Stem Cell Transplant Seen as Major Type 1 Diabetes Advance

Miriam E. Tucker

October 27, 2021

A novel investigational allogeneic stem cell-derived treatment resulted in near reversal of type 1 diabetes in a patient who had lived with the condition for about 40 years.

The patient was the first in Vertex Pharmaceuticals' phase 1/2 multicenter, single-arm, open-label clinical trial of the insulin-producing islet cell therapy VX-880 for patients with type 1 diabetes who have impaired hypoglycemic awareness and severe hypoglycemia.

The cells are delivered by infusion into the hepatic portal vein. As of now, chronic immunosuppression is required to prevent rejection, but several approaches are being studied to overcome the limitation.

"There's hope that this is a real advance. It's been long awaited, and it looks really encouraging," James Markmann, MD, PhD, the surgeon who performed the procedure, told Medscape Medical News.

The use of insulin-producing pancreatic beta cells derived from human pluripotent stem cells, first reported in 2014 by a team at the Harvard Stem Cell Institute, Boston, Massachusetts, is seen as a major advance over use of cadaveric donor islet cells because stem cell-derived islets are available in unlimited and uncontaminated supplies.

Cadaveric donor islets are being used in products such as donislecel (CellTrans), which was endorsed by a US Food and Drug Administration (FDA) advisory committee in the summer for the treatment of type 1 diabetes that can't be managed with current therapies.

The patient in the Vertex trial isn't the first reported stem cell-derived islet recipient with type 1 diabetes, but these cells are the first to be transplanted into the liver.

"This Vertex patient stood out because the reduction in insulin requirement...was so striking," noted Markmann, chief of the division of transplant surgery at Massachusetts General Hospital, Boston, who has been transplanting islet cells from cadaveric donors into humans via the hepatic portal vein for over 20 years.

"Nobody knew what to expect as it hadn't been done before, but certainly the results in this patient are better than what I would have expected from a deceased donor islet transplant," he added.

Asked to comment, A.M. James Shapiro, MD, agreed. "I think the most important finding is that a stem cell-derived islet is now transplanted into the liver of a patient safely, so far," he told Medscape Medical News.

Shapiro is clinical director of the living donor and islet cell transplantation programs at the University of Alberta, Edmonton, Canada. He pioneered cadaveric donor islet cell transplantation more than 20 years ago with the watershed Edmonton Protocol.

"A Pretty Impressive Finding...Bodes Well for Ongoing Efforts"

Vertex announced the result by press release. The company plans to transplant another 16 patients, staggering them over time at multiple centers.

The first patient was treated with a single infusion of VX-880 at half the target dose (per protocol for the first two study subjects), along with standard immunosuppressive therapy. At 90 days, the patient's C-peptide, a measure of endogenous insulin secretion, rose from undetectable to 280 pmol/L fasting and 560 pmol/L post mixed-meal tolerance testing.

Over the same period, the patient's A1c dropped from 8.6% at baseline to 7.2%. And within 7 days, the individual's daily exogenous insulin requirement dropped from an average of 34 units to just 2.9 units, a 91% decrease.

The patient had experienced five severe hypoglycemic episodes in the year prior to transplant. They experienced some mild hypoglycemia soon after the procedure while insulin doses were being adjusted, but none thereafter.

Shapiro told Medscape Medical News: "I was absolutely thrilled to see the first patient results with high C-peptide and a 91% reduction in insulin. That's a pretty impressive finding for half dosing in the very first patient in a trial. I think it bodes really well for ongoing efforts in this area by Vertex and by others that have similar kinds of cells. It's very exciting."

However, he cautioned, "We do need some longer-term data to be sure there's no off-target growth or other concerns. But based on the purity of this product, that risk is likely to be low."

And he noted, "I think we still have to address the challenges of setting this process up. A huge amount of work has gone into manufacturing the cell product for a single patient. I think it remains to be seen whether the same technology can be delivered at a larger, being able to treat hundreds or thousands of patients."

A blog post on the website of diabetes charity JDRF called the result "outstanding." "It's a big deal," they add. However, they also caution: "There are a few things to keep in mind while assessing the data. One is that these are only results from a single person. Data are needed from many more to fully evaluate the potential of this therapy. The second is that this person only received half the target dose of cells."

Shapiro is working with another company, ViaCyte, which has also developed stem cell-derived islets. In contrast to the Vertex product, which is fully differentiated and delivered to the liver, ViaCyte's PEC-Direct product is comprised of stem cell-derived pancreatic islet progenitor cells that are implanted subcutaneously in a pouch, allowing for vascularization.

In a late-breaking poster at the virtual American Diabetes Association (ADA) 81st Scientific Sessions in June 2021, ViaCyte reported on a patient given PEC-Direct. In that patient, stimulated C-peptide increased from 0.1 ng/mL at baseline to 0.8 ng/mL at week 39, and there was a drop in A1c from 7.4% to 6.6%, with no adverse events.   

Immunosuppression: Which Approach Will Come Closer to Cure?

Thus far, the requirement for lifelong immunosuppression has meant that any islet cell replacement approach, including with stem cell-derived islets, has been limited to use in people with type 1 diabetes who have hypoglycemic unawareness or severely unpredictable blood glucose levels.

Two broad approaches are simultaneously being explored to overcome the rejection problem: encapsulation of the cells to protect them from the immune system, and genetic modification of the cells so that they don't provoke the immune system in the first place.

In 2022, Vertex plans to file an investigational new drug application for an encapsulated islet cell program with the US FDA.

Markmann believes the genetic modification approach is more promising. "I'm not a believer in encapsulation. I think the foreign body response is hard to overcome. I think the answer will ultimately be genetically modifying the [cell] lines...The cell could express something that would potentially turn off the lymphocytes or interfere with the lymphocytes trying to attack them."

Moreover, he said, "You don't have to get rid of immunosuppression completely. It's all [a] risk-benefit [equation]. Even if you could get it down to a single less-toxic [immunosuppressive] agent that would be a huge step."

Shapiro commented: "All efforts and eyes are laser-focused on developing cells or approaches that will allow transplantation of this kind of stem cell without any immunosuppression or with low-dose immunosuppression that could be regarded as being exceedingly low-risk."

"Then, and only then, I think we could offer this kind of treatment to children who are just diagnosed with diabetes or to [a bigger proportion of] patients with type 1 or type 2 diabetes...The science has to be done in a step-wise fashion," he added.

Microencapsulation, Shapiro noted, "is a big challenge because the process of capturing the cells and putting them into a device is really injurious to their survival...That may or may not work."

Shapiro and his Edmonton team are now embarking on a new trial with ViaCyte and CRISPR Therapeutics using gene-edited cells that contain two knock-in genes and two knock-out genes shown to be less immunogenic and anti-inflammatory in rodent models.

"They look to be promising. We're going to start a first-in-human trial in the next few months with those cells to see if they really are able to withstand a transplant without the need for immunosuppression. That will be a very exciting trial in itself," Shapiro said, noting that they expect to enroll the first patients in the next few months.

However, he cautioned, "First we have to make sure that the gene-edited product continues to function in patients in the way that the original product did, that the cells survive, and that the gene modifications are actually effective...Maybe other iterations will be needed."

"I think, as we move forward, we will ultimately have a gene-edited stem cell-derived product that is immune evasive and will survive. So, I'm...optimistic that this is not as long term as you might think, and it's...happening much more rapidly — at least in first-in-human trials to test safety and preliminary efficacy."

Shapiro is a consultant for ViaCyte.

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 Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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