by Lisa Willemse
Recent innovations in the ability to expand the usable stem cells within a unit of cord blood may make the life-giving cells available to a much greater number of patients. At least, this is what one Canadian company is testing with a new clinical trial set to begin this fall.
In late June, two coincidental announcements, one by Canadian Blood Services and another by an emergent business, ExCellThera, marked the future of blood stem cell treatments in Canada. The two announcements were not coordinated, nor is there any formal link between the two organizations, but together, they promise significant impact: Canadian Blood Services’ new national cord blood bank enables collection of umbilical cord blood at four Canadian hospitals
that can be used for treatment or research purposes, while ExCellThera’s cord blood expansion technology will help make more of these units usable within the clinical setting, thereby allowing more patients to receive the life-giving stem cells each unit of cord blood contains.
Within a single unit of cord blood, there exists a mix of cells. At the most advanced end, there are mature or nearly mature blood cells, such as red and white blood cells that perform necessary functions of oxygen transport and conferring immunity against disease, while at the most primitive end, there exist blood stem cells, also known as hematopoietic stem cells or HSCs – cells that have the unique ability to form all of the different kinds of cells within the blood system, but can also make exact copies of themselves. HSCs replace tired and dying cells on a regular basis, but when we are faced with blood loss due to injury or disease, they kick into high gear to stimulate the rapid replacement of lost cells. That they are also able to maintain a reservoir of stem cells means that these replacement cells are always available. For patients with particular blood diseases, such as leukemia, this reservoir can be quickly depleted, either by the illness itself, or by aggressive treatment protocols. Under such circumstances, a hematopoietic stem cell transplant, rich in new stem cells, can help trigger the body to heal. Transplants, however, require a source of new stem cells – and one of these sources is umbilical cord blood.
“The success of a cord blood transplantation is proportional to the number of stem cells that a patient receives,” explains Dr. Steven Klein, CEO of ExCellThera, a Montreal-based company with strong ties to the biotechnology labs located in Toronto’s Centre for Commercialization of Regenerative Medicine (CCRM) and the Institute for Research in Immunology and Cancer – Commercialization of Research (IRICoR) of the Université de Montréal. “If you’re an adult, you’re only looking at the ability to access the five or six percent of the cords that have the required level of cells available in an unexpanded form.”
As a result, many adult patients currently require more than one unit of cord blood, and because the units must be matched as closely to the patient as possible in order to reduce the chance of immune rejection, it means there is high demand for cord blood units, particularly for certain ethnic groups, who are underrepresented in the global cache of cord blood.
ExCellThera would help remedy this challenge through a two-pronged approach that takes advantage of the world’s best blood stem cell expansion technology. The first facet of the technology is a small molecule, developed in the lab of Dr. Guy Sauvageau at the Université de Montréal capable of expanding the number of the most primitive blood stem cells in culture by at least ten times that of standard cultures. This, on its own, is a significant advance, but that number jumps significantly when combined with the second part of the protocol, a fed-batch culture bioreactor developed by Drs. Peter Zandstra and Elizabeth Csaszar at Toronto’s Centre for Commercialization of Regenerative Medicine (CCRM).
Csaszar, a development scientist at CCRM and former PhD student in the Zandstra lab, first began working on the fed batch system four years ago. “People have been refining the ability to expand blood stem cells for many years, but the challenge has always been that when you put these cells in culture, the stem cells tend towards differentiation and become mature blood cells, and over time you lose the real stem cell component,” she said.
Zandstra and Csaszar theorized that this occurs because the mature cells produce a particular signal that prevents the production of new stem cells; as the number of mature blood cells grows in the culture, so does the concentration of the inhibitory signal. Their goal was to find a way to prevent the over-accumulation of the inhibitory signal so that more stem cells would be produced.
Using a mathematical modelling approach that mimicked the blood system, the team tested several different scenarios for predicting optimal cell growth and arrived at the fed-batch culture system. “It was surprisingly simplistic,” Csaszar explains, “It operates on the principle of dilution. The system has a continuous inflow of culture media [food for the cells] but doesn’t have an outflow, so this means over time the volume will increase, but the concentration of the inhibitory signal remains low enough to allow the production of stem cells.”
The true power of the fed batch system comes when combined with an expansion molecule, such as UM-171. When coupled with the molecule, the results can be as high as 150-fold expansion in just 12 days.
“It’s currently the best system out there,” said Klein. “We’ve looked at the published literature and the public disclosures and can say with confidence that there is nothing better. With it, we’re hoping to achieve 80 percent usability of the cord blood units, rather than the current five or six percent.”
It’s a confidence that bears up in the pre-clinical data, but is yet lacking verification from human trials. If all goes according to plan, the human data will not be long in coming: the company is in the process of starting a phase I/II clinical trial in fall of this year. The first patients will be recruited in Quebec. Anticipating proof of concept through this first trial, ExCellThera has an eye to financing a phase III registration trial, for which multiple international centres have already expressed an interest.
For now, however, Klein is keeping the focus on the first trial and the partnership that is at the core of the company’s development.
“ExCellThera would not exist without CCRM or IRICoR. These kinds of groups are crucial for incubating the technologies to the point where it makes sense to take them out of an academic setting and put them into a vehicle for commercial development. It’s been a great partnership and I think it could be a model for other partnerships, not just between IRICoR and CCRM, but between other centres across the country.”
Photo credit: Umbilical cord at 120x magnification. Image: Josef Reischig, Wikimedia