cell therapy

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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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Type 1 diabetes goes on trial

2022 will offer many clinical clues on cell therapies for insulin-dependent disease.

This year might be make or break for several ambitious cell therapies designed to treat type 1 diabetes, a thoroughly puzzling and dangerous disease. Some clinical projects to watch:

Viacyte and CRISPR Therapeutics are launching a Canadian trial that will be the first in humans with insulin-producing beta cells that are genetically re-engineered to dodge the immune system with little or no immunosuppression drugs.*

Viacyte has been plugging away valiantly on therapies with beta cells derived from stem cells for more than 20 years. Results have been mixed. Most recently, two papers published in December showed partial success with partially differentiated pluripotent cells embedded in Viacyte’s latest capsule (above left), which is open to blood vessels and requires immunosuppression.

“It is the first reported evidence that differentiated stem cells implanted in patients can generate meal-regulated insulin secretion, offering real hope for the incredible potential of this treatment,” said James Shapiro of the University of Alberta, lead author on a Cell Reports Medicine paper. But only six of the 17 subjects in the study showed signs of significant insulin production and no clinical benefit was demonstrated, although that goal apparently was achieved for one subject enrolled later in the trial.

CRISPR Therapeutics will bring its genetic editing wizardry to create allogeneic (off-the-shelf rather than individually tailored) beta cells for the Canadian trial. The company first deployed this strategy in CAR-T cells, treating patients with B-cell blood cancers with allogeneic T cells. First results for the CAR-T trial appeared in October in a news release rather than a peer-reviewed paper. My non-expert guess is that the allogeneic engineering tricks worked fairly well, with the obvious caveats that blood cancers are very different from diabetes, these are very early days, and the type 1 autoimmune attack takes no prisoners.

This first generation of off-the-shelf-we-hope CAR-T cells combines tweaks to T-cell-specific proteins with removal of one class of major histocompatibility complex (MHC) proteins, which help T cells distinguish your own cells from outside threats. CRISPR Therapeutics may make additional immune-dodging engineering changes to its beta cells, among them immune checkpoint proteins (which reassure T cells that the cell is a good citizen) and/or suicide genes that can wipe out the cells if they go wrong and an otherwise non-toxic drug is administered.

Vertex Pharmaceuticals continues its early trial of stem-cell-derived beta cells with immunosuppressive drugs, which did restore one patient with type 1 to relative normality, which was mislabeled as a cure by the NY Times.

This year the large biotech hopes to launch a followup study that would package these cells in a capsule to bypass or minimize the need for immunosuppression drugs. The capsule builds on implantable device research acquired along with cell technology based on discoveries in Doug Melton’s Harvard lab when it bought Semma Therapeutics in 2019. “Semma has developed a very clever and effective encapsulation device,” Melton told me then. Details on the device or its performance aren’t public although there may be hints in Vertex patents (see one image from a patent application below).

Last week Sernova announced early results of a trial with its “Cell Pouch” (above right). Two participants achieved insulin independence, one of them for more than 21 months. “We believe Sernova is the first company to report that its first two transplanted T1D cell therapy study patients achieved sustained insulin independence,” said chief executive Philip Toleikis. The trial used immunosuppressive drugs and islet cells (clusters of cells in the pancreas that include beta cells and other hormone-producing cells) from cadavers (rather than the stem-cell-derived cells that are becoming available in vastly greater quantities).

“The Cell Pouch,” Sernova says, “is designed as a scaffold made of non-degradable polymers, formed into small cylindrical chambers which, when implanted in the abdominal wall, becomes incorporated with tissue and microvessels to the circumference of removable plugs within as early as two weeks as demonstrated in preclinical studies. After the tissue incorporation, the plugs are removed, leaving fully formed tissue chambers with central void spaces for the transplantation of therapeutic cells.”

2021 was not a good year for another corporate contender in encapsulated cell therapies, Sigilon Therapeutics. The FDA stopped the clinical trial for its lead candidate for hemophilia and then Sigilon found that in one trial participant its cell-holding microcapsules were becoming covered with fibers. Last fall, the company put hemophilia on hold and laid off more than a third of its employees. Sigilon is still partnering with Lilly on type 1 diabetes but there’s still no FDA approval for a clinical study.

