Outsourcing
and expanded outside the body. CAR T, for example, is a highly complex and innovative immunotherapy that involves collecting and using the patients’ immune cells to create a chimeric antigen receptor (CAR) that can bind to specific proteins on cancer cells.
Large numbers of CAR T cells are grown in the laboratory and can be used to treat certain blood cancers, though studies are assessing their efficacy in the treatment of other types of cancer. Products currently on the market include Yescarta for treating two types of non-Hodgkin lymphoma, and Tecratus, which is a CAR T-cell therapy for the treatment of relapsed or refractory mantle cell lymphoma (MCL). Also advancing rapidly is gene therapy delivered using a viral vector as a drug to insert a gene into a group of cells. In this technique, a recombinant adeno-associated virus (rAAV) enables the insertion, deletion or substitution of DNA sequences into the genomes of live mammalian cells. Gene therapy product Kymrhia, for example, is a genetically modified autologous T cell immunotherapy delivered by viral vector and made from a patient’s own white blood cells before it’s used to treat relapsed or refractory follicular lymphoma. In the case of autologous therapies, the starting material is unique, which makes it challenging to establish a manufacturing process and some adjustments are needed to ensure that the final product meets the required quality control specifications for safety and efficacy. “Because they involve the manipulation of genetic material, it is extremely important to detect and monitor potential changes,” says Montero- Julian. “For example, in the case of CAR T cells, the vector copy number (VCN) – a measurement of the transgene copies within a CAR T cell product – is a product-specific characteristic and must be quantified prior to patient administration.” High VCN increases the risk of insertional mutagenesis – a phenomenon which can itself cause malignant cell transformation – which makes transgene integration in the drug product an important safety parameter to measure for CAR T-cell release. “CGTs also require specialised storage and handling conditions to preserve their stability and potency,” adds Montero-Julian. “Thus, quality control is more challenging, and the manufacturing process must be carefully monitored and controlled.”
Recognising risk factors The development and delivery of CGTs bring their own unique risk profiles. With cell therapy, there is risk along the entire vein-to-vein journey, from when cells are taken from the patient, through the modification process and then in the phase where they are reintroduced to the body. Risks at every stage can be lowered as much as possible, but the process needs to be done fast, as these therapies are
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often made to order for patients in urgent need of treatment, and for whom other conventional treatments have failed. Time is of the essence in cell therapies, but speed must be balanced with quality control and safety. “Reducing manufacturing and lot disposition times is not as critical for viral vector- based gene therapy manufacturing,” notes Mike Brewer, director of regulatory at Thermo Fisher Scientific. “Unlike cell-based therapies, where time to deliver the drug to the patient is critical, for an rAAV, the overarching concern in manufacturing is to create a high quality, high purity product.
A diagram showing the process of developing and using CAR T cells as a therapeutic for cancer.
“CGTs also require specialised storage and handling conditions to preserve their stability and potency. Thus, the manufacturing process must be carefully monitored and controlled.”
Félix Montero-Julian, healthcare scientific director
“The challenge for a cell therapy is that the process is the product, especially if we are talking about ACT, so there is a smaller set of quality control release tests.” For both types of therapy, testing and safety protocols must be rigorous in order ensure compliance with regulatory standards and deliver a working therapy as quickly and efficiently as possible. These protocols must, however, address many challenges. As cell therapy products are manufactured at low volume and all of the product must be kept for the patient, analytical methods must be applicable to minimal volumes of sample to provide results. New analytical techniques are required to ensure accurate characterisation and to monitor the product’s consistency throughout its life cycle. “The short-shelf life of these products means traditional compendial analytical methods used in
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