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Fred Hutchinson Researchers Debut Proof-of-Concept Ex Vivo Gene Therapy Box

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NEW YORK (GenomeWeb) – A new hot-rodded, proof-of-concept instrument could help ex vivo gene transfer-based cellular therapies break out of the ivory tower of academia and into the wider world. At the same time, the semi-automated equipment could help standardize manufacture of hematopoietic stem cells for gene therapy.

Led by scientists from Fred Hutchinson Cancer Research Center, a team of researchers working in collaboration with Cologne, Germany-based Miltenyi Biotec have modified a magnetic-activated cell sorting (MACS) instrument to isolate human hematopoietic stem cells and genetically edit those using lentiviruses for use in potential gene therapies.

It's a proof-of-concept, partially automated machine that shows high-quality cells for gene therapy clinical trials can be produced outside of current good manufacturing practice (cGMP) facilities. Led by Jennifer Adair and Hans-Peter Kiem of Fred Hutchinson Cancer Center, the researchers published a study today in Nature Communications validating the cell products made with the device.

"Most of what we did was software modification, to do process the instrument wasn't equipped for," Adair told GenomeWeb. But those modifications make it possible to produce gene-edited cells in a semi-automated fashion, with a device that reduces the space and staffing required by existing facilities.

"This is truly transformative," Kiem, an expert on gene-editing technologies, said in a statement. "It will change the way we manufacture and deliver cell and gene therapy products and will have a major impact on making stem cell gene therapy and transplantation and likely also immunotherapy available to patients with genetic diseases, HIV, and cancer worldwide."

There are three major steps to editing HSCs for gene therapies and the box can be used for all of them: cell preparation, cell separation, and gene transfer. The device is already approved for use in the preparation step in FDA-approved clinical trials at the Hutch, and Adair's team is working with Miltenyi to codify the modifications and make them available to more researchers.

Clinical trials for gene-edited cellular therapies are springing up for a number of diseases, including hemoglobinopathies, HIV, cancers, and inherited immune deficiencies. Therapies harvesting a patient's own cells, editing them, and reintroducing them are showing incredible results, but that process is literally exhausting.

In a statement, Adair described an episode from several years ago, when she spent four days in a clean room to make cells for a single patient in a brain cancer trial. She questioned at the time whether she'd be able to treat more than one patient per week, given the physical and mental exhaustion of producing the cells. "It just seemed harrowing," she said.

In that trial, Adair used Miltenyi's MACS technology to separate the cells. It's a technology she's continued to use in her work on Fanconi anemia; in 2014, she began using a reprogrammed Miltenyi CliniMACS Prodigy to speed up her separation method for a clinical trial.

According to Adair, it was then that she decided she wanted to make the machine automate the entire cell-editing process. In addition to reprogramming, the team also had to reconfigure it to add the viral vector and remove residual reagents, as well as develop reagents for each of the different clinical trials.

In the Nature Communications paper, the Hutch-Miltenyi team showed that cells made using the device would meet current regulatory requirements for use in clinical trials. "We looked at the functionality of the cells that came out, using all the same tests used in clinical trials approved by FDA to measure quality," Adair said. The researchers also introduced the cells into animal models to make sure they still behaved like blood stem cells and did not increase the risk of infection.

So far, so good. The machine has already been approved by the US Food and Drug Administration for the preparation part of the cell-editing process in clinical trials for Fanconi anemia. Now, she's seeking an amendment to use it in the selection phase. She plans to pursue permission to use it for the critical gene transfer step as well.

"We used lentivirus because it's the most commonly used in clinical trials," Adair said, but as ex vivo gene therapies garner more interest, the contraption could be further modified for more advanced genome-editing technologies like zinc finger nucleases, transcription activator-like effector nuclease, and CRISPR. "The obvious choice is the CRISPR/Cas system, but we are still in early-stage development for that," she said. "Most of those use electroporation to deliver specific reagents. We don't have an electroporator on the device, but [that] could be configured."

The Hutch team is working with Miltenyi to make the modified CliniMACS Prodigy available to other researchers (unmodified instruments are commercially available).

"From a scientific perspective, there are lots of ways to make gene therapy more portable," Adair said. "Condensing this ex vivo process into a black box where it's something automated and deliverable at the point where the patient is treated could be used in clinics even in impoverished regions."

Adair has worked with researchers around the globe who are applying cell therapies, both in large cities like London and Madrid, which have advanced medical infrastructure, and cities like Curitiba, Brazil, which do not.

For many of the diseases that could be treated with ex vivo cell editing, like HIV and sickle cell disease, the disease burden is highest in impoverished countries, she said. "[Gene therapy] is not happening at all in countries that don't have the infrastructure. My hope is that this point-of-care technology will open the door to treating patients worldwide with these types of approaches."

But the device could be useful even in more advanced countries. "It's only done in a handful of centers because the facilities required are really sophisticated," she said. "There are probably 1,000 modifications that could improve how efficient it is," she said. "But by making a platform that doesn't require you to be at one of the expert academic institutions for gene therapy, we're facilitating more people being able to explore these processes and potentially incorporate their own changes."

Replacing a clean room with a self-contained box could be a boon if the clinical trials deliver on their early promise. "Instead of needing a big safety cabinet, you could have a room full of these that fit in a small footprint and heavily scale up commercial manufacture as well," she said. 

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