New therapy may improve stem cell transplants for blood cancers

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.

Orca Bio

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.”

Sarah Philip
Sarah Philip is a London-based freelance journalist who writes about science, film and TV. You can follow her on Twitter @sarahph1lip.
DNA gathered from animal poop helps protect wildlife

Alida de Flamingh and her team are collecting elephant dung. It holds a trove of information about animal health, diet and genetic diversity.

Courtesy Alida de Flamingh

On the savannah near the Botswana-Zimbabwe border, elephants grazed contentedly. Nearby, postdoctoral researcher Alida de Flamingh watched and waited. As the herd moved away, she went into action, collecting samples of elephant dung that she and other wildlife conservationists would study in the months to come. She pulled on gloves, took a swab, and ran it all over the still-warm, round blob of elephant poop.

Sequencing DNA from fecal matter is a safe, non-invasive way to track and ultimately help protect over 42,000 species currently threatened by extinction. Scientists are using this DNA to gain insights into wildlife health, genetic diversity and even the broader environment. Applied to elephants, chimpanzees, toucans and other species, it helps scientists determine the genetic diversity of groups and linkages with other groups. Such analysis can show changes in rates of inbreeding. Populations with greater genetic diversity adapt better to changes and environmental stressors than those with less diversity, thus reducing their risks of extinction, explains de Flamingh, a postdoctoral researcher at the University of Illinois Urbana-Champaign.

Analyzing fecal DNA also reveals information about an animal’s diet and health, and even nearby flora that is eaten. That information gives scientists broader insights into the ecosystem, and the findings are informing conservation initiatives. Examples include restoring or maintaining genetic connections among groups, ensuring access to certain foraging areas or increasing diversity in captive breeding programs.

Keep Reading Keep Reading
Gail Dutton
Gail Dutton has covered the biopharmaceutical industry as a journalist for the past three decades. She focuses on the intersection of business and science, and has written extensively for GEN – Genetic Engineering & Biotechnology News, Life Science Leader, The Scientist and BioSpace. Her articles also have appeared in Popular Science, Forbes, Entrepreneur and other publications.
DNA- and RNA-based electronic implants may revolutionize healthcare

The test tubes contain tiny DNA/enzyme-based circuits, which comprise TRUMPET, a new type of electronic device, smaller than a cell.

Courtesy Kate Adamala

Implantable electronic devices can significantly improve patients’ quality of life. A pacemaker can encourage the heart to beat more regularly. A neural implant, usually placed at the back of the skull, can help brain function and encourage higher neural activity. Current research on neural implants finds them helpful to patients with Parkinson’s disease, vision loss, hearing loss, and other nerve damage problems. Several of these implants, such as Elon Musk’s Neuralink, have already been approved by the FDA for human use.

Yet, pacemakers, neural implants, and other such electronic devices are not without problems. They require constant electricity, limited through batteries that need replacements. They also cause scarring. “The problem with doing this with electronics is that scar tissue forms,” explains Kate Adamala, an assistant professor of cell biology at the University of Minnesota Twin Cities. “Anytime you have something hard interacting with something soft [like muscle, skin, or tissue], the soft thing will scar. That's why there are no long-term neural implants right now.” To overcome these challenges, scientists are turning to biocomputing processes that use organic materials like DNA and RNA. Other promised benefits include “diagnostics and possibly therapeutic action, operating as nanorobots in living organisms,” writes Evgeny Katz, a professor of bioelectronics at Clarkson University, in his book DNA- And RNA-Based Computing Systems.

Keep Reading Keep Reading
Kenna Hughes-Castleberry
Kenna Hughes-Castleberry is a writer, podcaster, and science communicator. She currently works as the Science Communicator at JILA and is the Editor-in-Chief of their journal Light & Matter. She is also a freelance science journalist and writes for Inside Quantum Technology as a freelance staff editor. Her beats include deep technology, quantum technology, metaverse technology, and diversity within these industries. Kenna’s work has been featured in various publications including Scientific American, Discover Magazine, Ars Technica, Physics.org, Inside Quantum Technology, The Quantum Insider, The Deep Tech Insider, the Metaverse Insider, The Debrief, and Octonation. She currently sits on the board of SWARM (Science Writers Association of the Rocky Mountains) as well as teaches science writing to graduate students at JILA. You can find her on Twitter and Instagram: @kennaculture