Over in academia, scientists at the University of Miami are continuing a trial in which pancreatic islet cells are transplanted into the eyes of people with type 1 who are legally blind in at least one eye. The transplant will go in between the cornea and the iris, a location that seemed promising in animal tests. Recipients will get immunosuppression drugs, but “we believe the eye can confer some benefits that favor long term islet survival and, if we can demonstrate this concretely and over time, we may be able to reduce the anti-rejection drugs,” the researchers say. There’s been some question as to whether this location offers enough space for a sufficiently large transplant for diabetes; one experiment in a monkey suggested that it may.

And one more contender: James Shapiro of the University of Alberta, quoted above re the Viacyte trial, pioneered the Edmonton islet-transplantation protocol that proved cell therapies could work for type 1 diabetes. He is a major figure in the field, involved in a surprisingly broad spectrum of lab and clinical work. I was happy to interview him last year for a Nature story about ramping up cell therapies based on stem cells.

Shapiro and his colleagues are enlisting five participants for a small clinical trial somewhat along the lines of Sernova’s pouch, except without the pouch. That is, the transplant site is prepared in a separate procedure before the transplant. PubMed tells me that Shapiro was leading research in mice for both this concept and the Sernova approach a few years back.

The Shapiro lab’s device-less transplant method “was designed to harness an innate foreign body response in a favorable and controlled manner, to induce growth of new blood vessels to allow the survival of the insulin producing cells without the natural body response to foreign body. Briefly, this site transforms the inhospitable under-the-skin site into a viable location through the temporary implantation of a small tube called an angiocatheter.”

Will such a seemingly simple method work in humans? Let’s hope so. And let’s hope for the best with all the other attempts.

* The first patient in this Viactye/CRISPR Therapeutics trial now has been dosed.

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Celling up

Some stem-cell-based regenerative therapies will draw on cells from individual patients. Some won’t. How will those alternatives shake out?

Regenerative treatments based on induced pluripotent stem cells (iPSCs) fall into two camps, with the cells drawn either from each patient (autologous) or built off-the-shelf from donor cells (allogeneic). Writing for Nature about manufacturing iPSC-based medicines, I’m struck by the large bets being placed on allogeneic approaches, which haven’t yet been proven clinically.

There’s a lot of progress, in the lab, in solving the obvious big problem with these outside cells: reconfiguring them to slide under the radar of your immune system. Experiments aim to copy the molecular mechanisms by which tumors and fetal cells dodge immune bullets, or to remove the major histocompatibility complex (MHC) molecules by which your T cells recognize your own cells, and/or to pull off many other ingenious genetic tricks.

The potential benefits for off-the-shelf treatments are obvious, beginning with better control, availability and cost than painstakingly created individual treatments.

No surprise, cell therapies will not come cheap. Chimeric antigen receptor (CAR) T cell treatments for blood cancers (the remarkable predecessors for today’s cell therapy candidates) cost around a million bucks per patient. That’s too much for large numbers of cancer patients and waaay too much for the chronic conditions suffered by millions such as Parkinson’s disease, diabetes and heart disease.

And as tricky as it is to make autologous CAR-T cells, even years after those treatments have been commercialized, stem-cell-based therapies are even more laborious.

CAR-T cells are genetically modified to create a receptor protein that goes after bad B cells. OK, not easy. But stem-cell-based therapies require vastly greater modifications, in two huge steps. First, the cells must be pulled back to a pluripotent state. Second, these pluripotent cells must be differentiated into neurons or pancreatic islet cells or heart cells. This differentiation process recapitulates normal cell development and requires weeks or months. Each cell line behaves a little differently during this process. The safety and effectiveness of the results are not givens.

So, nice to need to perform all this magic only once!

Among studies of early allogeneic candidates, BlueRock Therapeutics has launched a trial of dopamine-producing cells that might help with Parkinson’s disease. (Curiously, the cells are derived from embryonic stem cells, not iPSCs; understandably, the company isn’t emphasizing that point.) The first of 10 patients received a transplant in June in surgery at Memorial Sloan Kettering.

Notably, the subjects in the BlueRock study will be given drugs to partly suppress the immune reaction.

This downside is one reason Ole Isacson of McLean Hospital, a pioneer in stem-cell-based treatments for Parkinson’s disease who published a key 2015 paper on research in primates, remains in the autologous camp.

“With allogeneic cells in general, there’s still recognition by the immune system, even in the brain, of these foreign cells,” Isacson noted during an Endpoints seminar last month.

