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OneThousandOne represents the amount of time, verbally, that it takes to count to one second. In this one second of time, a great thing happened at The Nebraska Medical Center. In fact, several great things probably happened. A patient was cured, a researcher found the missing link, a nurse treated an injury, a doctor comforted a family or maybe a child just smiled.
MOMENTS IN MEDICINE at THE NEBRASKA MEDICAL CENTER
Fall | Winter 2011

Limitless Possibilities

Stored in a liquid nitrogen freezer at temperatures below -150°C (-238°F) at The Medical Center’s Biologics Production Facility, are several thousand small bags of human hematopoietic stem cells. They are the link to life and a possible cure for many patients with cancer or other life-threatening illnesses.

One of these bags contains Nessie Swedlund’s stem cells.

In March 2008, Swedlund was diagnosed with multiple myeloma, a cancer of the bone marrow. Less than a year later, she received a life-saving stem cell transplant at The Nebraska Medical Center. During the stem cell procurement process, extra stem cells were collected and frozen and now serve as a backup for Swedlund in case her cancer should return. In this cryopreserved state, cellular products, such as stem cells, can remain stable for a minimum of 10 years, and probably longer.

While Swedlund knows there is no cure for multiple myeloma, she takes comfort in knowing that she is receiving care at one of the leading medical centers in the country for multiple myeloma and stem cell transplantation. She is also comforted by the fact that she has another dose of her own stem cells frozen and carefully preserved in the region’s only biologics production facility should she need a second transplant.

“I feel so fortunate to have access to this type of expertise right here in Omaha,” says Swedlund.

“I feel so fortunate to have access to this type of expertise right here in Omaha.”
Nessie Swedlund

The Biologics Production Facility, which opened in November 2010, allows The Nebraska Medical Center to take medicine to the next level in stem cell transplantation, as well as other cutting edge areas of cellular therapy.

Jointly operated by The Nebraska Medical Center and the University of Nebraska Medical Center (UNMC), it is designed to support scientific and clinical investigators in using the most modern medical techniques to develop and test promising new medical therapies to treat cancer, diabetes, degenerative diseases, serious injuries and other life-threatening disorders. Many of these therapies involve the collection, isolation, processing, modification, cryopreservation and/or storage of cells, tissues or cellular and tissue-derived products. This is an area of research that is growing rapidly but is limited to select institutions because of the expertise, comprehensive quality management, process controls and the stringent environmental controls required for such work to take place.

Biologics manufacturing laboratories must meet strict regulations known as Good Manufacturing and Good Tissue Practices (GMP/GTP). These federally mandated regulations prescribe the controlled conditions, product segregation, continuous monitoring and security required to safely manufacture and store products for administration to humans. GMP also requires consistent quality management systems that provide oversight and ensure quality products that meet user requirements.

“This facility gives us the ability to do almost anything from a manufacturing perspective,” says Phyllis Warkentin, MD, medical director of the Biologics Production Facility. “For many years, we’ve been able to process and preserve minimally manipulated products such as hematopoietic stem and progenitor cells. In this facility, we will be able to isolate, select and potentially expand selected cell populations and manufacture vaccines and other cellular products for our own patients or patients elsewhere. Such products can potentially improve patient outcomes, decrease complications and treat diseases that were previously resistant. We are very excited about the potential of these therapies, as well as the types of clinician investigators, scientists and projects this facility will attract to Nebraska. The possibilities are limitless.”

The 20,000 square foot Biologics Production Facility provides a critical venue for researchers to transition small scale basic science research findings to useful therapeutics at the bedside through phase I and II clinical trials.

Phyllis Warkentin, MD

“This facility makes bench research to bedside therapy possible,” explains Dr. Warkentin. “Research normally starts on a small scale in basic science research laboratories, using standard supplies, petri dishes, flasks and test tubes. But when a potential product is produced at a much larger scale in a manner suitable for administration to patients, the question is, will it still work? Technologists and scientists in the Biologics Production Facility have the expertise to scale up a project to get it ready for human trials using larger quantities of starting materials, reagents that have been approved for human use, and whenever possible, closed production methods that minimize the risks of contamination or cross-contamination. Ultimately, this facility allows us to take the most recent findings from a laboratory to the development of a product that potentially benefits patients.”

What makes this facility unique is the extraordinary means employed to meticulously monitor and keep the air and surfaces extremely clean and to follow precise quality control standards.

The Biologics Production Facility includes six individual clean room suites that achieve Class 10,000 to Class 100 air quality. Class 100 air quality means the air contains not more than 100 particles of 5 micrometers in a cubic foot of air space. These rooms are supplied with 100 percent outside air, filtered through high efficiency particulate air (HEPA) filters, dispensed from the ceiling and vented out near the floor at an air exchange rate up to six times per minute to achieve the appropriate air quality.

“GMP guidelines dictate that we have materials in place that are all cleanable and prohibit contamination,” says Charlie Branson, operations manager of the Biologics Production Facility. “The transitions from floor to wall are continuous resin-based paint surfaces. We have hard deck ceilings, stainless steel air diffusers, HEPA-filters that are rated 99.99 percent efficiency for particles of .03 microns and greater. Everything is cleanable. Everything is sealed. Nothing can get in. There are more than 285 equipment check points that are continuously monitored around-the-clock for quality control.”

