New therapy may improve stem cell transplants for blood cancers
Ivan Dimov, Jeroen Bekaert and Nate Fernhoff - pictured here - recognized the need for a more effective cell sorting technology to reduce the risk of Graft vs Host disease, which affects many cancer patients after receiving stem cell transplants.
In 2018, Robyn was diagnosed with myelofibrosis, a blood cancer causing chronic inflammation and scarring. As a research scientist by training, she knew she had limited options. A stem cell transplant is a terminally ill patient's best chance for survival against blood cancers, including leukaemia. It works by destroying a patient's cancer cells and replacing them with healthy cells from a donor.
However, there is a huge risk of Graft vs Host disease (GVHD), which affects around 30-40% of recipients. Patients receive billions of cells in a stem cell transplant but only a fraction are beneficial. The rest can attack healthy tissue leading to GVHD. It affects the skin, gut and lungs and can be truly debilitating.
Currently, steroids are used to try and prevent GVHD, but they have many side effects and are effective in only 50% of cases. “I spoke with my doctors and reached out to patients managing GVHD,” says Robyn, who prefers not to use her last name for privacy reasons. “My concerns really escalated for what I might face post-transplant.”
Then she heard about a new highly precise cell therapy developed by a company called Orca Bio, which gives patients more beneficial cells and fewer cells that cause GVHD. She decided to take part in their phase 2 trial.
How It Works
In stem cell transplants, patients receive immune cells and stem cells. The donor immune cells or T cells attack and kill malignant cells. This is the graft vs leukaemia effect (GVL). The stem cells generate new healthy cells.
Unfortunately, T cells can also cause GVHD, but a rare subset of T cells, called T regulatory cells, can actually prevent GVHD.
Orca’s cell sorting technology distinguishes T regulatory cells from stem cells and conventional T cells on a large scale. It’s this cell sorting technology which has enabled them to create their new cell therapy, called Orca T. It contains a precise combination of stem cells and immune cells with more T regulatory cells and fewer conventional T cells than in a typical stem cell transplant.
“Ivan Dimov’s idea was to spread out the cells, keep them stationary and then use laser scanning to sort the cells,” explains Nate Fernhoff, co-founder of Orca Bio. “The beauty here is that lasers don't care how quickly you move them.”
Over the past 40 years, scientists have been trying to create stem cell grafts that contain the beneficial cells whilst removing the cells that cause GVHD. What makes it even harder is that most transplant centers aren’t able to manipulate grafts to create a precise combination of cells.
Innovative Cell Sorting
Ivan Dimov, Jeroen Bekaert and Nate Fernhoff came up with the idea behind Orca as postdocs at Stanford, working with cell pioneer Irving Weissman. They recognised the need for a more effective cell sorting technology. In a small study at Stanford, Professor Robert Negrin had discovered a combination of T cells, T regulatory cells and stem cells which prevented GVHD but retained the beneficial graft vs leukaemia effect (GVL). However, manufacturing was problematic. Conventional cell sorting is extremely slow and specific. Negrin was only able to make seven highly precise products, for seven patients, in a year. Annual worldwide cases of blood cancer number over 1.2 million.
“We started Orca with this idea: how do we use manufacturing solutions to impact cell therapies,” co-founder Fernhoff reveals. In conventional cell sorting, cells move past a stationary laser which analyses each cell. But cells can only be moved so quickly. At a certain point they start to experience stress and break down. This makes it very difficult to sort the 100 billion cells from a donor in a stem cell transplant.
“Ivan Dimov’s idea was to spread out the cells, keep them stationary and then use laser scanning to sort the cells,” Fernhoff explains. “The beauty here is that lasers don't care how quickly you move them.” They developed this technology and called it Orca Sort. It enabled Orca to make up to six products per week in the first year of manufacturing.
Every product Orca makes is for one patient. The donor is uniquely matched to the patient. They have to carry out the cell sorting procedure each time. Everything also has to be done extremely quickly. They infuse fresh living cells from the donor's vein to the patient's within 72 hours.
