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Diabetes Therapy

Open Access 11-04-2025 | Type 1 Diabetes | Review

Cell Therapy for T1D Beyond BLA: Gearing Up Toward Clinical Practice

Authors: Yong Wang, YingYing Chen, James McGarrigle, Jenny Cook, Peter D. Rios, Giovanna La Monica, Wei Wei, Jose Oberholzer

Published in: Diabetes Therapy

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Abstract

Type 1 diabetes (T1D) remains a significant global health challenge and patients with T1D need lifelong insulin therapy. Islet transplantation holds transformative potential by replacing autoimmune-mediated destruction of insulin-producing beta cells. This review examines the trajectory of islet transplantation for T1D, focusing on the process and benefits of obtaining biologics license application (BLA) approval for cell-based therapies. Following US Food and Drug Administration (FDA) approval, the authors identify key steps urgently needed to foster islet transplantation as a viable treatment for a broader population of patients with T1D. Furthermore, the authors highlight recent advances in encapsulation technologies, stem cell-derived islets, xenogeneic islets, and gene editing as strategies to overcome challenges such as immune rejection and limited islet sources. These innovations are pivotal in enhancing the safety and efficacy of islet transplantation. Ultimately, this review emphasizes that while BLA approval represents a critical milestone, realizing the full potential of cell therapy for T1D requires addressing the scientific, clinical, and logistical challenges of its real-world implementation. By fostering innovation, collaboration, and strategic partnerships, the field can transform T1D care, offering patients a durable, life-changing alternative to traditional insulin therapy.
Literature
1.
Lacy PE, Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes. 1967;16:35–9.PubMedCrossRef
2.
Ballinger WF, Lacy PE. Transplantation of intact pancreatic islets in rats. Surgery. 1972;72:175–86.PubMed
3.
Lacy PE, Finke EH, Conant S, Naber S. Long-term perfusion of isolated rats islets in vitro. Diabetes. 1976;25:484–93.PubMedCrossRef
4.
Shibata A, Ludvigsen CW Jr, Naber SP, et al. Standardization of a digestion–filtration method for isolation of pancreatic islets. Diabetes. 1976;25:667–72.PubMedCrossRef
5.
Najarian JS, Sutherland DE, Matas AJ, et al. Human islet transplantation: a preliminary report. Transplant Proc. 1977;9:233–6.PubMed
6.
Ricordi C, Lacy PE, Finke EH, et al. Automated method for isolation of human pancreatic islets. Diabetes. 1988;37:413–20.PubMedCrossRef
7.
Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343:230–8.PubMedCrossRef
8.
Ryan EA, Lakey JR, Rajotte RV, et al. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes. 2001;50:710–9.PubMedCrossRef
9.
Markmann JF, Rickels MR, Eggerman TL, et al. Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes. Am J Transplant. 2021;21:1477–92.PubMedCrossRef
10.
Rickels MR, Eggerman TL, Bayman L, et al. Long-term outcomes with islet-alone and islet-after-kidney transplantation for type 1 diabetes in the clinical islet transplantation consortium: the CIT-08 study. Diabetes Care. 2022;45:2967–75.PubMedPubMedCentralCrossRef
11.
Chetboun M, Drumez E, Ballou C, et al. Association between primary graft function and 5-year outcomes of islet allogeneic transplantation in type 1 diabetes: a retrospective, multicentre, observational cohort study in 1210 patients from the Collaborative Islet Transplant Registry. Lancet Diabetes Endocrinol. 2023;11:391–401.PubMedPubMedCentralCrossRef
12.
