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 its cell-holding microcapsules were becoming covered with fibers in one trial participant. 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.

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.

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.

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).

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.

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.

 

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.

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.

Celling out cancer

As immunotherapies start to change clinical practice, we hope for more.

CI_cover_crop

For a blockbuster drug, pembrolizumab comes with a strange history, nicely told here by David Shaywitz.

Pembro is a “checkpoint inhibitor”, a biologic designed to take the brakes off T cells so that they can wipe out tumors. Back in 2014, it was the first drug that targets the PD-1 protein on the surface of T cells to get FDA approval. Also now known as Keytruda, pembro has received FDA green lights for many kinds of cancers. It accounts for billions of dollars each year and is in more than 500 clinical studies.

But it was born in a small Israeli biotech trying to develop treatments for autoimmune diseases by putting brakes on T cells (yes, the reverse of checkpoint inhibition).  The small biotech that created pembro and realized it was a promising cancer drug candidate was soon bought by a larger pharma firm, which was then acquired by Merck & Co. As Shaywitz notes, the giant pharma shut down development not once but twice, before successful trials of other checkpoint inhibitors changed its mind.

Today pembro comes as a colorless liquid in a small IV pouch, looking very much like saline solution. It lists at around $50 a milligram, one case in point for the extremely real concern about how any country can pay for such drugs as they start to become standard of care.

You don’t think about costs, however, if you’re in a clinic as I was earlier this month, watching a friend with metastatic melanoma joke with the nurse hooking up his IV. You just hope the treatment works.

It’s been a pleasure to edit this month’s Nature Outlook on cancer immunotherapy. Many thanks to the outstanding authors, editors and designers who put it together! And to Elin Svensson, who created the great cover art above.

Blossoms in biomedicine

The remarkable global push for cancer immunotherapies.
El_Talayón.byJose Ignacio Martinez Navarro
Editing a Nature special report on cancer immunotherapies, I’m struck most by the sheer scale of the development effort. Something like 3,000 clinical trials are underway, 800 of them combining treatments. The FDA has approved five checkpoint inhibitors, designed to unleash T cells against tumors. The agency seems close to approving the first CAR-T cell treatment, in which a patient’s T cells are removed, reengineered to attack cancer cells, regrown in volume and returned to the patient. Old dogs of immunotherapies are learning new tricks. Some newer approaches are getting much attention—notably personalized neoantigen vaccines, in which individual tumors are sequenced to give clues on how to best target their unique sets of immune-system-alarming antigens. Some clinical trials fail, some do surprisingly well.  The competition is more than intense and trials are not always carefully planned or analyzed. But the landscape is changing.

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!

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.”