Progress is ongoing in efforts to reduce the burden of immune suppression for people with type 1 diabetes (T1D) receiving islet cell transplants, thereby potentially allowing more patients to receive them.

Currently, use of both deceased donor and stem cell-derived pancreatic islets are reserved for the small proportion of people with T1D who experience severe hypoglycemia or hypoglycemic unawareness, for whom the risk of living with T1D is deemed greater than that of lifelong immune suppression. However, two recent updates of previously reported findings signal progress in shifting that equation.

Piotr Witkowski, MD, professor of surgery and director of the Pancreas and Pancreatic Islet transplantation program at the University of Chicago School of Medicine in Chicago, presented an update on a pilot study now including 12 individuals with T1D and severe hypoglycemia at baseline at the American Diabetes Association (ADA) 2026 Scientific Sessions.

All participants remain insulin independent after receiving donor islets with an immunosuppressive regimen substituting the investigational less-toxic monoclonal antibody tegoprubart (Eledon Pharmaceuticals) for the traditional calcineurin inhibitor tacrolimus, Witkowski reported.

“Overall, the goal is to keep the islets the same or better, as safe as possible, with no rejection and minimal toxicity compared to the previous regimen. And this is what’s happening,” he told Medscape Medical News.

Further in the future is the possibility of eliminating the need for immunosuppression altogether. In a research letter recently published in The New England Journal of Medicine, Per-Ola Carlsson, MD, PhD, professor in the Department of Medical Cell Biology at Uppsala University in Uppsala, Sweden, published an update on a single patient who received genetically modified islets transplanted without immune suppression.

“The study now at 14 months after islet cell transplantation demonstrates the continued safety of the transplanted pancreatic beta cells, as well as continued survival and function of these cells as measured by the presence of circulating C-peptide, a biomarker indicating that transplanted beta cells are producing insulin,” Carlsson told Medscape Medical News.

Can a Monoclonal Antibody Make Immune Suppression Safer?

In the initial pilot study, six people with T1D were given islet transplants and then received the investigative agent, tegoprubart, an anti-CD40 ligand monoclonal antibody used to replace the calcineurin inhibitor tacrolimus, a standard medication used in organ transplant recipients.

Tacrolimus has significant nephrotoxicity and neurotoxicity, can cause hypertension, and is toxic to the islets themselves, noted Witkowski, adding that in a phase 2B trial, tegoprubart outperformed tacrolimus in several outcomes among 127 kidney transplant recipients.

The 12 patients in the updated pilot study included eight females and four males, ranging in age from 19 to 59 years. Their BMIs ranged from 19 to 30 with baseline insulin requirements ranging from 35 to 90 units per day. All patients received tegoprubart as 1-hour weekly infusions following thymoglobulin induction along with mycophenolic acid and etanercept for the first month, then every 3 weeks thereafter.

All 12 participants showed instant improvement in blood glucose control after the first transplant. However, five were transplanted a second time because they still required insulin after 3 months, with a modified immunosuppression dosing regimen. Those requiring a second transplant had higher average BMIs and insulin requirements at baseline, Witkowski reported.

The patient with the longest follow-up, a 31-year-old woman, had been off insulin for nearly 2 years as of early June 2026. The islet graft remains stable and her A1c remains below 5.5%. Three other patients have had a similar trajectory. Compared with historical controls on tacrolimus, those receiving tegoprubart had higher levels of islet engraftment.

Impact on Estimated Glomerular Filtration Rate (eGFR) and Adverse Events

No negative impact was seen on eGFR as has been the case with tacrolimus-based regimens, and there was a tendency toward kidney improvement with tegoprubart. “This is very, very, promising,” said Witkowski.

There were no severe hypoglycemic episodes post-transplant and no unexpected adverse events. There were no thrombotic events, nor any signs of rejection. All lab values remained within normal limits or not clinically significant. And there were none of the signs of renal or neurotoxicity that has been seen with tacrolimus.

The adverse events that did occur included those related to thymoglobulin induction, ie, fever, rash, and headache, two procedure-related complications (liver hematoma and intrabdominal small hematoma in one each), and immunosuppression-related, including asymptomatic cytomegalovirus viremia in two, and norovirus diarrhea in two. All responded after lowering the mycophenolic acid dose. In two patients, lymphopenia persisted beyond 1 year after the thymoglobulin but subsequently resolved.

The tegoprubart therapy is now being extended for another year, up to 3 years total.