Ricordi C, Goldstein JS, Balamurugan AN, et al. National institutes of health-sponsored clinical islet transplantation consortium phase 3 trial: manufacture of a complex cellular product at eight processing facilities. Diabetes. 2016;65:3418–28.PubMedPubMedCentralCrossRef
13.
Hering BJ, Clarke WR, Bridges ND, et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care. 2016;39:1230–40.PubMedPubMedCentralCrossRef
14.
15.
Qi M, Kinzer K, Danielson KK, et al. Five-year follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience. Acta Diabetol. 2014;51:833–43.PubMedPubMedCentralCrossRef
16.
Gangemi A, Salehi P, Hatipoglu B, et al. Islet transplantation for brittle type 1 diabetes: the UIC protocol. Am J Transplant. 2008;8:1250–61.PubMedCrossRef
17.
Lablanche S, Vantyghem MC, Kessler L, et al. Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. 2018;6:527–37.PubMedCrossRef
18.
Maanaoui M, Lenain R, Foucher Y, et al. Islet-after-kidney transplantation versus kidney alone in kidney transplant recipients with type 1 diabetes (KAIAK): a population-based target trial emulation in France. Lancet Diabetes Endocrinol. 2024;12:716–24.PubMedCrossRef
19.
Witkowski P, Philipson LH, Kaufman DB, et al. The demise of islet allotransplantation in the United States: a call for an urgent regulatory update. Am J Transplant. 2021;21:1365–75.PubMedPubMedCentralCrossRef
20.
Weber DJ. FDA regulation of allogeneic islets as a biological product. Cell Biochem Biophys. 2004;40:19–22.PubMedCrossRef
21.
Wonnacott K. Update on regulatory issues in pancreatic islet transplantation. Am J Ther. 2005;12:600–4.PubMedCrossRef
22.
Choudhary P, Rickels MR, Senior PA, et al. Evidence-informed clinical practice recommendations for treatment of type 1 diabetes complicated by problematic hypoglycemia. Diabetes Care. 2015;38:1016–29.PubMedPubMedCentralCrossRef
23.
Bottino R, Wijkstrom M, van der Windt DJ, et al. Pig-to-monkey islet xenotransplantation using multi-transgenic pigs. Am J Transplant. 2014;14:2275–87.PubMedPubMedCentralCrossRef
24.
Lei Y, Wolf-van Buerck L, Honarpisheh M, et al. Neonatal islets from human PD-L1 transgenic pigs reduce immune cell activation and cellular rejection in humanized nonobese diabetic-scid IL2rgamma(null) mice. Am J Transplant. 2024;24:20–9.PubMedCrossRef
25.
Mourad NI, Gianello P. Gene editing, gene therapy, and cell xenotransplantation: cell transplantation across species. Curr Transplant Rep. 2017;4:193–200.PubMedPubMedCentralCrossRef
26.
27.
Cantley J, Boslem E, Laybutt DR, et al. Deletion of protein kinase C delta in mice modulates stability of inflammatory genes and protects against cytokine-stimulated beta cell death in vitro and in vivo. Diabetologia. 2011;54:380–9.PubMedCrossRef
28.
Kirchhof N, Shibata S, Wijkstrom M, et al. Reversal of diabetes in non-immunosuppressed rhesus macaques by intraportal porcine islet xenografts precedes acute cellular rejection. Xenotransplantation. 2004;11:396–407.PubMedCrossRef
29.
Gangappa S, Larsen CP. Immunosuppressive protocols for pig-to-human islet transplantation: lessons from pre-clinical non-human primate models. Xenotransplantation. 2008;15:107–11.PubMedCrossRef
30.
van der Windt DJ, Bottino R, Casu A, et al. Long-term controlled normoglycemia in diabetic non-human primates after transplantation with hCD46 transgenic porcine islets. Am J Transplant. 2009;9:2716–26.PubMedCrossRef
31.
Matsumoto S, Tan P, Baker J, et al. Clinical porcine islet xenotransplantation under comprehensive regulation. Transplant Proc. 2014;46:1992–5.PubMedCrossRef
32.
Elliott RB, Escobar L, Tan PL, et al. Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation. Xenotransplantation. 2007;14:157–61.PubMedCrossRef
