Modulation of Autoimmune T-Cell Memory by Stem Cell Educator Therapy: Phase 1/2 Clinical Trial

Abstract

BackgroundType 1 diabetes (T1D) is a T cell-mediated autoimmune disease that causes a deficit of pancreatic islet β cells. The complexities of overcoming autoimmunity in T1D have contributed to the challenges the research community faces when devising successful treatments with conventional immune therapies. Overcoming autoimmune T cell memory represents one of the key hurdles.MethodsIn this open-label, phase 1/phase 2 study, Caucasian T1D patients (N = 15) received two treatments with the Stem Cell Educator (SCE) therapy, an approach that uses human multipotent cord blood-derived multipotent stem cells (CB-SCs). SCE therapy involves a closed-loop system that briefly treats the patient's lymphocytes with CB-SCs in vitro and returns the “educated” lymphocytes (but not the CB-SCs) into the patient's blood circulation. This study is registered with ClinicalTrials.gov, NCT01350219.FindingsClinical data demonstrated that SCE therapy was well tolerated in all subjects. The percentage of naïve CD4+ T cells was significantly increased at 26 weeks and maintained through the final follow-up at 56 weeks. The percentage of CD4+ central memory T cells (TCM) was markedly and constantly increased at 18 weeks. Both CD4+ effector memory T cells (TEM) and CD8+ TEM cells were considerably decreased at 18 weeks and 26 weeks respectively. Additional clinical data demonstrated the modulation of C–C chemokine receptor 7 (CCR7) expressions on naïve T, TCM, and TEM cells. Following two treatments with SCE therapy, islet β-cell function was improved and maintained in individuals with residual β-cell function, but not in those without residual β-cell function.InterpretationCurrent clinical data demonstrated the safety and efficacy of SCE therapy in immune modulation. SCE therapy provides lasting reversal of autoimmune memory that could improve islet β-cell function in Caucasian subjects.FundingObra Social “La Caixa”, Instituto de Salud Carlos III, Red de Investigación Renal, European Union FEDER Funds, Principado de Asturias, FICYT, and Hackensack University Medical Center Foundation.

Platelet-Derived Mitochondria Display Embryonic Stem Cell Markers and Improve Pancreatic Islet β-cell Function in Humans

“…D). These data suggest that modulations in platelet populations may contribute to the clinical efficacy of SCE therapy for diabetic patients .…”

“…Exclusion criteria included clinically significant liver, kidney, or heart disease; pregnancy; immunosuppressive medication; viral diseases; or diseases associated with immunodeficiency. The primary study endpoints on feasibility and safety of the SCE therapy have been published elsewhere . Endpoints relevant to the current study were preliminary evidence of effects of SCE therapy on platelets in T1D and T2D subjects.…”

“…Based on their unique properties in immune modulation , we developed a new technology, called Stem Cell Educator (SCE) therapy, by using CB‐SCs in a closed‐loop system that circulates a patient's blood through a blood cell separator, briefly co‐cultures the patient's lymphocytes with adherent CB‐SCs in vitro, and returns the “educated” lymphocytes (but not the CB‐SCs) to the patient's circulation . A single treatment with SCE therapy provides lasting reversal of autoimmunity, leading to the regeneration of islet β cells and improvement of metabolic control in individuals with longstanding T1D and T2D . Specifically, a recent phase I/II study demonstrated the safety and feasibility of SCE therapy in the treatment of alopecia areata (AA) , one of the most common T cell‐mediated autoimmune diseases.…”

Released Exosomes Contribute to the Immune Modulation of Cord Blood-Derived Stem Cells

“…Human buffy coat blood units were purchased from the New York Blood Center (New York, NY). Human peripheral bloodderived mononuclear cells (PBMC) were harvested as previously described (5). PBMC were stained with carboxyfluorescein succinimidyl ester (CFSE) (Life Technologies) according to the manufacturer protocol, then stimulated with Dynabeads coupled with anti-CD3 and anti-CD28 antibodies (Life Technologies) for 72 h in the presence of treatment with exosomes at 10 µg/ml, 20 µg/ml, and 40 µg/ml in duplicate, respectively, and were incubated at 37 • C in 5% CO 2 in the tissue culture-treated 96-well plate.…”

“…We developed the Stem Cell Educator (SCE) therapy, which harnesses the unique therapeutic potential of cord blood-derived stem cells (CB-SC) to treat the multiple immune dysfunctions in diabetes (4)(5)(6)(7). SCE therapy circulates patient's blood through a blood cell separator, cocultures the patient's lymphocytes with adherent CB-SC in vitro, and returns "educated" lymphocytes to the patient's circulation (4,5,7). In contrast to conventional immune therapies, SCE therapy modifies rather than destroys the cells responsible for autoimmunity.…”