Experience with the approved CAR-T drugs from Novartis and Gilead has shown that being able to manufacture enough products fast enough is a major issue when it comes to marketing these cutting edge therapies – perhaps even more challenging than getting them approved.
Kisaco Research’s CAR-T Congress EU heard how various biotechs are trying to refine or change the process for making cells that are capable of tackling blood cancer, and more challenging solid tumours.
Novartis has been struggling to meet demand for its approved CAR-T Kymriah (tisagenlecleucel), and has been looking to find ways to make manufacturing more efficient.
CAR-T (chimeric antigen receptor T-cell) therapies are manufactured by harvesting a patient’s own T-cells, genetically modifying them so that they target the disease, and then reintroducing them to the patient.
While the effects can be powerful, the challenges of producing the therapy in time is proving a challenge and the hunt is on to find new and faster ways to genetically engineer the CAR-T cells and get them to patients before their disease gets worse.
The genetic engineering step is proving to be a sticking point in the process, and there is a range of approaches being trialled that could be faster and more efficient than the virus-based gene editing used in approved CAR-Ts.
The conference heard from Michael Hudecek, director of the CAR-T Translational Research Programme at Universitatsklinikum Wurzburg, Germany who is working on cells that are genetically engineered using “sleeping beauty” DNA transfer.
This aims to be faster than the virus-based gene transfer but also prevents the risk of any virus left over from the process being left in the end product.
There have been no such issues in the approved drugs, but prior to approval in 2017 the FDA sought assurances from manufacturers that the process would not generate left-over retroviruses that could lead to new cancers.
“We need to make sure that no active viruses are presenting,” said Hudecek, whose technique is not based around viruses but a system based on “minicircles” of DNA that can be used to insert a piece of DNA code at 10% the cost of a viral vector.
There was also a presentation from David Sourdive, executive vice president of technical operations at Cellectis, which is developing allogeneic “off-the-shelf” T-cell therapies in partnership with Servier and Allogene.
The gene editing system behind this technology is Cellectis’ system known as Talen – a class of proteins capable of inserting genes with high specificity and activity.
Sourdive described it as a “powerful platform” that will continue to deliver results in future research.
He also noted that CRISPR-Cas9 gene editing techniques are not suitable for use in CAR-T cells – while this technique is suitable for snipping out bits of DNA, they leave an awkward dog-end in the molecule that makes it difficult to insert a new gene.
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