March 15, 2018 (Vol. 38, No. 6)

Assembly Lines Are Preparing to Churn out Safe, Reliable, and Affordable Constructs

Brown hair frames the face of a vibrant, rosy-cheeked girl who has two reasons to consider the day, May 10, 2017, a good day to celebrate. One reason is no more remarkable than another birthday, her 12th. The other reason, however, is worthy of all the news coverage it received. A chalkboard held by the girl, one Emily Whitehead, said it all: “I am 5 years cancer free!”

Emily survived a terminal diagnosis of relapsed or refractory acute lymphoblastic leukemia (r/r ALL) after receiving CAR-T (chimeric antigen receptor T-cell) therapy during Phase I trials at the Children’s Hospital of Philadelphia. Her miraculous story has inspired hope and fortified the campaign for cell therapies.

The year 2017 marked a milestone not just for Emily but for the cell therapy industry, as the FDA approved its first CAR-T therapy and Novartis launched Kymriah™ commercially. According to Pascal Touchon, senior vice president and global head, cell and gene, Novartis Oncology, “Delivering this therapy to patients required an entirely new approach to both the supply chain and manufacturing.”

Regenerative medicine has shifted the healthcare paradigm away from alleviating symptoms and toward potentially curative approaches that address the underlying disease, but the continued success of these revolutionary therapies relies on establishing new manufacturing paradigms. Manufacturing cell therapies safely, reliably, and affordably at a commercial scale will require ingenuity in the design of custom equipment, facilities, and workflows.

Novartis declares that its Kymriah suspension for intravenous transfusion is the first FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy. Kymriah, which was granted priority review for treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, is manufactured at Novartis’ Morris Plains, NJ, facility. Each dose uses the patient’s own cells.

Scalable Solutions

“When stem cells were discovered, there was a surge of hope,” said Nina Bauer, Ph.D., associate director, commercial development, Lonza, as she chronicled the evolution of cell therapies, which began as an endeavor to cure diseases like Alzheimer’s and Parkinson’s. While the industry has made little headway against these giants, it has demonstrated the potential for allogeneic stem cell therapies to treat, and perhaps cure, a variety of other diseases like macular degeneration and type 1 diabetes.

Although allogeneic stem cell therapies, which use the same product batch to treat multiple patients, allow a traditional scaleup manufacturing model, expanding these sensitive cells to create a sufficient quantity for therapeutic applications while maintaining viability, pluripotency, and functionality presents a major challenge.

“The cells are very sensitive,” explained Antoine Heron, Ph.D., head of cell and gene therapy commercial development, MilliporeSigma. “Very limited changes in your process could lead to differentiation of the cells, and then you will lose your product.”

Over the past two years, Dr. Heron and Frank Edenhofer, Ph.D., a professor of anatomy and cell biology at the University of Würzburg, have collaborated on a scalable solution for manufacturing induced pluripotent stem cells (iPSCs). After culturing iPSCs for two weeks in a 3-L bioreactor, they achieved a 125-fold increase in cell number—essentially doubling the process yields reported in the literature with a final yield of 2 billion cells/L. Further characterization by immunocytochemistry, flow cytometry, karyotype analysis, and differentiation into all three germ layers confirmed that the human iPSCs retained their pluripotency and normal karyotype after expansion.

Their innovative strategy eliminates microcarriers or special surface coatings by culturing the iPSCs in small cell aggregates formed from single cells. They maintained cell viability and functionality by optimizing critical parameters, like aggregate size and agitation rate, to ensure delivery of oxygen and essential nutrients while also minimizing shear stress. According to Dr. Heron, their work “suggests that iPSCs can be cultured in stirred suspension for at least 49 days, possibly even longer, while remaining remarkably viable and pluripotent, which is definitely a strong foundation for a scalable manufacturing process.”

Taking the World by Storm

While allogeneic therapies follow a traditional scaleup model, albeit at a smaller scale than conventional biologics, autologous therapies, which are customized for each patient, require an unconventional “scale out” model. “From a manufacturing standpoint, producing autologous therapies at scale seemed ridiculously challenging,” remarked Phil Vanek, general manager, cell therapy growth strategy, GE Healthcare Life Sciences.

The apprehension around manufacturing custom therapies dissipated when CAR-T therapies, based on pioneering research conducted by Carl H. June, M.D., at the University of Pennsylvania, entered the clinic as a cancer treatment.

“These therapies were taking the clinical world by storm,” recalled Dr. Vanek. “Patients that typically had a less than 10% chance of survival suddenly had remission rates above 80%. It was that clinical success that made the entire industry take note and say, ‘okay, if these therapies really work, how can we manufacture them for everyone who needs them?’”

Bridging the gap between scientific discovery and industrial manufacturing meant tackling the labor-intensive, multistep workflow used to genetically modify patients’ T cells with a new modus operandi. GE Healthcare’s strategy simplifies this workflow by connecting multiple unit operations using semiautomated subroutines to increase overall efficiency and reduce the need for manual intervention.

In addition to offering semiautomated, closed systems for cell isolation, expansion, and harvesting, GE Healthcare’s portfolio includes an integrated end-to-end solution for cryogenically preserving cell therapies with Asymptote cryopreservation technology that includes VIA Freeze™ controlled rate freezers, automated thawers, and my.Cryochain software.

This past January, Cellular Biomedicine Group, a clinical-stage biopharmaceutical firm, announced its plans to configure part of its facility in Shanghai using GE Healthcare’s FlexFactory platform to commercialize its CAR-T therapies. According to Ger Brophy, Ph.D., general manager, cell therapy, GE Healthcare, the scalable, start-to-finish cell therapy manufacturing platform could cut in half the 18 months it typically takes a company to prepare a facility.

