insulin

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HIP transplants for diabetes

Sana Biotechnology’s ‘hypoimmune pluripotent’ genetic engineering creates insulin-producing cells that dodge immune attacks in monkeys and mice.

Any true cure for type 1 diabetes must successfully replace the insulin-producing pancreatic beta cells that have been destroyed by the body’s own immune system, and then defend those replacement cells from that trigger-happy immune system without immunosuppressive drugs.

Clinical studies, most dramatically the Vertex Pharmaceuticals VX-880 trial, have shown that we now can generate reasonably good replacement cells via pluripotent stem cell science. And this week Vertex received Food & Drug Administration approval for a trial to test its cells in a new encapsulation device without immunosuppression.

To date, however, no such encapsulation scheme has ever worked well in humans.

Given remarkable progress in immunology and gene editing, many labs are working to modify the beta cells themselves to pass muster with the immune system.

Vertex again leads in the clinic, by picking up a collaboration with CRISPR Therapeutics that it acquired with last-year’s purchase of Viacyte. The trial with Viacyte “VCTX210” cells began dosing patients early in 2022 but apparently no results have been reported to date, which might point to limitations. Vertex’s own inhouse quest for “hypoimmune” cell therapies continues under stem cell guru Doug Melton.

This week Sana Biotechnology published encouraging preclinical results in Nature Biology for its “hypoimmune pluripotent” (HIP) cells in rhesus macaques, which often act as the final animal model for drug candidates before first-in-human trials.

Most strikingly, Sana scientists took macaque pancreatic islets (which contain beta cells and various hormone-producing buddies) and created HIP-edited versions of the islet cells. When these cells were transplanted into another macaque, they survived for 40 weeks without immunosuppression. In contrast, transplanted unedited cells quickly died.

The collaborators also generated human HIP pancreatic islet cells that not only survived in humanized diabetic mice for 40 weeks but dramatically dropped blood sugar levels.

So, how do cells get HIP?

Sana researchers, who aim to make cells hypoimmune with as few genetic manipulations as possible, modify three genes for HIP.

Like every other attempt to cloak transplanted cells from the immune system, the Sana strategy starts by turning down the expression of human leukocyte antigen (HLA) proteins that are the cornerstones of attacks from T cells and other players in the adaptive immune system. To do so, the HIP genetic engineering targets the cBM2 and CIITA genes.

Cells also need to be protected from the innate immune system, including natural killer cells and macrophages. Here, HIP builds on years of research by Sonja Schrepfer, a professor of surgery at University of California/San Francisco and a scientific founder at Sana.

As a transplant surgeon, Schrepfer saw the desperate need for better ways to prevent the body’s rejection of transplanted organs. She began pondering why during pregnancy, the fetus is not rejected by the mother’s immune system although half its proteins are from the father. That search led her to the CD47 protein, sometimes called “the don’t eat me, don’t attack me molecule,” she told me in an interview for a 2019 Knowable story. After many many experiments, HIP’s third genetic modification is to overexpress the CD47 gene.

All candidate cell therapies based on pluripotent cells that go into trials probably also will bundle in a genetic suicide switch that can be induced by a drug to destroy the cells if they turn untrustworthy. (In this case, making them terminally HIP, sorry.)

Founded in 2019 and based in Seattle, Sana belongs to the rare lofty set of startup biotechs that gathers enormous amounts of capital long before kicking off any clinical trials. In 2021, the company raised $588 million in its initial public offering. Sana develops two main types of engineered cell treatments—allogeneic (off-the-shelf) cell therapies, like those we’re discussing here, and treatments designed to heal damaged existing cells in place, an even tougher goal.

Sana’s lead HIP program is an off-the-shelf chimeric antigen receptor (CAR) T-cell therapy for certain blood cancers, now in clinical trial. The company expects initial results this year. If successful, the CAR-T trial will be strong encouragement for the HIP approach.

Also in 2023, Sana may get early results from an unusual clinical study for patients with type 1 diabetes. This is an investigator-sponsored trial at an undisclosed European center with HIP-edited cadaveric islet cells. That’s about all we know about this trial, which doesn’t yet appear on European or U.S. clinical trial websites. As far as I know, this is the first clinical study to make such extensive genetic manipulations to cadaveric islets, which are highly difficult to acquire and typically not tremendously robust.

