PDF: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00415-X#
Introduction
Diabetes mellitus is a chronic disease that affects over 460 million people worldwide () and bears a significant financial, disability, and mortality cost for health care systems and patients globally (). Almost 130,000 new cases of type 1 diabetes are diagnosed each year, and patients face a lifetime of exogenous insulin therapy (). In 2000, a scientific breakthrough occurred in Edmonton, Canada, with the development of an islet transplantation protocol that successfully yielded insulin independence for seven patients with type 1 diabetes (). Since then, over 1,500 islet transplantation procedures have been performed worldwide, and between 2007 and 2010, 44% of patients registered with the Clinical Islet Transplant Registry achieved insulin independence at 3 years post-transplantation (). Median HbA1c levels dropped more than 1.5%, and 87.5% met HbA1c goals 1 year post-transplantation (; NCT00434811), leading to reduced risks of both acute hypoglycemic events and progression of chronic complications (). Despite these encouraging findings, widespread adoption of this procedure remains limited because of the paucity of islets from deceased donors.
Given the potential for an islet cell therapy to give patients insulin independence and to mitigate the complications of diabetes, there is a need for an abundant alternate supply of insulin-producing cells. Alongside interest in porcine islets, development of insulin-secreting cell lines, and in situ cellular reprogramming strategies, use of human pluripotent stem cells has made tremendous progress toward becoming a viable clinical option for the mass production of insulin-producing cells (). In 2001, Assady et al. reported spontaneous in vitro differentiation of human pluripotent embryonic stem cells (ESCs), which included the generation of cells with characteristics of insulin-producing β cells (). Based upon prior knowledge of pancreas development and empirical determination, stepwise protocols were created to control and direct ESCs to definitive endoderm () and subsequently pancreatic endoderm (). Pancreatic endoderm cells (PECs), marked by the transcription factors homeobox protein Nkx-6.1 (NKX6.1) and pancreatic and duodenal homeobox protein 1 (PDX1), produce little insulin but can adequately complete differentiation into pancreatic islet cells after implantation into mice to prevent onset of hyperglycemia following destruction of endogenous mouse β cells () and to reverse established diabetes in mice (), including when implanted subcutaneously in macroencapsulation devices (). Some protocols have been developed to differentiate ESCs to a more mature β cell phenotype in vitro (; ), but challenges with lower cell yield, longer culture time, higher oxygen requirements, and higher cost (; ) have been motivations to explore the clinical use of less mature PECs.
In 2014, ViaCyte launched a phase 1/2 prospective, multicenter, open-label trial (clinicaltrials.gov: NCT02239354) to investigate the safety, tolerability, and efficacy of their VC-01 product candidate. VC-01 is a combination of PECs (the drug candidate PECs produced by ViaCyte have been named “PEC-01”) in macroencapsulation devices (named “PEC-Encap” by the manufacturer) designed to be immunoprotective via use of a cell-impermeable layer. Although full results have not been released, the first 19 patients were reported to tolerate the product well and had few complications (). Although insulin-immunoreactive cells were identified in some explanted grafts 2 years post-implantation, cell survival was inconsistent because of a foreign body response to the encapsulation devices, and there was no reported evidence of insulin secretion ().
In an effort to mitigate cell loss due to device fibrosis, ViaCyte initiated a follow-up trial in 2017 (clinicaltrial.gov: NCT03163511) to investigate the safety, tolerability, and C-peptide production of PEC-01s macroencapsulated in non-immunoprotective devices that include portals designed to enable direct capillary vascular permeation into the device interior (the VC-02 combination product has been named “PEC-Direct” by the manufacturer). This approach requires use of immunosuppression to limit alloimmune, and possibly autoimmune, reactions to implanted cells. We present our initial results from a single site from this trial and provide evidence that PEC-01s survived and matured into glucose-responsive insulin-secreting cells within 26 weeks post-implantation and that patients spent more time in targeted blood glucose range. These findings support the conclusion that PEC-01s contained within vascularizing macroencapsulation devices can survive and mature into functional β-like cells when implanted subcutaneously in patients with type 1 diabetes.
Results
Patients underwent screening (full inclusion and exclusion criteria and the Consolidated Standards of Reporting Trials [CONSORT] flow diagram available; Methods S1 and S2) and were enrolled between November 2017 and March 2020. Patients had been diagnosed with diabetes for 10 to 54 years, were both sexes (male = 7, female = 8), had ages ranging from 36 to 56 years, predominantly identified as white (n = 14, one patient identified as “Hawaiian or native pacific islander”), and had variable degrees of chronic complications of diabetes (Table 1). During the first year of follow-up, all patients reported adverse reactions (total 175), of which three were serious adverse reactions (Table S1). Two patients terminated the study before 1 year because they elected to withdraw consent to take immunosuppressive medications after having serious adverse reactions: patient 04 withdrew consent after 6 months because of typhlitis (grade four) and a liver abscess (grade four), and patient 02 withdrew consent after 10 months because of a parvovirus B19 infection associated with aplastic anemia requiring treatment with intravenous immunoglobulin (grade three). Complications were documented as being “possibly related to immunosuppression,” given that tacrolimus and mycophenolate mofetil (MMF) are well documented to cause bone marrow suppression and increased risk for infections (; ). Five other patients (03, 08, 10, 11, and 12) were recommended to withdraw after 9 months because of failed risk-benefit assessment by the clinical trial sponsor, based primarily on undetected C-peptide by the contract research organization (limit of detection 33 pM) and histological assessment, as well as consideration of patient HbA1c, exogenous insulin requirements, and Clarke hypoglycemia awareness score. All data collected during the first year of patient enrollment and prior to final patient withdrawal have been included.
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