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.
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.”
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.
Maybe the culprit in type 1 diabetes isn’t T cells gone bad.
Follow diabetes research and you start obsessing about beta cells—maybe a gram of cells buried across the pancreas that produce the insulin we need to live. Or stop producing it, in the case of type 1 diabetes.
These cells are heroic microbeasts. “The beta cell is a wonder of nature,” Bart Roep of the City of Hope National Medical Center told me during an interview for a Knowablestory. “It’s the hardest-working cell in our body. Every second, each beta cell can make two thousand molecules of insulin; that’s daunting. It also has to be able to release insulin when it’s needed and only when it’s needed.”
In type 1 diabetes, some mix of fairly well understood genetics and not very well understood environmental factors goes wrong. T cells go haywire and begin to wipe out beta cells. So type 1 is described as an autoimmune disease in tens of thousands of research papers.
But maybe things work the other way around: Beta cells stress out and misbehave, and the immune system is just doing its job.
“I actually think that type 1 diabetes is not an immune problem, it is a beta cell problem,” said Roep.
He and his colleagues laid out some evidence in a 2017 Nature Medicinearticle. “We showed that if beta cells get stressed, which they do very quickly, they produce new antigens like those that expose cancers and infections to the immune system,” he noted.
“I now contend that the immune system is not making a mistake,” Roep said. “It’s the beta cell, and the immune system is actually responding with the best intentions, namely to target stressed tissue… The immune system is not interested in happy tissue.”
Roep is not the only prominent scientist who questions the T-cells-gone-wrong framework for type 1. At the Joslin International Symposium last month in Boston, Olle Korsgren of Uppsala University made another case, skimming through decades of studies on human pancreatic tissue samples analyzed by many researchers.
Among his points, Korsgren cited data suggesting that the T cell attack is surprisingly weak, this attack goes after the whole pancreas rather than just beta cells, and there are frequent signs of beta cell stress such as bleeding. “Could bleeding cells attract the immune system?” he asked.
His hypothesis: Type 1 is not an autoimmune disease that targets beta cells. Rather, it’s an inflammatory disease affecting the entire pancreas. Moreover, the inflammation might be driven by gut microbes invading the pancreas next door.
And Korsgren’s theory just might dovetail very nicely with recent research on the role of the gut microbiome in type 1, now well documented in large epidemiological studies and explored in many labs.
Advances in cancer immunotherapy may help autoimmune therapies defend themselves.
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.
An MIT alginate microcapsule holding islet cells (in green) and being covered by immune cells (in blue and magenta). Image credit: Omid Veiseh, Joshua Doloff, Minglin Ma and Arturo Vegas.
There’s a worldwide deficit in insulin-producing beta cells, for people with either type 1 or type 2 diabetes, Harvard’s Doug Melton told a session at the ADA annual scientific conference on Friday.
“It’s a completely non-trivial thing that you can now make billions of human beta cells,” he said. “We spent more than a decade trying to march these cells through this procedure.”
Currently, it takes his lab about 40 days to produce the cells at a cost of about $6,000 per flask, but Melton is confident that these numbers can be chopped down.
The achievement required not only brilliant scientific detective legwork, especially on the last steps of differentiation, but lab drudgework on a dramatic scale.
Picking apart the steps that drive cells into beta shape, “we had to sort out three or four factors at a time,” he noted. The lab ran screens of small molecules to find what combinations were effective. Testing eight small molecules, in three concentrations, for different periods, in triplicate meant about 65,000 combinations to examine per screen.
The lab of MIT bioengineer Dan Anderson, collaborating with Melton to build microcapsules for the beta cells, took high-volume testing to a much higher level for various capsule designs.
Over the decades, many groups have tried to encapsulate beta cells in tiny spheres of alginate. Historically, “all these capsules end up covered in scar tissue,” Anderson told the ADA session.
But after endlessly tweaking the properties of these spheres, “we have a growing list of materials we could use,” he said.
One capsule material seems to work well in mice with strong immune systems—and in very early testing in macaques. Details on the material aren’t yet public, but the secret isn’t in the material’s permeability but in how the immune system reacts to it, Anderson said.
His group’s exhaustive testing also gave clues to how capsule size affects immune scarring. Last month, he and colleagues reported in Nature Materials that 1.5-mm-diameter capsules do better than 0.5-mm structures. Was that a surprise? “It was for us,” Anderson replied. “We thought smaller would be better.”
Each year the percentage of U.S. children diagnosed with type 1 diabetes creeps up, and the average age at which they are diagnosed creeps down. As with so many other autoimmune illnesses, we don’t know what triggers the disease and we don’t know how to prevent it or delay it very long. The history of type 1 prevention trials is not a happy one: Many agents may help some patients to maintain insulin secretion but generally do so only for a few months.
Looking more closely at subgroups within those recently diagnosed with type 1, however, may give us better clues for drug strategies, suggested Carla Greenbaum, director of diabetes research at Benaroya Research Institute in Seattle, in a lecture this month at Joslin Diabetes Center.
If you plot the loss of insulin production over time among these patients and separate the patients by age, you see that “in adults, it’s a completely different pattern,” she said. Children typically are diagnosed with less insulin production and lose it far more quickly than adults.
That pattern argues for some clinical trials that only include children since the benefits of treatment may be easier to spot when the attack is moving so quickly, Greenbaum said. Studying this population may aid in understanding how autoimmune attacks progress in their most active periods, and to clarify whether these periods may include stages of remission and relapse, as found in multiple sclerosis. Moreover, trial groups could be much smaller.
Researchers would, of course, need to maintain exquisite care with this deeply vulnerable population, and to test treatments first in adults to make sure that no harm ensues to children. But we shouldn’t have to show efficacy in adults before we can try to show efficacy in children, she maintained, adding that the FDA hurdle should be efficacy before diagnosis, when the benefits of treatment are potentially far greater.
For decades we’ve had reasonably good tools to identify those at highest risks of type 1, and we can use these tools early on, Greenbaum noted. “To prevent disease, we’ll have to treat it in infancy or the first two years, turning it into a chronic disease like every other autoimmune disease for which we have therapy.”
Eric Bender 