Push to Scale Up Cell Therapy Manufacturing

Cellular Biomedicine Group, a clinical-stage biopharmaceutical company that develops immunotherapies for cancer and stem cell therapies for degenerative diseases, recently partnered with GE Healthcare to build a platform to produce therapies at scale for clinical trials. Aims to solve challenge of developing enough genetically modified cells to test products on large populations.

by Menaka Wilhelm
April 30, 2018

With two gene therapy cancer treatments already on the market— Kymriah and Yescarta — there’s a lot of excitement about new therapies that harness immune cells to target disease. Dozens of similar approaches are in clinical trials, and there’s a push to ready many more therapies for testing.

While cell therapies promise high recovery rates for patients, companies face the challenge of developing enough genetically modified cells to test their products on large populations. This involves growing cells faster while keeping yields high.

Cellular Biomedicine Group, a clinical-stage biopharmaceutical company that develops immunotherapies for cancer and stem cell therapies for degenerative diseases, recently partnered with GE Healthcare to build a platform to produce therapies at scale for clinical trials.

GE’s partnership with CBMG leverages GE’s relationship with the Canadian Center for Advanced Therapeutic Cell Technologies, a collaboration between Canada’s Center for Commercialization of Regenerative Medicine and GE Healthcare in Toronto. CATCT opened six months ago and is ready for business, says Rohin Iyer, a GE cell therapy development manager who will oversee process development for the partnership with CBMG.

For CMBG and clients like it, Iyer and his team are fine-tuning manufacturing processes to scale up T-cell production for clinical trials. They are also tinkering with other cell types that could potentially reach even more patients.

CAR-T Momentum

Both currently approved gene therapies are CAR-T treatments, named for the chimeric antigen receptor protein that incites immune cells to demolish cancer cells. Gene therapies typically work by separating some of the immune system’s T-cells from a patient’s blood, exposing the cells to a viral vector that activates them to target cancerous cells, and returning them to the patient for treatment.

After the patient’s immune cells undergo sorting and activation, they are cultured in a bioreactor to grow enough T-cells for an effective treatment. A blood sample from a cancer patient might deliver 10 million T-cells, while therapies typically require closer to 100 million cells. These expansions happen in a 10-liter or 25-liter bioreactor, but a patient’s infusion will be in the range of milliliters. The final preparations require washing cells to remove culture components, distilling the cells back down, and freezing them for preservation.

The momentum for this kind of therapy is exciting, Iyer says, but working out the kinks is an ongoing process.

Commercialization Comes with Challenges

One big challenge is that patient-to-patient variability affects the bioreactor culture. A patient’s age and health determine the initial T-cell count in a blood sample. Different patients’ cells also respond differently to the activation processes.

Manufacturing has to adapt to ensure consistent outputs from ingredients that can be mercurial. Iyer and his team leverage GE’s Xuri W25 Cell Expansion System. The machine automates many process parameters and aerates cells with a rocking motion. Beyond adjusting the mix of media that feeds the cells as they grow, process engineers might tweak the agitation rate, rocking angle, or the amount of oxygen delivered to cells. That variability offers Iyer and his team an advantage in developing a wide range of cell culture recipes.

Automating as many aspects of cell culture as possible is the fastest route to both speed and safety. That means using sterile tubing between steps rather than manually adding reagents, and testing culture properties through automated sampling, rather than opening up the bioreactor to collect cells.

For You: Read the latest in cell therapy advancements on AABME.org.

GE’s Xuri system offers this kind of closed environment, as well as several other bioreactors, including Miltenyi Biotec’s CliniMACS Prodigy, CESCA’s CAR-TXpress, and Terumo BCT’s Quantum cell expansion system. Generally, Iyer says, bioreactors avoid manual operations to keep cells sterile, but manufacturers are still working on other improvements, like leveraging new sensors between steps for in-line measurement of such parameters as cell count. 

Today’s CAR-T therapies ship frozen cells, which hospitals thaw in a water bath to treat a patient. To freeze cells while keeping them viable, manufacturers sometimes use dimethyl sulfoxide, or DMSO, because it freezes at a higher temperature and prevents the formation of ice crystals that might expand and rupture cells. Yet DMSO can be toxic to patients. Another freezing ingredient, liquid nitrogen, introduces problems with sterility, Iyer says. And thawing cells in a water bath also opens up contamination risks.

So Iyer and his team are working to create freezing and thawing approaches that are more sterile and less toxic. They are developing new cryopreserving agents to replace DMSO and using alternative approaches, like controlled rate freezing, to avoid liquid nitrogen. GE acquired a British company, Asymptote, last year for its expertise in cryopreservation technologies, which includes devices for controlled and sterile thawing at hospitals.

Future Frontiers

The possibility of developing treatments from other classes of cells could also be around the bend. Rather than relying on each patient’s own T-cells, new treatments (called allogeneic therapies) might eventually leverage one sample to treat many different patients at once. Pluripotent stem cells, which can develop into T cells or other immune cells, open up this possibility. Some researchers also believe they can modify pluripotent stem cells to prevent them from triggering immune reactions.

Iyer and his team recently expanded 36 billion pluripotent stem cells in a 10-liter reactor, which was a major milestone. “If you think about it, one pluripotent stem cell can become one T-cell, so that’s billions of T-cells that could potentially treat millions of patients,” he says.

Ultimately, that kind of scale-up is the goal. Whether the end result is T-cells or other cell types for entirely new therapies, researchers and industry are hoping to deliver cost-effective, sterile treatments to support many new clinical trials, maximizing the therapies available to patients who need them.

Menaka Wilhelm is an independent technical writer.

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