Moreover, autologous cells integrate better within the primate brain and deliver better recoveries, said Isacson. He pointed to a March paper by University of Wisconsin researchers showing that autologous dopamine-producing cells functionally outperformed allogeneic cells in rhesus monkeys that model Parkinson’s.

Isacson also suggested that creating individualized stem cells and then redifferentiated therapeutic cells will be done efficiently and affordably in the foreseeable future with closed-loop automated systems such as those being developed by Cellino Biotech.

Talking with researchers in various forms of cell therapies during the past year, I found that many expect walk-before-you-run progress: When and if autologous treatments work, there will be redoubled work on allogeneic alternatives.

“The immune system is an amazing force of nature that can detect the tiniest little differences,” Jeffrey Bluestone of Sonoma Biotherapeutics told me in an interview for a Nature story on regulatory T cells. “Engineering an invisible cell without the immune system ever seeing it will be a challenge… Having said all that, though, I think the field is moving really well in that space.”

Image of iPSC-derived neurons by Matheus Victor of MIT’s Li-Huei Tsai lab.

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Running the Engine for your own cells

MIT’s tough-tech accelerator joins the march toward truly individual therapies.

Sometimes, limitations on a given technology that seem set in stone instead will vanish pretty quickly. That might be happening in the field of cell therapies, where treatments that remove, turbocharge and reinfuse your own cells might seem way too difficult and expensive for all but the deadliest diseases.

But maybe not.

That’s what experts keep telling me as I work on a Nature story about regulatory T cell therapies for autoimmune diseases. Maybe the bring-your-own-cells approach will work out for a number of these conditions, and maybe even we’ll see that in clinics this decade.

If so, these living drugs will be built on progress in immunology, cell engineering for chimeric antigen receptor (CAR) T cell treatments for blood cancers, stem cell research, and genome editing tools headlined by CRISPR-Cas9. And the drugmakers will employ industrial tools provided by startup firms.

Two examples of such infrastructure platforms come from MIT’s Engine, a “tough-tech” accelerator for startup firms that attack global societal problems.

The Engine has placed very few bets on biomedical firms, but Cellino Biotech and Kytopen are exceptions.

Cellino “has the potential to manufacture personalized cell therapies at-scale for the first time,” as co-founder and CEO Nabiha Saklayen puts it. “Progressing towards scalable stem cell manufacturing is the only way to provide personalized cell therapies to all patients.”

“Kytopen aims to transform the cell and gene therapy industry with its microfluidics and electric-field-based platform that can automate and manufacture the genetic engineering of cells 10,000x times faster than current methods,” the company says.

In autoimmune labs and clinics, hopes are high for individualized cell therapies. “In the right context, these cells can be effective in resetting the immune system,” one prominent immunologist told me. “This can be really transformational.”

Image courtesy Doug Melton’s lab at Harvard, now routinely churning out batches of half a billion human cells that act very much like the pancreatic islet cells that fail in type 1 diabetes.

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Unleashing Tregs

Can therapies with defensive T cells fend off autoimmune diseases?

Within months, the FDA probably will approve the first drug to significantly slow the onset of type 1 diabetes among many at high risk of the disease. This success with the monoclonal antibody teplizumab will top three decades of struggles by immunologist Jeffrey Bluestone and partners.

This year, Bluestone launched Sonoma Biotherapeutics to take another giant leap against autoimmune disease—this one via reengineered immune cells.

“Cell therapy is really the next major medicine, but it’s hard and it’s not for the gentle,” Bluestone noted in an intriguing interview with John Carroll of Endpoints posted on September 30.

In Sonoma’s case, the defenders are a special force of T cells—T regulatory (Treg) cells, whose role in life is to prevent the main groups of T cells from shooting the wrong targets. Such rampages gone wrong drive type 1 diabetes, rheumatoid arthritis, lupus and other autoimmune diseases that together afflict more than 50 million in this country.

Rethinking and reconfiguring the Treg cells themselves might bring unique benefits, Bluestone believes.

“Our whole business model is that this is not a chronic treatment,” he told Carroll. “Your immune system is a living thing, so the drug you’re giving has to be a living thing. Otherwise you won’t control these diseases over the long run…. With Tregs, we can create something that might induce tolerance and require only a single therapy.”

Tregs already can act as multitalented natural pharmacies, churning out molecules for repair or regulation or many other cellular jobs, Bluestone pointed out. And since these regulatory cells evolved as brakes for the immune system, they also feature some built-in safety features.