As we’ve been seeing, the mainstream in cell therapies for diabetes instead is cells generated with pluripotent techniques. Sana is developing “SC451” HIP-edited pancreatic islet cells and hopes to file a clinical trial application with the FDA next year.

Top image, mouse pancreatic islet cells, courtesy the James Lo lab at Weill Cornell Medicine. Second image, rhesus macaques by Mark Murchison for Tulane University.

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Creating the next cell therapies for diabetes

As new encapsulation devices go on trial for type 1 diabetes, Vertex’s Doug Melton polishes strategies for insulin-producing cells that guard themselves against immune attack.

Two cell therapy candidates for treating type 1 diabetes took visible steps forward last week. Vertex Pharmaceuticals received Food & Drug Administration approval for a clinical trial of its VX-264 therapy, while Sernova announced that two patients in an ongoing trial received transplanted pancreatic islet cells in an upgraded version of its Cell Pouch capsule.

Vertex’s ongoing VX-880 clinical study, which combines stem-cell-derived islet cells with immune-suppressing drugs, in 2021 “cured” one patient of type 1 diabetes for at least several months. This drew great attention as the first clinical proof that stem-cell-derived islet cells could do useful work.

The VX-264 therapy now given an FDA green light employs the same cells but packages them in a surgically implanted “channel array” device. A VX-264 trial is already underway in Canada. The company expects to recruit about 17 volunteers globally.

As far as I know, Vertex has not released details on this device but it is based on an approach that began in the startup Cystosolv, which was acquired by Semma Therapeutics, which then was bought by Vertex. (Above, images of the approach in one perhaps-still-relevant patent.)

Sernova’s therapy is implanted in three steps: The Cell Pouch is surgically inserted, followed by two rounds of islet cell implants. The company expects to release interim results for this second cohort of patients by year-end. Its treatment uses cadaveric donor cells; Sernova plans to move future candidates to stem-cell-derived cells.

Also last week, Doug Melton outlined his research towards the next generations of stem-cell-drived cells during an American Diabetes Association webinar.

Melton, who led the development of stem-cell-derived insulin-producing beta cells for more than 20 years at Harvard and is on leave at Vertex, focuses on two main challenges. First, gaining complete mastery over cell composition. Second, eliminating the need for systemic immune suppression.

His group is bringing large-scale genetic screening to the job. “We can knock out one gene at a time in the embryonic stem cell stage, and then look for genes which improve composition or provide immune protection,” Melton said. “We’ve identified pathways that I had never thought about as being important for beta cell formation.”

He believes that optimal cell therapies will include the right mix of various types of hormone-producing pancreatic islet cells, not just the insulin-producing beta cells. Similar amounts of alpha cells, which produce glucagon that counter-acts insulin, also seem good. Additionally, there may be a helpful much smaller role for the delta cells that generate somatostatin, which inhibits the release of insulin, glucagon and other hormones. Other cell types should be weeded out.

While much work remains ahead, “we’re on the path to having complete mastery over the final composition of the stem-cell-derived product,” Melton said. “Now, how do we deal with this annoying immune system?”

Here his goal is genetically modified islet cells that provide some immune evasion, if not complete immune tolerance. Melton acknowledged that immunologists roll their eyes when he mentions immune tolerance, the Holy Grail for such therapies, but insisted that it may be achievable.

Many labs have pursued many ways to modify cells that might aid in dodging immune attacks. The standard method to evaluate these strategies for type 1 is by injecting candidate islet cells into an immuno-compromised mouse that models the disease. (“There’s no way in which it reproduces what happens in a human type one diabetic,” Melton acknowledged. “Nevertheless, it’s a start.”)

“There’s nothing novel about this approach,” he commented. “The novelty comes from figuring out what is the right combination.” In one early but encouraging achievement, published in a January Cell Reports Medicine paper, one combo (below) engineered by his Harvard group greatly improved mouse survival over nine weeks.

In a separate Vertex effort based on its acquisition of Viacyte last year, the giant biotech is already enrolling patients for a clinical trial of VCTX-211, a “hypoimmune” cell therapy Viacyte created with CRISPR Therapeutics.

May all of these efforts point toward a real cure.