33.
Assady S, Maor G, Amit M, et al. Insulin production by human embryonic stem cells. Diabetes. 2001;50:1691–7.PubMedCrossRef
34.
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.PubMedCrossRef
35.
Maehr R, Chen S, Snitow M, et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci USA. 2009;106:15768–73.PubMedPubMedCentralCrossRef
36.
D’Amour KA, Bang AG, Eliazer S, et al. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol. 2006;24:1392–401.PubMedCrossRef
37.
Rezania A, Bruin JE, Arora P, et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol. 2014;32:1121–33.PubMedCrossRef
38.
Millman JR, Pagliuca FW. Autologous pluripotent stem cell-derived beta-like cells for diabetes cellular therapy. Diabetes. 2017;66:1111–20.PubMedCrossRef
39.
Zhang D, Jiang W, Liu M, et al. Highly efficient differentiation of human ES cells and iPS cells into mature pancreatic insulin-producing cells. Cell Res. 2009;19:429–38.PubMedCrossRef
40.
Liang Z, Sun D, Lu S, et al. Implantation underneath the abdominal anterior rectus sheath enables effective and functional engraftment of stem-cell-derived islets. Nat Metab. 2023;5:29–40.PubMedCrossRef
41.
42.
Ramzy A, Thompson DM, Ward-Hartstonge KA, et al. Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell. 2021;28(2047–2061): e2045.
43.
Kirk K, Hao E, Lahmy R, Itkin-Ansari P. Human embryonic stem cell derived islet progenitors mature inside an encapsulation device without evidence of increased biomass or cell escape. Stem Cell Res. 2014;12:807–14.PubMedCrossRef
44.
45.
Wang S, Du Y, Zhang B, et al. Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. Cell. 2024;187(6152–6164): e6118.
46.
Hua H, Wang Y, Wang X, et al. Remodeling ceramide homeostasis promotes functional maturation of human pluripotent stem cell-derived beta cells. Cell Stem Cell. 2024;31(850–865): e810.
47.
Du Y, Liang Z, Wang S, et al. Human pluripotent stem-cell-derived islets ameliorate diabetes in non-human primates. Nat Med. 2022;28:272–82.PubMedCrossRef
48.
de Klerk E, Hebrok M. Stem cell-based clinical trials for diabetes mellitus. Front Endocrinol (Lausanne). 2021;12: 631463.PubMedCrossRef
49.
50.
Forbes S, Halpin A, Lam A, et al. Islet transplantation outcomes in type 1 diabetes and transplantation of HLA-DQ8/DR4: results of a single-centre retrospective cohort in Canada. EClinicalMedicine. 2024;67: 102333.PubMedCrossRef
51.
Lim F, Sun AM. Microencapsulated islets as bioartificial endocrine pancreas. Science. 1980;210:908–10.PubMedCrossRef
52.
Sambanis A. Engineering challenges in the development of an encapsulated cell system for treatment of type 1 diabetes. Diabetes Technol Ther. 2000;2:81–9.PubMedCrossRef
53.
Desai TA, Hansford DJ, Ferrari M. Micromachined interfaces: new approaches in cell immunoisolation and biomolecular separation. Biomol Eng. 2000;17:23–36.PubMedCrossRef
54.
Clayton HA, James RF, London NJ. Islet microencapsulation: a review. Acta Diabetol. 1993;30:181–9.PubMedCrossRef
55.
Basta G, Montanucci P, Luca G, et al. Long-term metabolic and immunological follow-up of nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts: four cases. Diabetes Care. 2011;34:2406–9.PubMedPubMedCentralCrossRef
56.
Vegas AJ, Veiseh O, Doloff JC, et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat Biotechnol. 2016;34:345–52.PubMedPubMedCentralCrossRef
57.
Mukherjee S, Kim B, Cheng LY, et al. Screening hydrogels for antifibrotic properties by implanting cellularly barcoded alginates in mice and a non-human primate. Nat Biomed Eng. 2023;7:867–86.PubMedPubMedCentralCrossRef
58.