In addition to equipment, GE Healthcare’s FlexFactory provides logistical solutions like Fast Trak training programs. Developed in collaboration with the Centre for Commercialization of Regenerative Medicine (CCRM), these programs aim to get staff up and running as quickly as the facility itself.

GE Healthcare and CCRM (Centre for Commercialization of Regenerative Medicine) scientists explain GE’s cell processing equipment while giving a tour of CCRM’s laboratories in Toronto, Canada. Funded by grants totaling $40 million from GE Healthcare and Canada’s FedDev program, the facilities substantiate Toronto’s bid to become “Stem Cell City.”

Anticipating a Metamorphosis

According to Dr. Bauer, autologous therapies now constitute approximately 60% of the cell therapy industry. Lonza responded to these turning tides by partnering with Octane Biotech, a regenerative medicine company, in 2015. Octane’s automated bioreactor, Cocoon™, performs core functions necessary for autologous cell therapy production, including cell seeding, expansion, feeding, and harvesting. “We call it a GMP-in-a-box system,” said Dr. Bauer.

Since adopting the technology, Lonza has worked with Octane to integrate additional unit operations, such as magnetic bead separation and electroporation, into the all-in-one production platform. Cocoon controls gas and temperature levels for the cells, which are introduced into a plastic cassette that slides into the bioreactor. The automated system moves cells between multiple chambers that perform separate steps of the production workflow inside the sterile cassette.

Sterile, closed environments are paramount for cell therapy manufacturing, but it’s not just adventitious bacterial or viral contamination that can have serious, even life-threatening, consequences. Cross-contamination from other cell therapies produced in the same facility could also adversely affect patient safety. One strategy to reduce the risk for cross-contamination segregates autologous therapies during manufacturing using small, individual manufacturing suites, but this space-intensive approach requires larger, more expensive facilities.

The closed, single-use, disposable cassettes at the nucleus of Cocoon provide a segregated, self-contained system that minimizes the risk of cross-contamination without requiring individual manufacturing suites. In addition, Octane has designed rotating stands, nicknamed “trees,” that hold 8–10 Cocoon bioreactors at once. The overall design resembles a futuristic orchard for regenerative medicine with rows of stands suspending the pod-shaped bioreactors. The small footprint, approximately 9 square feet per tree, enables production of up to 10 therapies simultaneously, potentially making its space-efficient design one of the technology’s biggest virtues.

Cocoon technology, currently under development by Lonza in collaboration with Octane Biotech, is based on an automated GMP-in-a-box concept for autologous cell therapy manufacturing. This image zooms in on the Cocoon instrument, which houses a patient-specific, presterilized, disposable cassette that provides a system of interlinked modules for processes such as seeding, expansion, feeding, and harvesting.

Is Hope Enough?

Whether it’s enabling a patient’s T cells to recognize tumor antigens or replacing dysfunctional beta islet cells, regenerative medicine promises more than disease management—it promises cures. In addition, according to Dr. Bauer, “It’s the curative aspect that brings a lot of hope to the cell therapy space.” However, the complexities involved in designing, manufacturing, and administering these therapies to patients at a commercial scale begs the question: Is hope enough?

“These are probably some of the most complex products that we’ve dealt with over the years,” commented Carl Burke, Ph.D., new platform integration, pharmaceutical development and manufacturing sciences, Janssen Research & Development. Last December, Janssen announced its intent to develop, manufacture, and commercialize a CAR-T therapy for multiple myeloma in collaboration with Chinese company Legend Biotech.

Janssen has developed custom equipment and disposables to close and automate their cell-manufacturing processes, but equipment constitutes only a portion of the overall costs and logistical challenges involved in cell therapy manufacturing. Dr. Burke also emphasized the importance of developing close partnerships with suppliers to ensure both the quantity and quality of materials, including custom disposables, custom media, and viral transduction vectors, as well as collaborating with healthcare facilities to make sure they have the appropriate infrastructure to receive, store, and track these sensitive, expensive therapies once they reach the hospital dock.

While the approval and commercial launch of the first CAR-T therapies, Kymriah (Novartis) and Yescarta™ (Gilead Sciences), marked an important milestone for the cell therapy industry, the $475,000 price tag for a one-time dose of Kymriah caused some sticker shock.

“Ensuring that patients have access to these therapies once they are approved by regulatory authorities is paramount,” said Sanjaya Singh, Ph.D., global head, Janssen BioTherapeutics, Janssen Research & Development. “The healthcare community—industry, payers, providers—all need to work together to figure out how best to create a sustainable environment that supports patients and further innovation.”

In an effort to improve patient access, Novartis has contracted an outcomes-based pricing approach for Kymriah with the Centers of Medicare and Medicaid. In the unprecedented arrangement, Novartis will receive payment only if the patient responds to treatment within one month, and since Novartis’ price only applies to its current indication for children and young adults with r/r ALL, the company could initiate indication-specific pricing in the future. These pricing models could set the precedent for future CAR-T therapies.

Increasing the market size for cell therapies would allow manufacturers to implement more efficient and cost-effective strategies. Novartis estimates that only 600 patients per year will be eligible to receive treatment for the current indication, but the company has studies underway to assess Kymriah’s effectiveness in diffuse large B-cell lymphoma and r/r follicular lymphoma. They also have several CAR-T therapies in development for glioblastoma, ovarian cancer, and mesothelioma, and demonstrating clinical success in solid tumors is considered the next big milestone for the industry.

“I am 5 years cancer free.” Emily’s chalkboard is emblematic of the hope inspired by CAR-T therapies. While the clinical success of cell therapies has taken the world by storm, delivering these therapies to the world will require a miraculous story of manufacturing ingenuity. However, as philosopher Bernard Williams once said, “There was never a night or a problem that could defeat sunrise or hope.”

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