…”

“…2A). If studies using the contralateral leg as a control 35 þ e þ e þ Gupta et al 9 þ þ þ þ þ Losordo et al 12 þ e þ þ /À þ Powell et al 34 þ þ þ þ þ Raval et al 10 e þ þ þ e Tateishi-Yuyama et al 4 þ þ þ e þ Teraa et al 11 þ þ þ þ þ Walter et al 33 e e þ þ þ…”

Stem Cell Therapies in Clinical Trials: Progress and Challenges

“…Clinical trial failures have been frequent for MSC therapies, and, more recently (Bersenev, 2015), MSC trials for ulcerative colitis and ischemic stroke (Athersys), cardiac repair (3 studies by Miltenyi Biotec; FBC Pharmicell, Korea; and Stempeutics Research), acute kidney injury (Allocure), ischemic stroke (Manipal Acunova, India), ARDS (China), critical limb ischemia (Raval et al, 2014), and MS (Spain) have failed or been terminated. While clinical trial failures are to be expected in the early days of clinical research, these disappointments are a reasonably common feature of this first wave of cell therapy trials involving autologous and allogeneic MSC products.…”

Bone Marrow-Derived Stem Cells: a Mixed Blessing in the Multifaceted World of Diabetic Complications

“…A recent double-blind, randomized, placebo-controlled, phase I/II study showed MSCs ameliorate the ankle brachial pressure index (ABPI) and ankle pressure in patients with established CLI [ 59 ]. Conversely, autologous supplementation of CD133+ cells through mobilization showed poor results due to senescence of the stem cell compartment [ 60 ].…”