*Purpose: Human stem cell-derived islet-like cells (SC-islets) represent a sustainable source for beta-cell replacement to achieve a functional cure for type 1 diabetes. We previously showed long-term glycemic correction by SC-islets microencapsulated with CXCL12 in alginate without systemic immunosuppression in mice. Translation of such findings in rodents into large animals and humans is often challenging, in part, due to the robust foreign body and immune responses that lead to early graft failure. Here, we report long-term functional survival of SC-islets microencapsulated with alginate that incorporates CXCL12 in nondiabetic (ND) and diabetic (DM) nonhuman primates (NHPs) without immunosuppression.

*Methods: Microencapsulated SC-islets were transplanted into the greater omental sac of a ND and three DM NHPs in parallel with the intraperitoneal transplantation in immunocompetent C57BL/6 diabetic mice. Biochemical, immunologic, and hematologic parameters, blood glucose levels, serum C-peptide and intravenous glucose tolerance tests were carried out over 24 weeks. Biopsies of microcapsules from the ND NHP were recovered at 4, 12 and at 24 weeks post-transplantation to assess their survival, function, and the local immune responses to the microcapsules.

*Results: Blood glucose levels of the ND NHP were within normal range throughout the study while insulin requirements of the DM NHPs were consistently reduced post-transplantation onwards allowing exogenous insulin dosing to be reduced by up to 60% relative to pre-transplant requirements. Normoglycemia was restored in transplanted diabetic mice. Serum C-peptide levels of the ND NHP were stable (~200 pM to 700 pM) and random and intravenous glucose-induced C-peptide was detectable in the DM NHPs post-transplant. Recovered SC-islets from ND NHP at 4, 12 and 24-weeks as well as those retrieved from the DM NHPs at completion of the study were glucose-responsive. Retrieved microcapsules at all time points in all animals were predominantly free-floating without evidence of fibrotic overgrowth. Messenger RNA transcript and protein expression of islet beta-cell markers were detectable, at 24 weeks post-transplant in the ND NHP, albeit at decreased levels compared to pre-transplantation, by qPCR and immunohistochemistry, respectively. There was no evidence of islet regeneration in the recipient pancreas or significant anti-human (SC-islet) T-cell mediated immune responses.

*Conclusions: These preclinical findings demonstrate function and safety of SC-islets in large animals and support further preclinical investigation and potential clinical translation.

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