The team is now enrolling a similar islet transplantation study of tegoprubart as part of a tacrolimus-free regimen in 10 patients with T1D and stage 1-3a chronic kidney disease (eGFR > 45). Currently, these patients can’t receive islet cell transplants because of the nephrotoxicity of tacrolimus. Here, everolimus will be used instead of mycophenolic acid.

While these studies will use islets from deceased donors, the ultimate goal is to transplant stem cell-derived islets to increase the supply for more people with T1D. Currently just one company, Vertex, is transplanting stem cell-derived islets but still using traditional immune suppression.

Commenting on the study, T1D expert, David M. Harlan, MD, co-director of the Diabetes Center of Excellence at UMass Chan Medical School in Worcester, Massachusetts, told Medscape Medical News, “current immunosuppression is the devil we know…we do not yet know the safety of their anti-CD40L-based approach.”

“I’m a bit concerned about the prolonged lymphopenia they observed,” he said.

Hypoimmune Allogeneic Islets: So Far, So Good

In their research letter, Carlsson and colleagues gave an update of the patient with longstanding T1D who had been treated with UP421, a therapeutic product consisting of allogeneic HLA class I- and II-depleted, CD47-overexpressing hypo-immune platform islet cells with no immunosuppression.

Both safety and survival of the transplanted islet cells have continued at 14 months. There is ongoing presence of circulating C-peptide, a biomarker indicating that the transplanted cells are producing insulin. C-peptide levels also increase during a mixed meal tolerance test (MMTT), consistent with insulin secretion in response to a meal. At baseline, the patient had undetectable C-peptide both fasting and during an MMTT, Carlsson and colleagues reported.

The man still needs to take insulin because the experimental islet dose given was only about 5% of “curing dose” although it was sufficient enough for the graft to be monitored with PET/MRI. He had been taking too little insulin at baseline and again at months 9 and 12, but once his dose was increased he achieved tighter control by month 14.

“Fasting and MMTT-stimulated C-peptide levels at month 14 are comparable to those observed in the first 6 months of the study and exceed levels measured at months 9 and 12….The improved insulin secretion at month 14 underscores the importance of glucose control in optimizing pancreatic beta-cell function,” Carlsson explained.

But Harlan, who is also the William and Doris Krupp Professor of Medicine at UMass, expressed skepticism that the islets were actually working, noting that in patients with longstanding T1D and high A1c, C-peptide production can be episodic so the patient may have actually had some baseline insulin secretion. “If the C-peptide is being generated by the transplanted islets, then they should be able so show higher C-peptide concentrations just downstream of the implant site and they don’t report that,” he said.

No safety issues were identified in the study.

The next step is to use the same genetic engineering with stem cell-derived islets. “This will bring the possibility to do a dose-escalation, hopefully up to curing doses,” Carlsson told Medscape Medical News.

A ‘Cause for Optimism’

Asked to comment, T1D researcher Mark A. Atkinson, PhD, the Jeffrey Keene Family Professor in the Department of Pathology, Immunology and Laboratory Medicine at the University of Florida in Gainesville, Florida, told Medscape Medical News, “Without question, both findings are of clear significance and represent additional steps toward the long-term goal of successful cell replacement therapy for [T1D].”

“While still ‘not there yet,’ one of the major hurdles to such therapies is the notion of a safe form of immunosuppression, one that provides therapeutic benefit while at the same time affording a safety profile that appears of equipoise,” he explained.

Specifically, regarding Carlsson and colleagues’ study, Atkinson said that it was “cause for optimism,” while at the same time noting that it was “a one-patient study and with that, interpretation needs to be cautious.”

“That said,” he added, “it provides proof of principle for a long hoped-for concept of genetically modifying surrogate insulin-producing cells as a treatment for [T1D] in the absence of immunosuppression. While a clear need exists for study expansion, this effort should provide a boost to the field for like studies.”

Witkowski’s study was funded by The Cure Alliance and Breakthrough T1D. He reported serving as a consultant to Eledon, Vertex, Seraxis, Sana, Sernova, Sanofi, and Novo Nordisk, and being a member of the Scientific Steering Committee for clinical trials sponsored by Vertex. Atkinson reported serving on advisory panels for Endsulin and Sernova, being a board member for Diamyd Medical, a consultant for Minutia, Quell Therapeutics, SAB Therapeutics, and Vertex, being on the speakers bureau for Sanofi; and a stock/shareholder of Diamyd Medical. Carlsson’s study was supported by funding from the Leona M. and Harry B. Helmsley Charitable Trust to Uppsala University Hospital. He reported no disclosures. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and diaTribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.