Moving the needles

Updates on progress in research against type 1 diabetes.


JDRF New England’s annual research briefing offers a quick summary of research for type 1 diabetes. Here are four snapshots from last night’s talks by JDRF’s Julia Greenstein and University of Colorado’s Peter Gottlieb:

  1. The march continues toward an “artificial pancreas” that automatically provides just the right amounts of insulin around the clock. The first of four NIH-sponsored pivotal clinical trials kicked off in February. Many of us are most intrigued by the Beta Bionics combo device, designed to deliver both insulin (which lowers blood glucose levels) and glucagon (which raises them). This device is a few years behind some of its competitors, but we like it for the same reason we would prefer a self-driving car with brakes.
  1. JDRF has awarded more than 50 grants for research on encapsulating insulin-producing beta cells derived from stem cells, to initiatives such as the Boston Autologous Islet Replacement Therapy Program. News from the much-watched Viacyte clinical trial, however, is not so good. The Viacyte capsule prevents against some immune response but generates a foreign-body reaction. Next–generation encapsulation technologies may do better on immune response but must still grapple with another fiendishly tricky issue—admitting suitably high levels of oxygen to the beta cells. (The pancreas is even hungrier for oxygen than the brain, Greenstein noted.)
  1. For decades, immunologists in both cancer and autoimmune diseases like type 1 diabetes made important discoveries that didn’t translate into better treatments. That unhappy situation has changed bigtime with cancer immunology, and diabetes researchers are now adopting two general strategies in cancer treatment. One strategy is to recognize that the disease may work quite differently in different people—for example, in trials of drugs designed to delay or prevent progression of the disease, often one group responds much better than another. So “personalized medicine”, tailored to specific groups of patients, may recast the field in type 1 just as it has done with many forms of cancer. The second strategy aims to confront the complexity of the disease by combining treatments, as the University of Miami’s Jay Skyler has proposed.
  1. No clear winners have ever emerged from the dozens of trials of drugs designed to delay or prevent type 1 diabetes onset. One contender that’s still standing is oral insulin acting as a vaccine. Drug companies have chased the elusive goal of an insulin pill for a century (with a few recent signs of progress) but such pills typically get ripped apart in your gut without lowering your blood glucose levels. However, the resulting fragments of insulin may generate an anti-immune protective response in the pancreas. Early clinical tests of this vaccine concept (such as this one reported in 2015) have shown promise for some patients. The latest clinical results, including early findings from a phase II trial with higher doses, will be announced on June 12th at the American Diabetes Association annual scientific sessions. We’ll be watching!

Beta living through stem cells

Insulin-producing cells will be tested first in patients lacking a pancreas.


Diabetes is way complex. “But it’s a simple disease conceptually—your body doesn’t produce enough insulin,” notes Joslin Diabetes Center researcher Gordon Weir.

In type 1 diabetes, an autoimmune attack wipes out insulin-producing beta cells, which are found in clusters of pancreatic cells called islets. In type 2 diabetes, the beta cells are still there but not hauling all the freight. That disease can be treated with many other types of drugs, along with lifestyle changes. But over time, beta cells wear out. In fact, more people with type 2 take insulin than people with type 1.

And there’s no way to make insulin injections pleasant or easily controllable or as good as insulin production by beta cells.

Thus the huge interest in a long-term research project spearheaded by Harvard’s Doug Melton to create working beta cells by manipulating stem cells. An update on the ambitious project from Melton, Weir and other partners drew a crowd at Harvard on Monday.

Making insulin-producing cells good enough for clinical trials “turns out to be rather difficult; it took more than a decade,” Melton said. “We haven’t made it really perfect, but it’s at the goal line.”

Technology from Melton’s lab has been licensed exclusively to the startup Semma Therapeutics, which is joining with Joslin, Brigham & Women’s Hospital and Dana-Farber Cancer Institute to move toward clinical trials. Traveling under the ungainly title of the Boston Autologous Islet Replacement Therapy Program (BAIRT), the collaboration launched in June.

The first BAIRT studies, starting at least three years from now, will not be among people with type 1 diabetes. Instead, they will recruit people who have had their pancreases removed, usually because of uncontrollable pain after the organs are chronically inflamed by years of heavy drinking.

This approach bypasses the biggest problem in cell treatments for type 1 diabetes: the body renews its autoimmune attack and wipes out the newly introduced cells. “We decided to solve one problem at a time,” Melton explained.

Patients who have prostatectomies often now are given islet cells salvaged from their own pancreas, which helps to improve their diabetes control, but those cells may themselves be damaged or in short supply, said Brigham surgeon Sayeed Malek. Transplants of brand-new beta cells, made from the patients’ own blood, should help.

