Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes

Adam Ramzy; David M Thompson; Kirsten A Ward-Hartstonge; Sabine Ivison; Laura Cook; Rosa V Garcia; Jackson Loyal; Peter T W Kim; Garth L Warnock; Megan K Levings; Timothy J Kieffer

doi:10.1016/j.stem.2021.10.003

Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes

Cell Stem Cell. 2021 Dec 2;28(12):2047-2061.e5. doi: 10.1016/j.stem.2021.10.003.

Authors

Affiliations

¹ Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
² Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
³ Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute (BCCHRI), Vancouver, BC V5Z 4H4, Canada.
⁴ Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
⁵ Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute (BCCHRI), Vancouver, BC V5Z 4H4, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
⁶ Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: tim.kieffer@ubc.ca.

PMID: 34861146
DOI: 10.1016/j.stem.2021.10.003

Abstract

An open-label, first-in-human phase 1/2 study is being conducted to evaluate the safety and efficacy of pancreatic endoderm cells (PECs) implanted in non-immunoprotective macroencapsulation devices for the treatment of type 1 diabetes. We report an analysis on 1 year of data from the first cohort of 15 patients from a single trial site that received subcutaneous implantation of cell products combined with an immunosuppressive regimen. Implants were well tolerated with no teratoma formation or severe graft-related adverse events. After implantation, patients had increased fasting C-peptide levels and increased glucose-responsive C-peptide levels and developed mixed meal-stimulated C-peptide secretion. There were immunosuppression-related transient increases in circulating regulatory T cells, PD1^high T cells, and IL17A⁺CD4⁺ T cells. Explanted grafts contained cells with a mature β cell phenotype that were immunoreactive for insulin, islet amyloid polypeptide, and MAFA. These data, and associated findings (Shapiro et al., 2021), are the first reported evidence of meal-regulated insulin secretion by differentiated stem cells in patients.

Trial registration: ClinicalTrials.gov NCT03163511.

Keywords: C-peptide; cell therapy; diabetes; embryonic stem cells; islet transplantation; pancreatic endoderm cells.

Publication types

Clinical Trial, Phase I
Clinical Trial, Phase II
Research Support, Non-U.S. Gov't

MeSH terms

C-Peptide
Cell Differentiation
Diabetes Mellitus, Type 1* / therapy
Endoderm
Glucose
Humans
Insulin
Insulin-Secreting Cells*

Substances

C-Peptide
Insulin
Glucose

Associated data

ClinicalTrials.gov/NCT03163511

Grants and funding

CIHR/Canada