“My dream would be that when a young child is diagnosed with type one diabetes, the endocrinologist says, I’m sorry for you and your family, but I have good news for you,” Melton said. “I have here in my freezer some cells which will control your blood sugars, and your body won’t reject them for a long time. I’m going to inject them into your belly. And good luck, get back to kindergarten!”

“That sounds like a dream, and it is sort of a dream,” Melton added. “But I don’t see any reason we shouldn’t aim for that.”

P.S. Decades of experimentation with encapsulated cell therapies have not been encouraging. But Sigilon Therapeutics, another contender, hopes to ask the FDA next year to approve a type 1 trial with its “Shielded Living Therapeutics” 1.5mm alginate spheres. Sigilon argues (below) that its capsules will guard islet cells better than any modification of the cells themselves.

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Cell help for diabetes

Clinical trials designed to cure type 1 diabetes with insulin-producing cells derived from stem cells are slowly ramping up.

Our best hope for curing type 1 diabetes is transplants of insulin-producing pancreatic beta cells created from induced pluripotent stem cells (iPSCs). So how’s that quest going? Some recent highlights:

The lead player is Vertex, whose VX-880 clinical trial has produced encouraging preliminary results. The Boston biotech giant is enrolling a few more patients for this study and seeking FDA approval for another trial that would protect the transplanted cells not with the usual immunosuppression drugs but within a protective device whose design has never been published.

Vertex bought Viacyte, the first major player in cell therapy for diabetes and Vertex’s most likely competitor, in September. Viacyte had partnered with CRISPR Therapeutics on the first-ever trial with beta cells that had been genetically modified to minimize the need for immunosuppression. I haven’t seen any public update on the status of that trial, which had planned to recruit 40 volunteers.

In November, the FDA gave Sernova of London, Ontario a thumbs-up to recruit up to seven more patients for the type 1 trial of its Cell Pouch system. “The Cell Pouch is made of cylindrical chambers of polymers with removable plugs that are implanted against the abdominal muscle and become wrapped with blood vessels,” says the company. Surgeons then remove the plug and transplant islet cells (beta cells and their hormone-producing pancreatic neighbors). These cells will come from human cadavers, the default source until now. The latest trial recruits will be given an updated version of the Pouch. Sernova expects to release early clinical results for that cohort this year.

iPSC-derived pancreatic islet cells manufactured by Evotec in Hamburg, Germany, will replace the donor cells in Sernova’s next clinical trials. The two companies plan to seek regulatory approvals for this round in 2024.

Sernova also is working with the lab of Alice Tomei at the University of Miami on a way to shield transplanted islet cells against immune system attack with a “conformal coating” of hydrogels that encapsulates the cells. This procedure has an encouraging history of results with animal models.

With iPSC-derived cells now commercially available from Evotec and other suppliers, solving this immunosuppression puzzle seems to be the one remaining (huge) barrier to successful cell therapies for type 1 diabetes. It’s particularly tough in this illness because the immune system is already fully geared up to wipe out the patient’s own beta cells.

Startup firm iTolerance is taking another approach to protectively wrapping the transplanted cells, with a technique that performed well in a study of macaque monkeys over six months. The strategy is based on a protein called Fas that is expressed on the surface of T cells; those cells die if a Fas ligand (FasL) protein binds to the Fas protein.

The researchers whipped up a dual-protein combination of FasL and streptavidin, a protein that dampens T cell activation and proliferation. These protein combos were attached to microgel beads, then mixed with islet calls “and then transplanted to a bioengineered pouch formed by the omentum—a fold of fatty tissue that hangs from the stomach and covers the intestines.” (Yes, it’s hard to visualize the omentum; islet transplants traditionally have gone into the liver.)

This work was a joint project among investigators at Georgia Tech, the University of Missouri, Massachusetts General Hospital and other institutions. Camillo Ricordi of the University of Miami, a prominent pioneer in diabetes and cell therapy studies, is chief scientist for the Miami-based iTolerance.

Delivering FasL locally like this should work out better than genetically modifying islet cells to over-express the protein, which doesn’t always work out in immunosuppression experiments, the researchers suggested.

But other approaches to gene therapy for immunosuppression keep marching ahead. One group is targeting the A20 protein, which is “like a thermostat for the immune system; it can turn it down to a simmer, or ramp it up to be more aggressive,” according to Shane Grey at Sydney’s Garvan Institute of Medical Research.