“We’ve treated almost 200 patients in all the Orca trials, and you can't do that if you don't fix the manufacturing process,” Fernhoff says. “We're working on what we think is an incredibly promising drug, but it's all been enabled by figuring out how to make a high precision cell therapy at scale.”
Clinical Trials
Orca revealed the results of their phase 1b and phase 2 trials at the end of last year. In their phase 2 trial only 3% of the 29 patients treated with Orca T cell therapy developed chronic GVHD in the first year after treatment. Comparatively, 43% of the 95 patients given a conventional stem cell transplant in a contemporary Stanford trial developed chronic GVHD. Of the 109 patients tested in phase 1b and phase 2 trials, 74% using Orca T didn't relapse or develop any form of GVHD compared to 34% in the control trial.
“Until a randomised study is done, we can make no assumption about the relative efficacy of this approach," says Jeff Szer, professor of haematology at the Royal Melbourne Hospital. "But the holy grail of separating GVHD and GVL is still there and this is a step towards realising that dream.”
Stan Riddell, an immunology professor, at Fred Hutchinson Cancer Centre, believes Orca T is highly promising. “Orca has advanced cell selection processes with innovative methodology and can engineer grafts with greater precision to add cell subsets that may further contribute to beneficial outcomes,” he says. “Their results in phase 1 and phase 2 studies are very exciting and offer the potential of providing a new standard of care for stem cell transplant.”
However, though it is an “intriguing step,” there’s a need for further testing, according to Jeff Szer, a professor of haematology at the Peter MacCallum Cancer Centre at the Royal Melbourne Hospital.
“The numbers tested were tiny and comparing the outcomes to anything from a phase 1/2 setting is risky,” says Szer. “Until a randomised study is done, we can make no assumption about the relative efficacy of this approach. But the holy grail of separating GVHD and GVL is still there and this is a step towards realising that dream.”
The Future
The team is soon starting Phase 3 trials for Orca T. Its previous success has led them to develop Orca Q, a cell therapy for patients who can't find an exact donor match. Transplants for patients who are only a half-match or mismatched are not widely used because there is a greater risk of GVHD. Orca Q has the potential to control GVHD even more and improve access to transplants for many patients.
Fernhoff hopes they’ll be able to help people not just with blood cancers but also with other blood and immune disorders. If a patient has a debilitating disease which isn't life threatening, the risk of GVHD outweighs the potential benefits of a stem cell transplant. The Orca products could take away that risk.
Meanwhile, Robyn has no regrets about participating in the Phase 2 trial. “It was a serious decision to make but I'm forever grateful that I did,” she says. “I have resumed a quality of life aligned with how I felt pre-transplant. I have not had a single issue with GVHD.”
“I want to be able to get one of these products to every patient who could benefit from it,” Fernhoff says. “It's really exciting to think about how Orca's products could be applied to all sorts of autoimmune disorders.”
Technology is Redefining the Age of 'Older Mothers'
Scientists are working on technologies that would enable more 70-year-old women to have babies.
In October 2021, a woman from Gujarat, India, stunned the world when it was revealed she had her first child through in vitro fertilization (IVF) at age 70. She had actually been preceded by a compatriot of hers who, two years before, gave birth to twins at the age of 73, again with the help of IVF treatment. The oldest known mother to conceive naturally lived in the UK; in 1997, Dawn Brooke conceived a son at age 59.
These women may seem extreme outliers, almost freaks of nature; in the US, for example, the average age of first-time mothers is 26. A few decades from now, though, the sight of 70-year-old first-time mothers may not even raise eyebrows, say futurists.
“We could absolutely have more 70-year-old mothers because we are learning how to regulate the aging process better,” says Andrew Hessel, a microbiologist and geneticist, who cowrote "The Genesis Machine," a book about “rewriting life in the age of synthetic biology,” with Amy Webb, the futurist who recently wondered why 70-year-old women shouldn’t give birth.
