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The Other CAR-T Race: Manufacturing

The biosphere is still buzzing about the FDA’s approval of Kymriah – Novartis’ CAR-T treatment for acute lymphoblastic leukemia that, in many ways, marks the true beginning of the cell and gene therapy era. Approvals of other CAR-Ts are expected soon. But behind the scenes, there’s another race going on: the effort to develop efficient manufacturing for CAR-T therapeutics.

That race, which has nothing to do with drug development, may prove critical to the overall success of these therapies. The company that really succeeds in the CAR-T space may not be the first to win approval for a particular indication, but rather the one that develops the best manufacturing strategy. Manufacturing CAR-T products is fundamentally different from more conventional biopharmaceuticals. CAR-T therapies involve autologous manufacturing, using the patient’s own cells. Typically, human T-cells are isolated, activated, genetically modified (often by viral transduction) and expanded before being returned to the donor. The autologous approach means using T-cells of widely varying quality, which in turn makes it enormously challenging to standardize CAR-T manufacturing.

In general, making biomanufacturing more reliable often involves automation and moving from open to closed systems. These factors often lower the cost of manufacturing, especially at larger scales. The information below from Invetech suggests that as the number of patients increase for an autologous product, the cost of manufacturing decreases moderately when manual and open system are used. But in an automated, closed and integrated environment, the cost change is more significant:

Since manufacturing autologous CAR-T therapy requires patient-scale manufacturing, it seems particularly well suited to small, closed production vessels capable of carrying out multiple manufacturing steps and automated testing. Many of these production technologies have recently appeared. The list includes Biosafe, the recent GE Healthcare acquisition, Octane’s Cocoon technology (a partner of Lonza), and Terumo BCT’s Quantum technology (which has a partnership with Athersys). Miltenyi offers the most wide range functions in its CliniMACS Prodigy.

These various technologies have similar goals: protect the product by manufacturing in a closed system; automate monitoring; complete manufacturing without human intervention; and simplify logistics with the use of bar codes. Looking ahead, one might envision a system in which patient cells are fed in one end, progress is monitored remotely, and cells may be collected at the other end in a bar-coded bag, ready for infusion. Such standardized CAR-T manufacturing should allow manufacturing at a number of decentralized hospital sites instead of the more traditional centralized manufacturing model.

The question remains whether CAR-T therapies will be manufactured using a centralized or decentralized model. In this context, it is surprising how many companies are investing in CAR-T manufacturing facilities. This might be expected from larger companies with manufacturing experience like Novartis. But Kite Pharma (just acquired by Gilead) and Juno Therapeutics have also announced plans to build facilities. Others have pursued partnerships. Bluebird linked up with Lonza to provide manufacturing, and GE Healthcare China and CBMG combined to build a large 70,000-square-foot cell therapy facility.

The history of biotechnology is littered with companies that stumbled or failed based on the decision to build its own manufacturing facility. There are many examples of companies with great products with inadequate manufacturing capacity, companies with gleaming facilities for products that flopped in the market, and companies with fundamentally flawed manufacturing processes.  At this point, CAR-T facilities are being built and large investments are being made, but CAR-T manufacturing paradigms have yet to emerge.

In the race for dominance in CAR-T, look beyond marketing approvals and focus also on who will solve the manufacturing puzzle. The field is splitting into two separate competitions: a sprint to discover and develop products, and a marathon to develop scalable, efficient manufacturing.

Blog article by: Mike Jenkins