“These rooms are generally cleaner than a standard operating room,” adds Dr. Warkentin. The facility also includes a completely segregated clean room suite with surrounding support areas where clinical projects requiring stricter isolation can take place, such as processing of animal cells or tissues that may play a role in human therapies.”

“As this field has grown, so have the regulations,” says Cindy Owens, vice president, Corporate Affairs at The Nebraska Medical Center. “Now everything is done in a much more controlled environment so that there is no exposure to air and contaminants. Transplant patients are severely immunocompromised, so this is critical to their survival. Patients are living much longer post-transplant because of these improved processes and improved medical care.”

The Biologics Production Facility currently focuses on four promising areas of therapeutic medicine: stem cell collection and processing, cellular-based vaccines and therapies, tissue-based therapies and regenerative medicine therapies.

Stem cell collection and transplantation involves the use of bone marrow or peripheral blood-derived stem cells, which are taken from a patient for autologous use or from a related or unrelated matched donor. These cells are minimally processed, frozen and stored, if necessary, and infused into the patient. Since the program’s founding by James O. Armitage, MD, more than 25 years ago, physicians and researchers at The Nebraska Medical Center program have been pioneers in the field of bone marrow and stem cell transplantation, having treated more than 4,300 patients with stem and progenitor cell transplantation.

“The Biologics Production Facility will allow us to do more manipulation of these products, such as enriching or depleting certain cell subtypes that might be useful for the patient, which could ultimately lead to further improvements in patient outcomes,” says Dr. Warkentin.

“Everything is cleanable. Everything is sealed. Nothing can get in. There are more than 285 equipment check points that are continuously monitored around-the-clock for quality control.”
Charlie Branson

Another area of expertise involves cellular therapy. Cellular therapy that entails more complex processing, genetic manipulation, ex vivo expansion or maturation is only possible in the environment of the Biologics Production Facility. “By changing the expression of cells, we may be able to treat immune deficiencies and restore cell populations that are missing in severely immune-deficient people,” says Dr. Warkentin. These cells can also be used to develop vaccines or immune therapies, which are completely customized for a patient using the patient’s own cells.

The Nebraska Medical Center has been involved in gene therapy and the development of cellular vaccines since this field’s early beginnings. James Talmadge, Ph.D., a research specialist in transplant immunology at UNMC, has been active in molecular, cellular and gene therapies for the treatment of breast cancer for many years. Gene therapy and cellular vaccines show much promise in providing additional treatment options for cancer patients. The first cell-based cancer vaccine was recently approved by the FDA and is currently being used to help treat prostate cancer.

The use of tissue-based therapies is also growing. Tissue-based therapies involve the manipulation of tissues or organ-derived cells that are intended for implantation, transplantation, infusion or transfer into a human for disease treatment. One of the most promising areas is in the development of new ways to use organs that are not suited for transplant. Researchers have had some success in making a suspension of cells and then infusing them into another organ so the organ performs the function of both.

An example of this is the Medical Center’s pioneering work in autologous islet and hepatocyte transplantation. Transplant Surgeon Jean Botha, MB, BCh, has been perfecting autologous islet transplantation, most commonly performed in cases of chronic pancreatitis. The procedure involves removing the pancreas, isolating the islets from the other pancreas cells, and then transplanting the cells into the patient’s own liver. This allows the islets to produce insulin in their new location, avoiding the complication of diabetes that would otherwise result from pancreatectomy.

Regenerative medicine, the development of therapies to reconstitute or restore function to diseased or damaged cells, tissues or organs, is an exciting area of medicine that is likely to be one of the most important therapeutic advances. Scientists are currently developing and testing the manipulation of human cells and tissues to restore function to diseased organs; growing new cells and tissues that can be matured to serve new roles in the body; and developing customized therapies and vaccines that are trained to attack tumors and other diseases.

Under the directorship of Nora Sarvetnick, PhD, the Nebraska Regenerative Medicine Project is poised to take a leading role in this area. UNMC scientists currently are involved in the production of cells and tissues for clinical use as well as basic research that will advance the field in a variety of areas. These include bone and cartilage repair, islets, liver and neurologic diseases. Researchers predict the effects of many catastrophic diseases may someday be reversed through cellular therapies and tissue engineering.

The Biologics Production Facility meets the highest standards of quality control to keep air and surfaces extremely clean with features such as floor to wall continuous resin-based paint surfaces, hard deck ceilings, stainless steel air diffusers and an in-house USP purified water system for cleaning and terminal sterilization.

Although the Biologics Production Facility was developed with a focus on cellular therapies, the design of the clean room suites is purposefully versatile to facilitate adaptation to new processing techniques and the production of non-cellular products as well. One of these areas is in new drug development. UNMC is a leader in the field of nanomedicine, a rapidly growing field in which small particles are used to improve drug delivery systems. The Biologics Production Facility provides the perfect environment for manufacturing therapeutic products for pre-clinical evaluation and clinical trials.

“Much of biologics medicine is still investigational, but the results have been very promising,” says Dr. Warkentin. “I foresee that there will be many more diseases in the future that we will be able to treat with products or vaccines that can be produced here. We are only limited by our creativity and our imagination.”

Previous article in the Fall | Winter 2011 issue of One Thousand And One:
A Deep Breath