Vegas AJ, Veiseh O, Gurtler M, et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med. 2016;22:306–11.PubMedPubMedCentralCrossRef
59.
Doloff JC, Veiseh O, Vegas AJ, et al. Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates. Nat Mater. 2017;16:671–80.PubMedPubMedCentralCrossRef
60.
Syed F, Bugliani M, Novelli M, et al. Conformal coating by multilayer nano-encapsulation for the protection of human pancreatic islets: in-vitro and in-vivo studies. Nanomedicine. 2018;14:2191–203.PubMedCrossRef
61.
Zhi ZL, Kerby A, King AJ, et al. Nano-scale encapsulation enhances allograft survival and function of islets transplanted in a mouse model of diabetes. Diabetologia. 2012;55:1081–90.PubMedCrossRef
62.
Bochenek MA, Veiseh O, Vegas AJ, et al. Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques. Nat Biomed Eng. 2018;2:810–21.PubMedPubMedCentralCrossRef
63.
Rafael E, Wernerson A, Arner P, Tibell A. In vivo studies on insulin permeability of an immunoisolation device intended for islet transplantation using the microdialysis technique. Eur Surg Res. 1999;31:249–58.PubMedCrossRef
64.
El-Halawani SM, Gabr MM, El-Far M, et al. Subcutaneous transplantation of bone marrow derived stem cells in macroencapsulation device for treating diabetic rats; clinically transplantable site. Heliyon. 2020;6: e03914.PubMedPubMedCentralCrossRef
65.
Boettler T, Schneider D, Cheng Y, et al. Pancreatic tissue transplanted in TheraCyte encapsulation devices is protected and prevents hyperglycemia in a mouse model of immune-mediated diabetes. Cell Transplant. 2016;25:609–14.PubMedCrossRef
66.
Evron Y, Colton CK, Ludwig B, et al. Long-term viability and function of transplanted islets macroencapsulated at high density are achieved by enhanced oxygen supply. Sci Rep. 2018;8:6508.PubMedPubMedCentralCrossRef
67.
Barkai U, Weir GC, Colton CK, et al. Enhanced oxygen supply improves islet viability in a new bioartificial pancreas. Cell Transplant. 2013;22:1463–76.PubMedCrossRef
68.
Ludwig B, Ludwig S, Steffen A, et al. Favorable outcome of experimental islet xenotransplantation without immunosuppression in a nonhuman primate model of diabetes. Proc Natl Acad Sci USA. 2017;114:11745–50.PubMedPubMedCentralCrossRef
69.
Su J, Hu BH, Lowe WL Jr, et al. Anti-inflammatory peptide-functionalized hydrogels for insulin-secreting cell encapsulation. Biomaterials. 2010;31:308–14.PubMedCrossRef
70.
Hwang DG, Jo Y, Kim M, et al (2021) A 3D bioprinted hybrid encapsulation system for delivery of human pluripotent stem cell-derived pancreatic islet-like aggregates. Biofabrication 14
71.
72.
73.
Parent AV, Faleo G, Chavez J, et al. Selective deletion of human leukocyte antigens protects stem cell-derived islets from immune rejection. Cell Rep. 2021;36: 109538.PubMedCrossRef
74.
Hu X, Gattis C, Olroyd AG, et al. Human hypoimmune primary pancreatic islets avoid rejection and autoimmunity and alleviate diabetes in allogeneic humanized mice. Sci Transl Med. 2023;15: eadg5794.PubMedCrossRef
75.
Gerace D, Zhou Q, Kenty JH, et al. Engineering human stem cell-derived islets to evade immune rejection and promote localized immune tolerance. Cell Rep Med. 2023;4: 100879.PubMedPubMedCentralCrossRef
Metadata
Title
Cell Therapy for T1D Beyond BLA: Gearing Up Toward Clinical Practice
Authors
Yong Wang
YingYing Chen
James McGarrigle
Jenny Cook
Peter D. Rios
Giovanna La Monica
Wei Wei
Jose Oberholzer
Publication date
11-04-2025
Publisher
Springer Healthcare
Published in
Diabetes Therapy
Print ISSN: 1869-6953
Electronic ISSN: 1869-6961
DOI
https://doi.org/10.1007/s13300-025-01732-9

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