These reengineered cells will be injected in the arm, where they will be easy to monitor  and to remove if necessary, said Semma CEO Robert Millman. Decades of experience transplanting cells from cadavers has shown that “you can put beta cells just about anywhere,” Weir added.

Against autoimmunity. If all goes well, the project will continue into trials for type 1 diabetes with non-personalized beta cells, where the autoimmune attack will be blunted via encapsulating the cells. Seema is spending about half its budget on encapsulation technologies, Millman said.

Encapsulation is the near-term solution to fend off the autoimmune attack. “The long-term solution is to use the power of biology to understand why the immune system has made this mistake,” Melton remarked.

He briefly mentioned two promising research thrusts. One effort is to learn from the rapid advances in knowledge about how cancer cells dodge the immune system.

Another, led by Chad Cowan of Massachusetts General Hospital, aims to create a “universal donor pluripotent stem cell.” Missing all the billboard signs that alert immune enforcers, these cells could play a role like that of O-positive cells in blood transfusions.

Asked about his own take on the causes of type 1, Melton mentioned one theory that the autoimmune attack may be triggered by gut cells that naturally produce insulin or similar substances under certain conditions.

Slow and steady. Bringing beta cell therapies to the clinic will be a marathon march with not only many scientific steps but many regulatory steps. Millman emphasized, however, that “the FDA is working with us very early on the regulatory path.”

Among potential safety risks, all stem cell therapies must be carefully vetted to avoid the growth of teratomas—tumors with a jumbled mix of cells, usually benign. These cellular junk piles would be relatively easy to remove, but much better to avoid altogether, Millman said.

Another concern is that the cells will secrete insulin even when it’s not needed, dropping the recipient’s blood sugar levels to dangerously low levels.

There also is much cause for worry that the cells won’t last long, a major problem in transplants of cadaver beta cells. However, built-from-scratch cells function “for more than a year in mice, which bodes well for people,” Weir commented. And Millman pointed out that the cells resemble juvenile cells, which may help them withstand the high stresses of transplantation better than worn-out adult beta cells do. “We hope these almost pristine cells going into the patients will last a lot longer,” he said.

None of this will come cheap. Asked about pricing for cell therapies, way down the road when and if they hit the market, Millman was understandably wary. Initial costs for these treatments will be very high, accompanied by very close regulatory scrutiny. Semma has raised about $50 million, but “we need philanthropy and we need institutions to support this,” he said.

Melton suggested, though, that successful cell-based therapies will make complete  economic sense, given the soaring numbers of people with diabetes and the huge costs of diabetes care. Each year the world spends about $30 billion on insulin alone. “Diabetes is not an orphan disease,” he said. “The cost will come down very quickly.”

Unlocking the combinations

tsMouse regulatory T cell and human T cell, courtesy NIAID.

The autoimmune attack that triggers type 1 diabetes has been beaten in the non-obese diabetic mouse, the best animal model of the disease.

More than 500 times, in fact, notes Jay Skyler, professor of medicine at the University of Miami.

But in humans: never.

Researchers have painstakingly picked apart the genetics of the disease and many of the intricacies of the immune attack that wipes out insulin-creating cells in the pancreas. And recent studies suggest that we might, just might, have a smoking gun in the form of disease-triggering populations of gut microbes. But we don’t really know the trigger mechanisms and we really can’t stop the disease.

However, as Skyler reviewed the disappointing decades of type 1 trials in a lecture last week at Joslin Diabetes Center, he pointed out research approaches that might lead closer to a cure.

Among them: examining the effects of treatments by subgroups (such as age), coordinating dosing with the timing of immune events, and administering multiple doses or higher doses of a drug.

Given the unending complexity of the immune system, though, maybe the most promising strategy is to hit it at multiple points. That’s the thinking behind Skyler’s upcoming Diabetes Islet Preservation Immune Treatment (DIPIT) trial.

DIPIT will compare two groups of people recently diagnosed with type 1, one group given five drugs and the other a placebo. The drugs, all giving hints of helpfulness in earlier type 1 trials and approved by the Food and Drug Administration for other conditions, are

• anti-thymocyte globulin (an antibody used to prevent rejection in organ transplants)
• etanercept (which inhibits tumor necrosis factor, a master regulator of immune response)
• pegylated granulocyte colony stimulating factor (a growth factor that boosts production of certain white blood cells)
• Interleukin 2 (a cytokine whose effects include increasing growth of the regulatory T cells that can guard against autoimmune onslaughts), and
• exenatide (a synthetic hormone that boosts glucose-dependent insulin secretion).

