By Julianna LeMieux, PhD
The opening keynote of the In Vivo Gene Therapy Manufacturing track at the BioProcess International meeting, taking place this week in Boston, was a riveting kickstart to the meeting. Over two hours, the speakers covered multiple aspects of cell and gene therapy—not only celebrating the triumphs, but also addressing some of the tough challenges like scale and accessibility while sharing the latest updates in manufacturing and commercialization.
The session was chaired by Morten Sogaard, PhD, president and division head of gene therapy research and technical operations at Astellas Gene Therapies. He opened by declaring that one need look no further than the recent high-profile cell and gene therapy approvals to know that it is “an incredibly exciting time in our industry.”
Tim Hunt, CEO of the Alliance for Regenerative Medicine, a nonprofit known as “the global voice of the cell and gene therapy sector” offered a state of the industry for the first presentation of the session.
Hunt started with patient stories—a child (Weston Cook) who received a gene therapy for spinal muscular atrophy (SMA) and Jimi Olaghere, a man with sickle cell disease who was dosed in the CRIPSR therapeutics/Vertex trial and no longer requires care for his condition.
Hunt then moved to data: global numbers from the first quarter of 2023: There were 2,760 total developers (companies and academics) of cell and gene therapies, 1,687 (917 in North America) clinical trials, and roughly $3.0B in investment.
Out of the trials, the majority (739) were in cell-based immune-oncology, with 477 in cell therapy and 509 in gene therapy.
Gene therapy approvals are accelerating, he noted. There were five approvals in the past five years (from 2017–2022) but five approvals may come in 2023 alone. Indeed, three have already been approved: 1) Omisrige, a cell therapy by Gamida Cell to reduce infections in patients with tumors; 2) Vyjuvek, a gene therapy by Krystal Biotech to treat the skin disorder rare dystrophic epidermolysis bullosa; and 3) Elevidys, a gene therapy by Sarepta Therapeutics to treat Duchenne muscular dystrophy (DMD). In addition, the year will bring two more highly anticipated possible approvals: Exa-cel, CRISPR Therapeutics and Vertex’s first ever ex vivo CRISPR/Cas9 gene-edited therapy for sickle cell disease and Lovo-cel, Bluebird Bio’s sickle cell gene therapy. Hunt noted that the FDA aims to approve 10–20 new cell and gene therapies per year by 2025.
But are our healthcare systems ready, he asked. Today’s policies are ill-equipped to handle the medicines of the future, he asserted, with questions about payor readiness and the need for the payment systems across Medicaid, Medicare, and private insurers to be modernized.
Washington, DC, has taken some steps in the right direction, he explained, as the House Committee on Energy and Commerce passed the Medicaid VBPs for Patients (MVP) Act, promoting access to cell and gene therapies for Medicaid patients who need them. And noted that Healthcare Management Solutions (HMS) and CMS’ Center for Medicare and Medicaid Innovation (CMMI) are testing new policies and testing a new cell and gene therapy access model.
Hunt ended with the hopeful example of Emily Whitehead, the first pediatric CAR-T patient who was diagnosed with ALL at age 5. Now, over 10 years after her treatment, led by Carl June, MD, director of the Center for Cellular Immunotherapies and director of the Parker Institute for Cancer Therapy at the University of Pennsylvania Perelman School of Medicine, Whitehead is still cancer-free.
A tag team presentation followed Hunt, given by Thomas Bieringer, SVP global head at Bayer and Aaron Dulgar-Tulloch, PhD, the CTO of genomic medicine at Cytiva. The pair discussed how partnering can enable allogeneic therapy and, specifically, develop a platform for scale up of manufacturing of allogeneic cell therapy.
Bayer focuses on allogeneic iPSC-based cell therapies. Their strategy has been to build an ecosystem of companies with innovative technologies, including AskBio, Mammoth Biosciences, BlueRock Therapeutics, and Atara Biotherapeutics. Bieringer noted that Bayer shields the companies from some of the bureaucracy surrounding commercialization. “Bluerock should do what they do best,” he asserted.
To develop cell therapies, Bayer analyzed different cell types, CER-NK, CER-T, iPSC, etc., and looked for both synergies and differences in the production process. They then mapped out a modular platform to enable industrialization of cell therapies.
Dulgar-Tulloch noted that Cytiva and Bayer were well-aligned from the beginning of their collaboration. They both knew that new tools were needed for manufacturing, pointing to the challenges that need to be considered when developing an allogeneic bioreactor: aggregate and cell suspension, high sheer sensitivity, large range of oxygen transfer, and low metabolic stress tolerance (perfusion). The team took a two-pronged approach to develop a solution. But more advancements are needed. For example, developing cell lines with genetically engineered advancements.
Samir Acharya, PhD, associate director of process development at Andelyn Biosciences then brought the end-to-end approach to the conversation. Andelyn Biosciences is a CDMO with a history in AAV, spun out of Nationwide Children’s in 2020. The 225 employees work in three facilities in Columbus, OH.
Acharya described how their strategy of upstream development (maximizing titers) and downstream development (purification strategies) has established an AAV suspension platform. Using a case study, he explained how the strategy allowed scaling up to 50 L. And, in working with the PALL/Cytiva team, they successfully scaled to 500 L and 780 L and evaluated growth parameters and productivity.
The final speaker, Clive Glover, PhD, vice president of viral vectors at Cytiva, presented a talk entitled, “Genomic medicine keeps innovating, manufacturing should too.” He noted that the field’s bullish attitude about genomic medicine, with sweeping innovation in targets and delivery, needs to be applied to innovation for manufacturing.
He asserted that the scale of viral vector-based therapy is increasing, in large part because they are targeting bigger indications. But manufacturing capacity is going to be a problem; there will be a practical limit to the number of batches.
Most improvements, he predicts, will come from upstream—cell line improvements. The foundation that allowed mAbs to treat more diseases was stably integrated cell lines. So, moving toward a producer cell line makes sense for gene therapy.
But it is challenging. Viral vectors are toxic for cells, so the cell will die a few days after producing them.
One technology may be in the Elevecta producer cell line, developed in Cologne, Germany. Because the genes to make the viral vectors are on an inducible switch, they are silenced until induced at high cell levels.
This cell line is one way to bring the approach solidified in the mAb industry to the AAV space. Because, he concluded, prevalent indications are the next frontier for AAV-based gene therapies. And transient transfection is not efficient or scalable enough to support those titers.
Glover ended on a note that represented the goal of the speakers in the session, the people in the audience, and the conference attendees. With robust processes that scale, the field of cell and gene therapy can hope to treat hundreds of thousands.
Julianna LeMieux, PhD, is the Deputy of GEN ([email protected]).