As everywhere else in immunology, many open questions remain on Tregs, Bluestone and co-authors noted in a 2019 Nature Reviews article. Scientists don’t really understand how to distinguish Tregs in lymph nodes from Tregs in tissue, or in which location they’re active, or how to generate the most effective Treg therapeutic cells, or whether Treg cells will survive and keep functioning properly within patients, or….?

When and if these devils in the details are mastered, there’s a chance to build a unique treatment platform for many autoimmune diseases, he said. Maybe the method also will aid selected non-immune diseases such as brain degenerative illnesses.

Sonoma has gathered $70 million in early funding, during a year in which six other Treg companies also debuted. Bluestone applauds the competition: “It’s a great thing for the field.”

Treg cells in red (NIAID).

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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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Talking about regeneration

What experts are telling me about the march of pluripotent stem cell therapies.

Yes, it takes years to translate brilliant science into therapies, and the routes to translation aren’t predictable. Case in point, the California Institute for Regenerative Medicine, launched via state referendum 15 years ago among the excitement about pluripotent embryonic stem cells. The Institute has sponsored 56 clinical trials. By a quick count, only five of these trials are looking at pluripotent stem cells, the remainder testing adult stem cells for regeneration or cancer treatments.

The waters are muddied by hundreds of for-profit “stem cell clinics” that offer treatments with little or no clinical evidence. “There is no scientific basis for what these people are doing,” one prominent researcher told me. “It’s very important to draw a distinction between the malpractice and quackery of these unsubstantiated stem cell clinics and the incredibly high-tech serious science that is using all of the new targeted approaches to improve patient outcomes for really terrible diseases.”

Therapies based on induced pluripotent stem cells (iPSCs) are entering early studies. The first iPSC clinical trial for Parkinson’s disease launched last year in Japan, for example. jCyte kicked off a successful first trial to treat a degenerative eye condition in 2017 and should post early results of a follow-up study soon. Studies for cardiac condition are likely to launch in 2020, one based on research shown successful in macaques. Also next year, Sigilon Therapeutics expects to kick off a study for hemophilia A, and Semma Therapeutics is planning trials for insulin-producing pancreatic beta cells for type 1 diabetes. “I’m happy to tell you that Semma has solved the production problem for beta cells,” co-founder Douglas Melton told me.

Labs are gearing up for off-the-shelf cell therapies, by engineering “universal donor cells” that dodge immune reaction and/or retraining T cells and other bodyguards of the immune system. This is a very long road with many complexities and safety concerns. But progress is being made, with one example this year from Melton and colleagues.

Other researchers seek to apply what we’re learning about cell plasticity to form  desired cells directly within the body. Kristen Johnson of Scripps Research’s Calibr institute, for instance, leads a trial of a small molecule designed to make healthy new knee cells. At an earlier stage, diabetes researchers aim to develop insulin-producing cells by altering pancreatic alpha cells or a recently found population of pancreatic progenitor cells. Startups OxStem and Sana Biotechnology have wildly ambitious programs in this space.

We’ll see what actually translates but the scientists I talk with believe that stem cell research will change medicine dramatically and it won’t take 15 more  years.

Images courtesy Harvard Stem Cell Institute. On left, mouse induced muscle progenitor cells at various stages of differentiation, from Konrad Hochedlinger’s lab. Top right, human green kidney cells and red blood vessels, from work led by Jennifer Lewis and Ryuji Morizane. Bottom right, from the Melton lab, two clusters of human insulin-producing cells (pink), the cluster on the right demonstrating enrichment of these cells.

 

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Capsule cures get beta

We’ve learned how to churn out zillions of insulin-producing cells and maybe even guard them from the immune system for a year or two.

The commercial “stem cell clinics” that have popped up across the U.S. like mosquitoes after rain, offering treatments with little clinic evidence, typically begin with the patient’s own cells. But the stem-cell-based therapies that will soon fundamentally change regenerative medicine will come off the shelf. Case in point, the insulin-producing treatments for type 1 diabetes that I’ve just covered in The Scientist, which are headed for the clinic in the next year or two. Scientists are mastering ways to make reasonably functional beta cells in high volume. ViaCyte is readying a new version of its capsule that doesn’t require immunosuppression and expects to resume clinical trials soon. Semma Therapeutics and Sigilon Therapeutics are reporting progress in pre-clinical studies. Fingers crossed here, but definite progress.

Images courtesy Sigilon Therapeutics.

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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.