As Skyler told the Miami Herald, “we have one drug to stop the cavalry; one drug to stop the artillery; two drugs that help bring in support systems that favor the immune response; and one drug that helps beta cell health so they can resist the attack better.”

When he first proposed this kitchen-sink idea, “everybody said I was crazy,” Skyler remarked to his Joslin audience. The trial did get FDA approval. He’s still looking for funding, though.

Okay, let’s contrast these combinations with those in another arena of biomedical research that’s almost the reverse of type 1: cancer immunotherapy.

This field tries to activate (rather than suppress) the immune system at multiple points. Also unlike the case with type 1 and other autoimmune diseases, it is awash in drug-discovery money.

In fact, we’re living in the breakthrough decade for cancer immunotherapy. The two clear winners so far are CAR-T cells (chimeric antigen receptor T cells, in which a patient’s own cells are re-engineered to seek and destroy blood cells gone bad) and checkpoint blockade drugs (which prevent tumors from presenting false IDs).

The first checkpoint blockade drug approved by the FDA targets CTLA-4, a surface receptor on T cells and B cells. About a fifth of advanced melanoma patients given the drug survive for ten years with no further treatment. And in clinical trials, combining a CTLA-4 inhibitor with a drug that clogs up another checkpoint receptor, PD-1, has significantly broadened the population of survivors.

Combination is a familiar theme in cancer treatment, since tumors are so adept at evolving to resist whatever you throw at them. There are very high hopes for adding immunotherapies to the mix.

And in that mix, proven treatments like checkpoint blockaders will be joined by other drugs that hit different points of immune activation. There’s much excitement, for instance, about agents that activate the STING (stimulator of interferon genes) pathway, which can kick off defenders in both the innate and the adaptive immune systems and maybe act as a kind of cancer vaccine.

In both cancer and diabetes, nothing will be easy in bringing combination therapies into clinical trials and then ideally into regular practice. Researchers must identify exactly which patients might benefit from which combos, juggle drug dosages and timing, watch for serious side effects and struggle to quantify any improvements in health. These will be long rough roads. But for some patients, we hope, combos will lead to cures.

Capping off

sphere_scarringAn MIT alginate microcapsule holding islet cells (in green) and being covered by immune cells (in blue and magenta). Image credit: Omid Veiseh, Joshua Doloff, Minglin Ma and Arturo Vegas.

There’s a worldwide deficit in insulin-producing beta cells, for people with either type 1 or type 2 diabetes, Harvard’s Doug Melton told a session at the ADA annual scientific conference on Friday.

“It’s a completely non-trivial thing that you can now make billions of human beta cells,” he said. “We spent more than a decade trying to march these cells through this procedure.”

Currently, it takes his lab about 40 days to produce the cells at a cost of about $6,000 per flask, but Melton is confident that these numbers can be chopped down.

The achievement required not only brilliant scientific detective legwork, especially on the last steps of differentiation, but lab drudgework on a dramatic scale.

Picking apart the steps that drive cells into beta shape, “we had to sort out three or four factors at a time,” he noted. The lab ran screens of small molecules to find what combinations were effective. Testing eight small molecules, in three concentrations, for different periods, in triplicate meant about 65,000 combinations to examine per screen.

The lab of MIT bioengineer Dan Anderson, collaborating with Melton to build microcapsules for the beta cells, took high-volume testing to a much higher level for various capsule designs.

Over the decades, many groups have tried to encapsulate beta cells in tiny spheres of alginate. Historically, “all these capsules end up covered in scar tissue,” Anderson told the ADA session.

But after endlessly tweaking the properties of these spheres, “we have a growing list of materials we could use,” he said.

One capsule material seems to work well in mice with strong immune systems—and in very early testing in macaques. Details on the material aren’t yet public, but the secret isn’t in the material’s permeability but in how the immune system reacts to it, Anderson said.

His group’s exhaustive testing also gave clues to how capsule size affects immune scarring. Last month, he and colleagues reported in Nature Materials that 1.5-mm-diameter capsules do better than 0.5-mm structures. Was that a surprise? “It was for us,” Anderson replied. “We thought smaller would be better.”

Beta than the real thing?

Melton_ beta_cellsHuman stem cells implanted successfully in a mouse. Image courtesy Doug Melton.

We know a true cure for type 1 diabetes will require both a new supply of insulin-producing beta cells and a new way to stop the autoimmune attack that wipes out the original cells. We’ve seen great progress in the past decade on the first challenge, as researchers have learned to morph embryonic stem cells and then normal skin cells into beta cells that now might be very much like the real thing. But despite all we’ve learned about the autoimmune attack and all the clever ideas that have emerged to stop it, so far there’s no clear way to do so.

