May 2007 | Back to Table of Contents
Pulse
Bringing Cells to Service
A cell-therapy facility at the University of Minnesota turns scientists’ ideas into potential treatments.
The call may come at any hour of the day or night. Somewhere in the country, an organ donor has died; a pancreas suddenly is available. As the tissue is whisked to the University of Minnesota’s St. Paul campus, a hardy team of scientists and technicians at the Molecular and Cellular Therapeutics (MCT) facility scrambles to be ready the instant the organ appears. Over several hours, the team will process the cadaverous tissue, isolating the insulin-producing clusters of cells known as the islets of Langerhans that are dotted throughout the organ. The cells they isolate and cultivate, representing a mere 2 percent to 3 percent of the entire pancreas, may be candidates for use in a clinical trial—an infusion of islets for a patient with type 1 diabetes.
Transplanted donor islet cells recently became a promising treatment for patients with some of the most severe cases of diabetes. Nearly 30 patients at the University of Minnesota Medical Center, Fairview, have received islet cells from deceased donors as part of recent clinical trials. But these meticulously cultured cells, isolated at the MCT using the strictest aseptic techniques and handled with exacting adherence to federal regulations, are among a burgeoning array of new cell-based therapies for all types of medical conditions.
With the resources of the MCT, a mere idea hatched by a clinician-scientist gets walked through all the necessary steps until a biotherapeutic product is scaled-up for a human trial. “It’s really about patient care,” says David McKenna, M.D., medical director of the facility. “Our role is to help investigational therapies move into the clinic.”
Big Hope in Tiny Cells
All this work takes place in an unassuming brick building, doors down from a horse corral on the quiet, bucolic campus that’s a stone’s throw from the state fairgrounds. Inside the facility, bright labs gleam, set apart from the hallways with double sets of doors. When the MCT was established in 1992, it took over the space where the experimental anti-rejection drug, Minnesota ALG, had been manufactured—space that had been designed for the manufacture of biotherapeutics under the rigid federal requirements known as cGMP, current good manufacturing practices. Surfaces in the labs can be sanitized easily. The floors curl upward where they meet the walls so no dirt can gather in corners. The air pressure blows particles out of the rooms instead of letting contaminants waft in.
At first, the lab focused on processing hematopoietic stem cells from bone marrow, adult peripheral blood, and umbilical cord blood for bone marrow transplants at the University of Minnesota. The now-routine techniques continue to be its “bread and butter,” says McKenna, and enormous temperature-regulated tanks store the precious progenitor cells in a single room of the basement. (The bone marrow transplant program at the University of Minnesota Medical Center, Fairview, is the nation’s most active user of hematopoietic stem cells from cord blood.)
But in the mid 1990s, pediatric oncologist and hematologist John Wagner, M.D., scientific director of the MCT, began to steer the facility toward developing a wider range of novel cell-based therapies. In 1996, Bernhard Hering, M.D., was recruited to the department of surgery to advance the technology of pancreatic islet transplants.
Today, MCT staff are undertaking an imaginative and ambitious set of projects. Fourteen are in the works with scientists at the university such as Hering and four with external institutions and start-up firms.
The MCT is one of only three facilities in the country with a PACT (Production Assistance for Cell Therapies) contract, a five-year investment from the National Institutes of Health (the others are at Baylor and the University of Pittsburgh). Although similar cell-therapy facilities exist at other large universities and medical centers, none supports as wide a range of products, says program director Randall Tlachac. Tlachac notes that 25 biotherapeutic and pharmaceutical products are currently in the pipeline.
On a tour of the facility, Tlachac points out how Hering’s group is preparing both autologous and allogeneic pancreatic islet cells for transplantation. Researchers also are developing human natural killer cells to treat acute leukemia. These immune cells are given to patients who have failed more standard medical therapies; patients might also receive them in addition to a bone marrow transplant regimen in order to improve engraftment and prevent graft-versus-host disease. And a recently recruited faculty member from the University of Kansas is looking to the MCT to help develop new pharmaceuticals and bring them to the clinic.
In a partnership with clinicians at Mayo Clinic, MCT technicians were able to purify a monoclonal antibody that had never before been isolated on a scale that would allow for clinical trials on patients with multiple sclerosis. Tlachac explains that other proteins are now being tested in preclinical toxicity trials and may turn out to be useful in treating cancer.
Incubating Ideas
For scientists who are new to matters of the marketplace, MCT staff members offer guidance in commercializing their products. Most important, the MCT provides the infrastructure needed to maintain compliance with FDA regulations for investigational new drugs (INDs), as the government considers new cell-based therapies. (Helping clinician-scientists dot the i’s and cross the t’s is no small matter. “A physician could face a multiyear delay just omitting one detail from an FDA application,” says Tlachac.)
The regulations for INDs may be strict, but as the field of cell-based therapeutics expands, the guidelines continue to evolve. “It’s not the same as manufacturing a drug,” says Klearchos Papas, Ph.D., a chemical engineer who oversees islet cell processing. “If you generate a drug, you look at the chemical structure, you make sure the manufacturing is consistent. You know you have quality control.” In the case of pancreatic islet cells from a donated organ, for instance, even a short delay during transport can have a dramatic impact on viability and function and make them more immunologically challenging for a patient to accept.
Even as staff engage all the concerns of industry, they also maintain the spirit of their academic surroundings. On a visit to a cancer center lab on campus, for instance, McKenna and his team meet and chat with scientists to find out what they’re working on. On another day, scientists may come to him with a modified cell that’s already been an effective treatment in mice and that they’d like to take to the next stage. “We bring those ideas back to the MCT,” McKenna says, “and start to do modifications.” Those modifications involve all kinds of problem-solving, from how to purify a cell type to how to transport it to its clinical destination. One recent troubleshooting session involved puzzling through how to ship a certain cultured cell type across the country at body temperature.
The thrust is to get scientists’ ideas past practical hurdles and quickly into the form of treatment. Says McKenna: “We hear what they envision and try to make their vision a reality.”—Kate Ledger