2022 will offer many clinical clues on cell therapies for insulin-dependent disease.
This year might be make or break for several ambitious cell therapies designed to treat type 1 diabetes, a thoroughly puzzling and dangerous disease. Some clinical projects to watch:
Viacyte and CRISPR Therapeutics are launching a Canadian trial that will be the first in humans with insulin-producing beta cells that are genetically re-engineered to dodge the immune system with little or no immunosuppression drugs.*
Viacyte has been plugging away valiantly on therapies with beta cells derived from stem cells for more than 20 years. Results have been mixed. Most recently, two papers published in December showed partial success with partially differentiated pluripotent cells embedded in Viacyte’s latest capsule (above left), which is open to blood vessels and requires immunosuppression.
“It is the first reported evidence that differentiated stem cells implanted in patients can generate meal-regulated insulin secretion, offering real hope for the incredible potential of this treatment,” said James Shapiro of the University of Alberta, lead author on a Cell Reports Medicine paper. But only six of the 17 subjects in the study showed signs of significant insulin production and no clinical benefit was demonstrated, although that goal apparently was achieved for one subject enrolled later in the trial.
CRISPR Therapeutics will bring its genetic editing wizardry to create allogeneic (off-the-shelf rather than individually tailored) beta cells for the Canadian trial. The company first deployed this strategy in CAR-T cells, treating patients with B-cell blood cancers with allogeneic T cells. First results for the CAR-T trial appeared in October in a news release rather than a peer-reviewed paper. My non-expert guess is that the allogeneic engineering tricks worked fairly well, with the obvious caveats that blood cancers are very different from diabetes, these are very early days, and the type 1 autoimmune attack takes no prisoners.
This first generation of off-the-shelf-we-hope CAR-T cells combines tweaks to T-cell-specific proteins with removal of one class of major histocompatibility complex (MHC) proteins, which help T cells distinguish your own cells from outside threats. CRISPR Therapeutics may make additional immune-dodging engineering changes to its beta cells, among them immune checkpoint proteins (which reassure T cells that the cell is a good citizen) and/or suicide genes that can wipe out the cells if they go wrong and an otherwise non-toxic drug is administered.
Vertex Pharmaceuticals continues its early trial of stem-cell-derived beta cells with immunosuppressive drugs, which did restore one patient with type 1 to relative normality, which was mislabeled as a cure by the NY Times.
This year the large biotech hopes to launch a followup study that would package these cells in a capsule to bypass or minimize the need for immunosuppression drugs. The capsule builds on implantable device research acquired along with cell technology based on discoveries in Doug Melton’s Harvard lab when it bought Semma Therapeutics in 2019. “Semma has developed a very clever and effective encapsulation device,” Melton told me then. Details on the device or its performance aren’t public although there may be hints in Vertex patents (see one image from a patent application below).
Last week Sernova announced early results of a trial with its “Cell Pouch” (above right). Two participants achieved insulin independence, one of them for more than 21 months. “We believe Sernova is the first company to report that its first two transplanted T1D cell therapy study patients achieved sustained insulin independence,” said chief executive Philip Toleikis. The trial used immunosuppressive drugs and islet cells (clusters of cells in the pancreas that include beta cells and other hormone-producing cells) from cadavers (rather than the stem-cell-derived cells that are becoming available in vastly greater quantities).
“The Cell Pouch,” Sernova says, “is designed as a scaffold made of non-degradable polymers, formed into small cylindrical chambers which, when implanted in the abdominal wall, becomes incorporated with tissue and microvessels to the circumference of removable plugs within as early as two weeks as demonstrated in preclinical studies. After the tissue incorporation, the plugs are removed, leaving fully formed tissue chambers with central void spaces for the transplantation of therapeutic cells.”
2021 was not a good year for another corporate contender in encapsulated cell therapies, Sigilon Therapeutics. The FDA stopped the clinical trial for its lead candidate for hemophilia and then Sigilon found that in one trial participant its cell-holding microcapsules were becoming covered with fibers. Last fall, the company put hemophilia on hold and laid off more than a third of its employees. Sigilon is still partnering with Lilly on type 1 diabetes but there’s still no FDA approval for a clinical study.
Over in academia, scientists at the University of Miami are continuing a trial in which pancreatic islet cells are transplanted into the eyes of people with type 1 who are legally blind in at least one eye. The transplant will go in between the cornea and the iris, a location that seemed promising in animal tests. Recipients will get immunosuppression drugs, but “we believe the eye can confer some benefits that favor long term islet survival and, if we can demonstrate this concretely and over time, we may be able to reduce the anti-rejection drugs,” the researchers say. There’s been some question as to whether this location offers enough space for a sufficiently large transplant for diabetes; one experiment in a monkey suggested that it may.
And one more contender: James Shapiro of the University of Alberta, quoted above re the Viacyte trial, pioneered the Edmonton islet-transplantation protocol that proved cell therapies could work for type 1 diabetes. He is a major figure in the field, involved in a surprisingly broad spectrum of lab and clinical work. I was happy to interview him last year for a Nature story about ramping up cell therapies based on stem cells.
Shapiro and his colleagues are enlisting five participants for a small clinical trial somewhat along the lines of Sernova’s pouch, except without the pouch. That is, the transplant site is prepared in a separate procedure before the transplant. PubMed tells me that Shapiro was leading research in mice for both this concept and the Sernova approach a few years back.
The Shapiro lab’s device-less transplant method “was designed to harness an innate foreign body response in a favorable and controlled manner, to induce growth of new blood vessels to allow the survival of the insulin producing cells without the natural body response to foreign body. Briefly, this site transforms the inhospitable under-the-skin site into a viable location through the temporary implantation of a small tube called an angiocatheter.”
Will such a seemingly simple method work in humans? Let’s hope so. And let’s hope for the best with all the other attempts.