Today the best bet for autoimmune defense is to embed engineered beta cells in intricately designed porous capsules. While most attempts use spherical capsules on a millimeter scale, last fall Viacyte launched a clinical trial for a device the size of a credit card. We’re all rooting for this trial’s success. But even if it works well, the encapsulated cells won’t function quite normally or last forever.

“I want a forever solution,” says Harvard’s Doug Melton, who has led much of the stem cell engineering work.

At a JDRF session in Boston back in March, Melton suggested two approaches to further modify those engineered cells to dodge the autoimmune bullets. “These are two of my favorite ideas, but I’ll remind you that most of my ideas turn out to be wrong,” he said wryly.

One idea follows the playbook of the hot new class of cancer immunotherapies known as “checkpoint blockaders” —or rather turns it on its head.

As cancer researchers began to discover two decades ago, T cells that charge in to wipe out tumor cells are stopped in their tracks if the tumor cells express certain proteins on their surfaces. Well, how about engineering beta cells to defend themselves by expressing these proteins on their surfaces? (Work in mice by other labs indeed has demonstrated protective effects.)

Melton prefers a second concept, which taps into one of the large questions of immunology: Why doesn’t a mother’s immune system attack the fetus she carries?

Cells called trophoblasts that initially wrap the embryo help to provide the immune shield, he notes. So why not express key trophoblast surface proteins in beta cells, so that the beta cells look like fetal cells to the immune system?

While autoimmune researchers have been kicking around both of these ideas for years, it’s still very early days for bringing beta cells with self-protective surfaces toward the clinic.

But some year, Melton told the JDRF crowd, “my dream is to tell you, not only can we make billions of beta cells but we can transplant them into any person and they won’t be rejected.”

I’m looking forward to hearing about more and better betas from him and from other leading researchers this Friday afternoon, at a session during the American Diabetes Association’s annual scientific conference in Boston.

Encapsulating answers to type 1 diabetes

People with type 1 diabetes are understandably excited about progress toward an “artificial pancreas” but they never lose the hope for a true cure, in which they can live like everyone else, without juggling synthetic hormones and hardware clomped on their skin that pierces their skin and will never work perfectly.

A true cure is a blue-sky goal built on two sets of major medical advances, and we have no idea what year those advances might arrive.

One set is to understand the autoimmune onslaught that brings on type 1 and then find a way to stop it. Serious and sometimes brilliant research keeps charging ahead, but autoimmune diseases hold extremely devious secrets and guard them very well.

The second set is to create a cells that replace those wiped out by the autoimmune attack and can generate insulin (and maybe related pancreatic hormones) at appropriate levels. Stem cell research aimed to do so is going gangbusters but is generally a long way from clinical trials.

With one big exception:

Yesterday Viacyte filed with the FDA for permission to run a trial for its VC-01 device, which encapsulates human progenitor cells—human embryonic stem cells that in this case have gone partly down the development path to hormone-producing cells. (The company, then known as Novocell, began work with embryonic stem cells years before the 2006 discovery of ways to create induced pluripotent stem cells, which possess very similar abilities to differentiate into almost any kind of cell but can be created from adult cells.)

Viacyte’s encapsulation container is a Teflonish cartridge about the size of a band-aid and thickness of a credit card, with holes too small for immune cells to enter but big enough to allow oxygen, glucose and other key ingredients to flow in and to allow insulin and other hormones to flow out.

The theory is that the capsule is inserted via an outpatient procedure, the immune system mostly ignores it, blood vessels build up to feed the cells, the cells are driven by signals within their fairly normal local human microenvironment to differentiate into a range of hormone-producing cells, the cells churn out insulin and its hormone cousins, and normal blood glucose levels and related metabolism are maintained. A functional cure, in short, for a year or two or three while the device functions properly.

This all works nicely in mice, but mice are not always man’s best friend in diabetes research. Investigators have struggled with encapsulation techniques for many years, and stem-cell-derived cells are unproven. The list of what could go wrong in the Viacyte trial is very long. Patients might reject the capsule. The cells might die quickly or slowly or never gather suitable blood vessels or fail in other ways. They might generate side effects that no one has imagined.

But Viacyte seems to have the science on its side and its head on straight and a good step-by-step plan. Assuming the FDA agrees, I don’t expect a home run in the first trial, but simply getting on base would be huge. And we should know within a year.

Viacyte Encaptra