Modulation of Autoimmune T-Cell Memory by Stem Cell Educator Therapy: Phase 1/2 Clinical Trial
Elias Delgado,
Marcos Perez-Basterrechea,
Beatriz Suarez-Alvarez,
Huimin Zhou,
Eva Martinez Revuelta,
Jose Maria Garcia-Gala,
Silvia Perez,
Maria Alvarez-Viejo,
Edelmiro Menendez,
Carlos Lopez-Larrea,
Ruifeng Tang,
Zhenlong Zhu,
Wei Hu,
Thomas Moss,
Edward Guindi,
Jesus Otero,
Yong Zhao
Affiliations
Elias Delgado
Endocrinology Section, Department of Medicine, University de Oviedo, Oviedo 33006, Spain
Marcos Perez-Basterrechea
Unit of Transplants, Cell Therapy and Regenerative Medicine, Hospital Universitario Central de Asturias, Oviedo 33011, Spain
Beatriz Suarez-Alvarez
Cellular Biology of Renal Diseases Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid 28049, Spain
Huimin Zhou
Section of Endocrinology, The First Hospital of Hebei Medical University, Shijiazhuang 050031, PR China
Eva Martinez Revuelta
Hematology and Hemotherapy Service, Hospital Universitario Central de Asturias, Oviedo 33011, Spain
Jose Maria Garcia-Gala
Hematology and Hemotherapy Service, Hospital Universitario Central de Asturias, Oviedo 33011, Spain
Silvia Perez
Unit of Transplants, Cell Therapy and Regenerative Medicine, Hospital Universitario Central de Asturias, Oviedo 33011, Spain
Maria Alvarez-Viejo
Unit of Transplants, Cell Therapy and Regenerative Medicine, Hospital Universitario Central de Asturias, Oviedo 33011, Spain
Edelmiro Menendez
Endocrinology Section, Department of Medicine, University de Oviedo, Oviedo 33006, Spain
Carlos Lopez-Larrea
Department of Immunology, Hospital Universitario Central de Asturias, Oviedo 33011, Spain
Ruifeng Tang
Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050031, PR China
Zhenlong Zhu
Department of Pathology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050031, PR China
Wei Hu
Department of Research, Hackensack University Medical Center, Hackensack, NJ 07601, USA
Thomas Moss
CORD:USE Cord Blood Bank, Orlando, FL 32810, USA
Edward Guindi
CORD:USE Cord Blood Bank, Orlando, FL 32810, USA
Jesus Otero
Unit of Transplants, Cell Therapy and Regenerative Medicine, Hospital Universitario Central de Asturias, Oviedo 33011, Spain
Yong Zhao
Department of Research, Hackensack University Medical Center, Hackensack, NJ 07601, USA
Background: Type 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. Methods: In 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. Findings: Clinical 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. Interpretation: Current 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. Funding: Obra 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.