Grey and colleagues have followed this track for many years, with promising early results for diabetes in mice, and in human and pig cells. “The genetically engineered cells seem to re-educate the immune system to accept the transplant as self,” Grey commented in a news release. “The transplant can tweak the whole immune system.” The Royal Adelaide Hospital in Adelaide, South Australia will kick off a trial with A20-enhanced islet cells in mid-2024.

Perhaps more dramatically, this month stem cell maestro Doug Melton and co-workers published research on a Swiss army knife approach to genetically modifying human islet cells to become “immune-tolerizing”. The scientists modified the cells to target human leukocyte antigens (keystones in activating T cells) and the PD-L1 immune checkpoint protein and to secrete three cytokines that help to recruit regulatory T cells to protect the transplanted islets. This seemed to work quite well in humanized versions of the standard mouse model for type 1 diabetes.

“Overall, our approach may eliminate the need for encapsulation or immunosuppression, a longstanding goal of the islet transplantation field,” the researchers wrote. Maybe it’s no coincidence that Melton announced plans to take a leave from Harvard to join Vertex last April, just about the time this paper was submitted.

About 8 million people worldwide live with type 1 diabetes, with half a million more diagnosed each year. So says the Type 1 Diabetes Index, which predicts this population will soar to more than 13 million people by 2040. (And maybe 10 times more people with type 2 diabetes will need insulin by then.) Let’s hope that actual cures will be widely available and affordable many years before that.

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Costing out a cure

As Vertex buys Viacyte, is that good news for people with type 1 diabetes?

For 20 years I’ve been rooting for Viacyte, the pioneering startup in growing insulin-producing cells for transplant into people with type 1 diabetes.

Founded in 1999 as Novocell, the San Diego company began its research with human embryonic stems cells rather than the not-yet-discovered induced pluripotent stem cells (the cells re-engineered from adult cells that quickly became the most likely source of stem cell therapies).

Viacyte launched its first clinical trial in 2014 and has doggedly moved ahead in many attempts to optimize its cells and the enscapsulation devices designed to hold the cells. Last month, one patient in a trial finally showed clear clinical benefit, although on immunosuppression drugs.

This month, though, Viacyte announced it will merge with Vertex Pharmaceuticals, its major rival, in a $320 million cash deal.

Based in Boston’s Seaport (above), Vertex is a very different biotech, selling $7 billion of cystic fibrosis drugs each year. In 2021, Vertex’s net income was 31% of revenues and the company was sitting on $7.5 billion in cash.

Vertex broke into the diabetes field with the $950 million acquisition in 2019 of Semma Therapeutics. Semma was a well-funded startup built on research by Doug Melton, Harvard superstar of stem cell research. Melton, who joined Vertex this spring, told me back then that the problem of churning out functional insulin-producing cells in volume had been solved. Melton also was impressed with a “very clever and effective” encapsulation device that Semma was quietly polishing.

Viacyte holds many patents but its encapsulation devices have never lived up to our hopes, and Vertex already owns the world’s most advanced technologies to churn out insulin-producing cells. So it seems that Viacyte’s highest technology card probably is progress in genetically modifying insulin-producing cells to dodge attacks from the immune system, done in partnership with CRISPR Therapeutics.

In February, the two companies announced that a volunteer in a clinical trial had received such genetically redesigned cells. This was a “historic, first-in-human transplant of gene-edited, stem cell-derived pancreatic cells for the treatment of diabetes designed to eliminate the need for immune suppression,” commented James Shapiro of the University of Alberta, an investigator in the trial and world expert on such matters.

Melton has been working on such immune-dodging-cell techniques for years, and Vertex was an early investor in CRISPR Therapeutics. But knowledge gained from the Viacyte/CRISPR trial can only help.

However, my guess is that Vertex mostly bought the smaller firm to take out its leading competitor, and that this move eventually will bring higher pricing for patients.

Case in point, Vertex’s lead cystic fibrosis combo costs almost $300,000 a year.

In 2020 the Institute for Clinical and Economic Review (ICER), a well-respected Boston non-profit that analyzes cost-effectiveness for prescription drugs, took a look at Vertex’s suite of cystic fibrosis products. Among ICER’s findings:

“Despite being transformative therapies, the prices set by the manufacturer – costing many millions of dollars over the lifetime of an average patient – are out of proportion to their substantial benefits. When a manufacturer has a monopoly on treatments and is aware that insurers will be unable to refuse coverage, the lack of usual counterbalancing forces can lead to excessive prices. Patients who receive the treatments will benefit, but unaligned prices will cause significant negative health consequences for many unseen individuals.”