Technically, we're already doing this, says Hessel, pointing to a technique known as in vitro gametogenesis (IVG). IVG refers to turning adult cells into sperm or egg cells. “You can think of it as the upgrade to IVF,” Hessel says. These vanguard stem cell research technologies can take even skin cells and turn them into induced pluripotent stem cells (iPSCs), which are basically master cells capable of maturing into any human cell, be it kidney cells, liver cells, brain cells or gametes, aka eggs and sperm, says Henry T. “Hank” Greely, a Stanford law professor who specializes in ethical, legal, and social issues in biosciences.
Mothers over 70 will be a minor blip, statistically speaking, Greely predicts.
In 2016, Greely wrote "The End of Sex," a book in which he described the science of making gametes out of iPSCs in detail. Greely says science will indeed enable us to see 70-year-old new mums fraternize with mothers several decades younger at kindergartens in the (not far) future. And it won’t be that big of a deal.
“An awful lot of children all around the world have been raised by grandmothers for millennia. To have 70-year-olds and 30-year-olds mingling in maternal roles is not new,” he says. That said, he doubts that many women will want to have a baby in the eighth decade of their life, even if science allows it. “Having a baby and raising a child is hard work. Even if 1% of all mothers are over 65, they aren’t going to change the world,” Greely says. Mothers over 70 will be a minor blip, statistically speaking, he predicts. But one thing is certain: the technology is here.
And more technologies for the same purpose could be on the way. In March 2021, researchers from Monash University in Melbourne, Australia, published research in Nature, where they successfully reprogrammed skin cells into a three-dimensional cellular structure that was morphologically and molecularly similar to a human embryo–the iBlastoid. In compliance with Australian law and international guidelines referencing the “primitive streak rule," which bans the use of embryos older than 14 days in scientific research, Monash scientists stopped growing their iBlastoids in vitro on day 11.
“The research was both cutting-edge and controversial, because it essentially created a new human life, not for the purpose of a patient who's wanting to conceive, but for basic research,” says Lindsay Wu, a senior lecturer in the School of Medical Sciences at the University of New South Wales (UNSW), in Kensington, Australia. If you really want to make sure what you are breeding is an embryo, you need to let it develop into a viable baby. “This is the real proof in the pudding,'' says Wu, who runs UNSW’s Laboratory for Ageing Research. Then you get to a stage where you decide for ethical purposes you have to abort it. “Fiddling here a bit too much?” he asks. Wu believes there are other approaches to tackling declining fertility due to older age that are less morally troubling.
He is actually working on them. Why would it be that women, who are at peak physical health in almost every other regard, in their mid- to late- thirties, have problems conceiving, asked Wu and his team in a research paper published in 2020 in Cell Reports. The simple answer is the egg cell. An average girl in puberty has between 300,000 and 400,000 eggs, while at around age 37, the same woman has only 25,000 eggs left. Things only go downhill from there. So, what torments the egg cells?
The UNSW team found that the levels of key molecules called NAD+ precursors, which are essential to the metabolism and genome stability of egg cells, decline with age. The team proceeded to add these vitamin-like substances back into the drinking water of reproductively aged, infertile lab mice, which then had babies.
“It's an important proof of concept,” says Wu. He is investigating how safe it is to replicate the experiment with humans in two ongoing studies. The ultimate goal is to restore the quality of egg cells that are left in patients in their late 30s and early- to mid-40s, says Wu. He sees the goal of getting pregnant for this age group as less ethically troubling, compared to 70-year-olds.
But what is ethical, anyway? “It is a tricky word,” says Hessel. He differentiates between ethics, which represent a personal position and may, thus, be more transient, and morality, longer lasting principles embraced across society such as, “Thou shalt not kill.” Unprecedented advances often bring out fear and antagonism until time passes and they just become…ordinary. When IVF pioneer Landrum Shettles tried to perform IVF in 1973, the chairman of Columbia’s College of Physicians and Surgeons interdicted the procedure at the last moment. Almost all countries in the world have IVF clinics today, and the global IVF services market is clearly a growth industry.
