Nohla Therapeutics Inc., a 2015 spin-off of the Fred Hutchinson Cancer Research Center, has a simply stated yet ambitious goal, according to CEO Ben Bergo: to create a “truly universal, off-the-shelf” ex vivo-expanded umbilical cord blood stem cell product that can be administered to patients on demand without the need for human leukocyte antigen (HLA) matching.

The company’s founding was based on more than two decades of research, capped by promising results from a phase I trial showing not only that donor cord blood progenitor cells expanded using the ex vivo platform were safe, but that the cells could be infused without T cells from the same donor and could significantly decrease the time to hematopoietic recovery of both neutrophils and platelets.

Those were “great data,” Bergo said. “And from there we started negotiations with Fred Hutch . . . to bring the expansion platform into the company.”

Last year, Seattle-based Nohla inked a 20-year exclusive licensing agreement with Fred Hutch, gaining access to seven patent families relating to the expansion platform, including a non-HLA-matched expanded cord blood product already in the clinic, currently in a phase IIb trial. The patents also include manufacturing know-how. Rather than expanding cord blood stem cells in real time, doses can be manufactured well ahead of treatment; “they go through cold chain and cryopreservation and can be infused in the time of need,” Bergo explained. That on-demand capability and lack of matching requirement – in fact, the company’s name is intended to reflect the “no HLA” needed – is really what differentiates the platform. It’s also what attracted investors. Nohla ended the year by closing an oversubscribed $21 million first capital round, which Bergo said “gives us runway through to the middle of next year.”

The company is “actively hiring,” he added, aiming to grow the staff from fewer than 10 to 25 or 30 this year.

Additional funding could come through partnerships. Bergo, along with Chief Business Officer Michael Sistenich and Chief Medical Officer Colleen Delaney, also the co-inventor of the company’s technology, were in San Francisco in January during the J.P. Morgan Healthcare Conference where they met with prospective collaborators, though they are in no rush to partner, likely waiting until after the interim analysis from the phase IIb trial, expected later this year. “That’s a very important inflection point,” Sistenich said.

The randomized phase IIb trial, which is being funded by a grant received by Fred Hutch prior to the inception of Nohla, is enrolling 160 patients. As of the J.P. Morgan meeting, enrollment had nearly hit the halfway mark. “In the meantime, we are tweaking the product,” Delaney said, planning for a pivotal trial “in about a year.”

Beyond that, the expansion platform has broad potential across other indications, including chemotherapy-induced severe neutropenia, sepsis and accidental radiation exposure.

“It’s a true bench to bedside story,” Delaney said, involving “many, many years of basic science funded by the NIH [and other sources] and now through the formation of this company.”

THE EXPANSION OF ADVANTAGE

While umbilical cord blood stem cell transplants offer an alternative to bone marrow transplants – mostly because there’s no HLA matching needed, the small amount of cord blood that can be harvested means that time is not on the patient’s side; it takes roughly a month for white blood cell counts to recover, leaving the patient open to infection all the while. So finding a way to boost the number of stem cells found in cord blood was crucial.

“The technologies go back to the early 90s,” Delaney said. A leader in stem cell biology, Irwin Bernstein, now chief of the hematology, oncology and bone marrow transplantation divisions at the Seattle Children’s Hospital, discovered the role of Notch signaling as key in stem cell self-renewal. Delaney said she came onto the scene in 2000 and “discovered ways to tightly regulate and titrate the Notch ligand” to direct what the stem cell does.

“My focus was entirely on CD34-positive cells,” she told BioWorld Today. Her work found that isolating cord blood CD34-positive hematopoietic stem progenitor cells and expanding them by manipulating the Notch signaling pathway resulted in a greater than 2-log increase in the number of CD34-positive cells. Those cells, infused in patients, could repopulate diminished white blood cell counts much more rapidly – early data showed about 11 days – than current cord blood stem cell technology.

“The other cool differentiator,” she explained “is that this one product can be used for multiple indications . . . in theory, any patient at risk of becoming neutropenic.”

Other plans could include myeloablative cord blood transplant, specifically extending it to older patients. The intensity of the existing regimen limits use in patients 45 and younger, Delaney said. “So we could extend access by enhancing the regimen patients get.” That would be a boon to treatment, especially since it is older patients who are at greater risk of acute myeloid leukemia.

And, as with most companies in the burgeoning cell therapy field, Nohla will be watching other players carefully, as they advance negotiations with regulators and continue reporting clinical data that could, hopefully, help advance the entire space.

Delaney, for instance, pointed to Cellectis SA, which drew attention at last year’s American Society of Hematology meeting with data from a single patient, an 11-month-old with high-risk acute lymphoblastic leukemia, who received the French firm’s allogeneic CAR T-cell candidate UCART19 on a compassionate use basis, showed the product successfully induced remission. Though, Cellectis’ approach is “not really competitive” with Nohla’s, she acknowledged. “We’re not genetically modifying our product at all.” Instead, Nohla aims to “use the endogenous machinery in that cell, basically tickling it and turning that protein on. So nothing is genetically modified.”

At least not yet. The company could feasibly expand into that area, but those efforts would be much further down the road. In addition to getting the interim analysis this year for its cord blood stem cell product and planning future trials, company executives right now are focused on establishing a manufacturing process, a crucial element to any cell therapy firm.

“A lot of technical expertise is required,” CEO Bergo noted. Fortunately, the agreement with Fred Hutch includes that manufacturing know-how. In addition to its license deal, Nohla also has in place a five-year sponsored research agreement with Fred Hutch, aimed at accelerating preclinical and clinical research. That involves a $1.5 million yearly commitment directed toward manufacturing transfer.