That’s Vertex’s current economic model. That’s my worry.

True, diabetes unlike cystic fibrosis is not a rare disease. Something like 1.9 million people in the U.S. have type 1 diabetes, which makes it more than 50 times as common as cystic fibrosis. And most insulin actually goes to people with type 2 diabetes that can’t be managed well by other medications, who would also be candidates for cell treatment.

So, given this widespread need, would diabetes be different? The sad story of insulin, which people with type 1 need to stay alive, says not.

Insulin has been available around the world for decades and costs maybe $3/vial to manufacture. But about one in four people dependent on insulin in the U.S. go through periods when they can’t afford the surprising high pricetags for the drug, whose lack immediately puts those folks at truly serious risk. A small number of them die.

Lilly, Novo Nordisk and Sanofi see that situation as a minor public relations problem. And despite an ever-expanding public chorus of cries for cheaper insulin, insulin provisions magically disappeared last week from the pending Senate bill on medications.

Moreover, in a problem extending far beyond the realm of diabetes, nobody knows what limits will be set on costs for cell therapies, those shiny super-powered new kids on the block.

Partly the charges for these treatments will be based on actual effectiveness and value, as per ICER analyses. Beyond that, we might expect biotechs to follow the classic pricing strategy here: charge as much as you can while keeping a straight face. In preliminary public discussions of pricing, cell treatments often are lumped together with the gene therapies that generally seem to cost more than a million bucks.

My guess is that Vertex will create successful cell therapies for type 1 diabetes in my lifetime. My hope is that everyone who desperately needs these therapies can afford them. I’m a little less hopeful now.

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Lacking the smarts for smart insulins

In an era of science-fiction medicine, why can’t we engineer the hormone to adjust itself?

More than 40 years ago, diabetes researchers began trying to modify insulin so that it would be released in just the right amounts at the right time, to keep blood glucose levels in a good range.

Today, there’s no such smart insulin in the clinic or apparently even in clinical trials.

Why not?

Designer insulins keep millions of people with type 1 diabetes alive and improve the health of many millions more with advanced type 2 diabetes. But to over-generalize only slightly, these folks always have the wrong amounts of insulin circulating. Too little insulin, and people are prone to nasty long-term complications, including heart and kidney failure. Too much, and they can pass out within minutes from low blood glucose levels.

So, the quest for smart insulins is still underway in labs around the world. Occasionally smart insulin expertise gets purchased by a large pharmaceutical company. Sometimes those initiatives proceed into early clinical trials. Which fail.

Meanwhile, diabetes afflicts more than 400 million people and is ramping up. The annual insulin market is at least around $30 billion. Smart insulins could grab the lion’s share and become some of the best-selling medicines in history.

Perhaps we are waiting on conceptual breakthroughs, because insulin is a famously tricky protein and a keystone of human metabolism. Perhaps only Big Pharma firms have the necessary scientific chops, clinical experience, funds and oh yeah patents to pull it off.

But really, what’s the logjam? How will it be broken?

Designer insulins Humalog, Tresiba and Novolog, courtesy Protein Data Bank.

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Quest for beta understanding

Biologists patiently unravel the mysteries of insulin-producing cells.

While we stay tuned to Covid-19, biomedical researchers keep reporting major progress on other fronts. Here are three recent papers on key questions about the insulin-producing pancreatic beta cells that are wiped out in type 1 diabetes.

1. Why are beta cells so prone to autoimmune attack? “There is mounting evidence that type 1 diabetes is a disease not only of autoimmunity, but also of the target beta cell itself,” say Roberto Mallone of the University of Paris and Decio Eizirik of the Free University of Brussels.

In a Diabetologia paper, the scientists analyze three main weaknesses of beta cells.

First, cranking out insulin and other proteins in high volume “is a stressful job,” so the cells are likely to show signs of inflammation and compensate in various ways that are not healthy in the long run, thus worrying the immune system. Second, the pancreatic islets where beta cells live are closely embraced by blood vessels, “which favours face-to-face encounters between immune cells and beta cells.” Third, insulin and related proteins flow directly into the networks of blood vessels and can raise alarms at a distance.