Besides, you don’t have a baby at 70 by accident: you really want it, Greely and Hessel agree. And by that age, mothers may be wiser and more financially secure, Hessel says (though he is quick to add that even the pregnancy of his own wife, who had her child at 40, was a high-risk one).
As a research question, figuring out whether older mothers are better than younger ones and vice-versa entails too many confounding variables, says Greely. And why should we focus on who’s the better mother anyway? “We've had 70-year-old and 80-year-old fathers forever–why should people have that much trouble getting used to mothers doing the same?” Greely wonders. For some women having a child at an old(er) age would be comforting; maybe that’s what matters.
And the technology to enable older women to have children is already here or coming very soon. That, perhaps, matters even more. Researchers have already created mice–and their offspring–entirely from scratch in the lab. “Doing this to produce human eggs is similar," says Hessel. "It is harder to collect tissues, and the inducing cocktails are different, but steady advances are being made." He predicts that the demand for fertility treatments will keep financing research and development in the area. He says that big leaps will be made if ethical concerns don’t block them: it is not far-fetched to believe that the first baby produced from lab-grown eggs will be born within the next decade.
In an op-ed in 2020 with Stat, Greely argued that we’ve already overcome the technical barrier for human cloning, but no one's really talking about it. Likewise, scientists are also working on enabling 70-year-old women to have babies, says Hessel, but most commentators are keeping really quiet about it. At least so far.
New Cell Therapies Give Hope to Diabetes Patients
Researchers are developing new cell therapies that could cure Type 1 diabetes and make constant management of the disease a way of the past.
For nearly four decades, George Huntley has thought constantly about his diabetes. Diagnosed in 1983 with Type 1 (insulin-dependent) diabetes, Huntley began managing his condition with daily finger sticks to check his blood glucose levels and doses of insulin that he injected into his abdomen. Even now, with an insulin pump and a device that continuously monitors his glucose, he must consider how every meal will affect his blood sugar, checking his monitor multiple times each hour.
Like many of those who depend on insulin injections, Huntley is simultaneously grateful for the technology that makes his condition easier to manage and tired of thinking about diabetes. If he could wave a magic wand, he says, he would make his diabetes disappear. So when he read about biotechs like ViaCyte and Vertex Pharmaceuticals developing new cell therapies that have the potential to cure Type 1 diabetes, Huntley was excited.
You also won’t see him signing up any time soon. The therapies under development by both companies would require a lifelong regimen of drugs for suppressing the immune system to prevent the body from rejecting the foreign cells. It’s a problem also seen in the transplant of insulin-producing cells of the pancreas – called islet cells – from deceased donors. To Howard Foyt, chief medical officer at ViaCyte, a San Diego-based biotech specializing in the development of cell therapies for diabetes, the tradeoff is worth it.
“A lot of the symptoms of diabetes are not something that you wear on your arm, so to speak. You’re not necessarily conscious of them until you’re successfully treated, and you feel better,” Foyt says.
For many with diabetes, managing these symptoms is a constant game of Whack-a-Mole. “Any form of treatment that gets someone closer to feeling good is a victory,” he says.
“Am I going to be trading diabetes for cancer? That’s not a chance I
want to take."
But not everyone is convinced. What’s more, it’s likely that the availability of these cell therapies will be limited to those with life-threatening diabetes symptoms, such as hypoglycemia unawareness. To Huntley, these therapies remain a bit of a Faustian bargain.
“Am I going to be trading diabetes for cancer? That’s not a chance I want to take,” he says.
The discovery of insulin in 1921 transformed Type 1 diabetes from a death sentence into a potentially manageable condition. Even as better versions of insulin hit the market—ones that weren’t derived from pigs and wouldn’t provoke an allergic response, longer-acting insulin, insulin pens—they didn’t change the reality that those with Type 1 diabetes remained dependent on insulin. Even the most advanced continuous glucose monitors (which tests blood sugar levels every few minutes, 24/7) and insulin pumps don’t perform as well as a healthy pancreas.
