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Scientists at the Fred Hutchinson Cancer Research Center and the University of Washington have developed a semi-automated benchtop system to produce clinical-grade genetically modified haematopoietic stem cells (HSCs). The research was recently published in Nature Communications. Genetically modified HSCs have significant therapeutic potential for patients with bone marrow disorders. However, producing such cells so they remain contamination-free and fit for purpose usually requires cell handling and manipulation at sophisticated Good Manufacturing Practices facilities, which limits the availability of these cells. The researchers were able to use a closed, semi-automated benchtop system to produce genetically-modified HSCs in just one night and hope that such systems will increase the availability and affordability of cell therapies.
Medgadget had the chance to interview the lead author on the study, Professor Jennifer Adair of the Fred Hutchinson Cancer Research Center.
Conn Hastings, Medgadget: Can you give us a brief overview of how this technology works?
Jennifer Adair, Fred Hutchinson Cancer Research Center: This technology includes a benchtop device, several liquid components in individual packages and a disposable, closed tubing set that is mounted on the device for single-patient use. A cell product such as bone marrow or blood is collected and connected to the disposable tubing set, along with the other liquid components in a defined configuration. Using a touch screen, the user follows prompts to mount the tubing set and liquid components onto the device. The user is then prompted to initiate a program to begin processing the blood cell product. Depending on the type of blood cell product, the user might interface with the touch screen on the device to make decisions or enter additional information for the process.
The whole automated process includes initial preparation of the blood cell product for target cell separation, separation of the target cells for genetic modification and the genetic modification step. For blood stem cells this process takes less than 36 hours. At the end of the process, the genetically modified cells are prepared for infusion and transferred to an infusion bag on the tubing set. Once the process is completed, the user is notified and removes the infusion bag containing the genetically modified cells from the device for transport back to the patient. The user can then dismount the tubing set and any leftover components and dispose of them. The device is immediately ready for the next patient product.
Medgadget: Despite their promise, cell therapy and gene therapy have not yet achieved widespread clinical use, in large part because of safety concerns. Do genetically modified cells compound safety issues?
Jennifer Adair: The safety concerns of genetically modified cells are synonymous with the safety concerns of gene therapy. While earlier clinical trials raised safety concerns for genetically modified cells, especially in the context of inherited blood diseases such as X-linked severe combined immunodeficiency (X-SCID), the risk-to-benefit ratio for these patients favors gene therapy. Building on the lessons learned from those trials, we now have adjusted the tools we use in genetic modification to address these safety concerns. There are numerous clinical trials applying these adjustments in genetically modified cells for various diseases including X-SCID which have not raised safety concerns in hundreds of treated patients to date.
Medgadget: How does the system compare with conventional methods to produce clinical-grade cell therapies?
Jennifer Adair: We were able to show that our system results in cell products which meet the same criteria as conventionally produced cell products for use in patients. Many of the components used to manufacture clinical-grade cell therapies are the same in this system as they are in the conventional methods. The major difference is that the technology in our approach is dramatically more compact and requires less infrastructure than the current Good Manufacturing Practices clean room facility. Some other differences include physical and chemical components that are typically used in the conventional method but that we removed from this system. For example, we no longer use individual bags or flasks to culture cells in this system. Instead we use a disposable chamber and tubing. In the conventional approach, most processes require the bags or flasks to be coated with a protein prior to gene modification. We have also removed this protein-coating from the current system.
Medgadget: Could the system be applied in a point-of-care situation, to treat a patient with their own cells?
Jennifer Adair: Yes, we believe it could be applied in a point-of-care approach, and that is our goal. Cell therapy and gene therapy need to be available worldwide, and many nations could not support the current infrastructure necessary for such treatments. We hope that our work can help to offer a solution.
Medgadget: Are there any plans to trial the cells produced by the system in humans, to validate their safety and therapeutic potential?
Jennifer Adair: Yes. We are testing this technology in a clinical trial of gene therapy for an inherited disease called Fanconi anemia. We hope to expand its use into clinical trials of other gene therapies in the next few years.
Medgadget: Do you think that benchtop technologies such as this can play a role in a more widespread use of cell therapies?
Jennifer Adair: Absolutely. While the point-of-care approach is our ultimate goal, more immediately this technology could be used in commercial manufacturing to scale up production, permitting more patients to be treated. It also could increase the number of researchers who can investigate and study these therapies. Right now, there are only a dozen or so research centers worldwide that have the technology and staffing to produce such cells. Our approach could change that.
Study in Nature Communications: Semi-automated closed system manufacturing of lentivirus gene-modified haematopoietic stem cells for gene therapy