“Agents aimed at limiting the autoimmune vulnerability of beta cells should find their place in the search for disease-modifying treatments, either alone or in combination with immunotherapies,” the authors suggest.

2. Can we create islet organoids with not only beta cells but their islet buddies? Beta cells probably live most happily in pancreatic islet neighborhoods with their homies—other endocrine cells. So, ideally, we would replace the beta cells destroyed in type 1 diabetes with complete islets. Good news, we now can create organoids, 3D tissues with multiple cell types derived from stem cells.

In a Nature paper, Ron Evans of the Salk Institute and colleagues report human islet-like organoids (HILOs) that indeed act very much like islets in controlling blood glucose levels when transplanted into mouse models of type 1 diabetes.

More dramatically, HILOs can do this even in mice with working immune systems, by expressing a cell-surface protein called PD-L1. (An enormous amount of cancer research has laid out how proteins such as PD-L1 can ward off immune-system cells.)

3. Are there better methods to transplant beta cells and other islet cells? For decades, researchers have struggled to find practical ways to embed these cells into people with type 1 diabetes. The most successful route has been the “Edmonton protocol” developed more than 20 years ago at the University of Alberta. Here, islet cells from cadavers are infused into a vein going into the livers of people with particularly difficult-to-control disease. These recipients then are put on immunosuppressive drugs. The treatment is often initially successful but the cells typically die within a few years. And donor islets will always be in extremely short supply.

Fortunately, with stem cell technologies engineered by Doug Melton’s Harvard lab and other groups, we now can grow remarkably beta-like cells in high volumes. These cells release hormones directly into the bloodstream, so they could in theory work well enough in many locations around the body. The transplants would be tiny.

But keeping the implanted cells well and active raises many tough challenges—especially in guarding them from the immune system while they stay fully connected to blood vessels.

Many labs have grappled with this paradox for many years. Startup companies are building clever encapsulation devices but none of these capsules has proven itself in clinical trials. (One intriguing candidate made by Semma Therapeutics, which Melton cofounded, vanished from public view after biotech giant Vertex Therapeutics paid almost $1 billion for the startup.)

Last week in a Nature Metabolism paper, Ali Naji and coworkers at the University of Pennsylvania gave details on an unusual approach with no device at all. Instead, islets were harbored within a mixture mostly made up of collagen (connective protein). This “islet viability matrix” (IVM) then was injected under the skin—a very handy site for transplants, if workable.

IVM proved highly promising in experiments with mouse, pig and human islet cells in various animal models of diabetes, including some animals with working immune systems. One part of the recipe is that the matrix seems to activate a molecular pathway with multiple mechanisms that protect beta cells. IVM “represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type 1 diabetes,” the UPenn team claims.

In an accompanying commentary, Thierry Berney and Ekaterine Berishvili of the University of Geneva School of Medicine note that the IVM strategy could include beta cell protective measures that might range from novel biomaterials to amniotic cells that act as shields. “This method is technically simple, minimally invasive in easily accessible sites and acceptable from a regulatory standpoint,” they conclude. “The door is now wide open for the initiation of a pilot clinical trial.”

Beta cells image courtesy the lab of Douglas Melton at Harvard.

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Crossing the Ts in diabetes

Advances in cancer immunotherapy may help autoimmune therapies defend themselves.

allogeneic label

Is human immunology basically too crazy complex for the human mind? Evidence to date suggests yes, at least for my mind.

In almost every story I write about cancer immunology or autoimmune disease, I learn about previously unknown (to me) functions within the three-ring circus of immune cells. Or I find out about yet more types of these cells, like double-negative T cells, which can defend against graft disease and maybe type 1 diabetes. Who knew?

Well, yeah, thousands of immunologists.

All of us who follow cancer research, though, do know a (simplified) version of one genuine breakthrough in immunology, checkpoint blockade inhibitors, which garnered Nobel Prizes last October.

These drugs take on one of deepest questions in cancer biology: why the immune system doesn’t snuff out cancer cells, which by definition are genetically abnormal, often wildly abnormal.