Whether by injection or pump, someone with diabetes needs to administer the insulin their body no longer makes. With advances in organ transplantation, the concept of transplanting insulin-producing pancreatic beta cells seemed obvious. After more than a decade of painstaking work, James Shapiro, who directs the Islet Transplant Program at the University of Albania, honed a process called the Edmonton Protocol for pancreas transplants. For a few patients who couldn’t control their blood sugars any other way, the Edmonton Protocol became a life saver. Some of these patients were even able to stop insulin completely, Shapiro says. But the high cost of organ transplant and a chronic shortage of donor organs, pancreas or otherwise, meant that only a small handful of patients could benefit.
Stem cells, however, can be grown in vats, meaning that supply would never be an issue. “We would be going from a very successful treatment of today to a potential cure tomorrow,” Shapiro says.
In 2014, spurred by his own children’s diagnoses with Type 1 Diabetes, stem cell biologist Doug Melton of Harvard University figured out a way to differentiate embryonic stem cells into functional pancreatic beta cells. It was a long process, explains immunoengineer Alice Tomei at the University of Miami, because “the islet is not one cell, it's like a mini-organ that has its own needs.”
Add on the risk of rejection and autoimmunity, and Tomei says that scientists soon realized that chronic and systemic immunosuppression was the only way forward. Over the next several years, Melton improved his approach to yield more cells with fewer impurities. Melton partnered with Boston-based Vertex Pharmaceuticals to create a cell therapy called VX-880.
The first patient received his dose earlier in 2021. In October, Vertex released 90-day results from the Phase 1/2 trial, which revealed the patient was able to reduce his insulin usage from an average of 34 units per day to just 2.9 units per day. The tradeoff is a lifelong need for immunosuppressive drugs to prevent the body from attacking both foreign cells and pancreatic beta cells. It’s what recipients of ViaCyte’s first-gen PEC-Direct will also need. For Foyt, it’s an easy choice.
“At this point in time, immunosuppression is the necessary evil,” he says. “For parents, would you like to worry about going into your child’s bedroom every morning and not knowing if they’re going to be alive or dead? It’s uncommon, but it does occur.”
Not everyone, however, finds the trade-off easy to swallow. Especially with COVID-19 cases reaching record highs, the prospect of reducing his immune function at a time when he needs it most doesn’t sit well with Huntley. The risks of immunosuppression also mean that diabetes cell therapies are limited to those patients with life-threatening complications.
It’s why ViaCyte has created two new iterations of cellular therapies that would eliminate this need. The ViaCyte-Encap contains the cells in a permeable container that allows oxygen, insulin, and nutrients to flow freely but prevents immune system access. Their latest model, PEC-QT, just began safety trials with Shapiro’s lab at the University of Alberta and uses gene editing to eliminate any cellular markers that would trigger an immune response.
Sanjoy Dutta, vice president of research at JDRF International, a nonprofit that funds the study of diabetes, is thrilled with the progress that’s been made around cell therapies, but he cautions it’s still early days. “We have proven that these cells can be made. What we haven’t seen is are they going to work for six months, two years, five years? It’s a challenge we still need to overcome,” he says.
Iowa social worker Jodi Lynn’s concerns echo Dutta’s. Lynn was diagnosed with diabetes in 1998 at age 14 after a bout of severe influenza, spends each day inventorying supplies, planning her food intake, and maintaining her insulin pump and glucose monitor. These newer technologies dramatically improved her blood sugar control but, like everyone with diabetes, Lynn remains at high risk for complications, such as diabetic ketoacidosis, heart disease, vision loss, and kidney failure. Lynn, already considered immunocompromised due to medications she takes for another autoimmune condition, is less concerned with immune suppression than the untested nature of these therapies.
“I want to know that they will work long-term,” she says.