Checkpoint blockades can hold off the T cells on patrol for just such outsiders. It turns out that a protein on the surface of tumor cells called PD-L1 can grab onto a surface protein on the T cell called PD-1 and so disarm the T cell. (Nothing to look at here, officer! Ignore my multiple heads and antitank guns!)

Other headlines in cancer immunotherapy come from chimeric antigen receptor T (CAR-T) cell drugs, treating patients with certain blood cancers in which B cells go bad. The two such drugs with FDA approval work by taking T cells from the patients, reengineering the T cells to attack those cancerous B cells, and reinserting the T cells.

This method is often effective when nothing else works, but is always worryingly slow and extremely costly.

So there’s plenty of work in labs, and a few clinics, to take a logical but intimidating next step: Engineering off-the shelf T cells to do the job, hiding them from each patient’s immune system with tricks learned from checkpoint blockade research and similar  immunology findings.

Still with me?

Okay, if those cell-shielding techniques eventually work, can a similar attack be made in autoimmune diseases such as type 1 diabetes?

In type 1 diabetes, effective ways to stop the autoimmune attacks from trigger-happy T cells exist only in lab mice. And that’s a problem not just in slowing or stopping disease progression but in trying to treat it. The most promising current approach is to encapsulate insulin-producing beta cells. This has been pursued for many decades, with many barriers. Perhaps the highest (if least surprising) barrier is that the capsules always get clogged up.

The latest capsule approaches, starting with beta cells made by reprogramming cells, try sophisticated material-science strategies to blunt this attack and may do much better.

But as long as we’re already playing genetic games with those engineered beta cells, why not also try  immune-evading tricks similar to those being studied in CAR-T experiments?

That’s the basic idea behind efforts by Altheascience, a Viacyte/CRISPR Therapeutics collaboration, and others. Which just maybe will produce capsules that, replaced every year or so as necessary, are working cures for type 1 diabetes. Which we would all fully understand.

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Raging hormone

Why is insulin so expensive in this country?GoFundMe insulin

We run on sugar, and sugar needs insulin to get into our cells. It’s no surprise that insulin was the first genetically engineered drug, approved by the FDA in 1982. Synthetic insulin keeps millions of people with type 1 diabetes, and a greater number of people with type 2 diabetes, alive.

Basic research keeps turning up surprises about the hormone—its starring roles in the brain, for instance, and its production by some viruses.

Drug companies mostly focus, though, on fiddling with how quickly the body absorbs it. Insulin variants that work either very quickly or very slowly are very important, but why can’t we have insulin that doesn’t need refrigeration? Or “smart insulin” that responds to blood glucose levels, first proposed when Jimmy Carter was president? Although Sanofi supports interesting projects aimed at smart insulin, as do the other market leaders Novo Nordisk and Lilly, there’s little visible progress toward the clinic.

But the biggest question about insulin is: Why is it so expensive in this country?

A 2016 study published in JAMA, for instance, showed that insulin costs doubled between 2002 and 2013. This trend is only accelerating, because there’s no price competition. Irl Hirsch, an endocrinologist at the University of Washington, summarized the story well in an ADA presentation back in 2016 and his points still apply. Year after year,  extremely profitable drug makers and pharmacy benefit managers point their fingers at each other. But as Hirsch noted, “we can point our fingers at everyone.”

New entries such as Basaglar, the first biosimilar insulin approved by the FDA, delayed by predictable patent battles but now available, don’t seem to change the story.

And the story has plenty of human faces. Among them was Shane Patrick Boyle, who died a year ago, unable to raise the money to buy insulin for his type 1 as he saved up for his mother’s funeral. Look at GoFundMe today to see similar personal pleas for help.

As with every other problem in healthcare cost, there are no simple solutions.

One new approach comes from the Open Insulin Project and similar biohacking groups that are making worthy efforts to create generic insulins. But those are  only early steps in the process, and clinical trials are too expensive to crowdfund.

You can argue that in a more rational world, the federal government would step in. Why not launch a 28th National Institute of Health that develops selected high-value high-need generics and biosimilars, brings them through clinical testing and into the clinics? Or simply control the costs of crucial drugs, lowering prices in the years after generics or biosimilars enter the market, as Australia apparently is now doing? OK, not likely. But what actually would help?

 

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Moving the needles

Updates on progress in research against type 1 diabetes.

BetaBionics

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!
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Beta living through stem cells

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

insulin

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.”

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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.

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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.