Over the last four years we have witnessed an increasing number of promising studies and clinical trials aimed to harness the innate potential of T-cells to fight cancer. These cells can be engineered to get around the natural protection mechanisms and target tumour cells either via a chimeric antigen receptor (CAR) or by affinity-enhanced T-cell receptor (TCR).The former have proven to be more effective for haematological malignancies as they can mainly target antigen on the cell surface. The latter have the potential to target also intracellular antigens and this makes them, potentially, a more suitable candidate for solid tumours. Other than Novartis, which is developing a CAR-T cell therapy (known as CTL019) with an exclusive agreement with the University of Pennsylvania, successful companies in this field include Bluebird Bio, Juno Therapeutics and Kite Pharma. Adaptimmune, which partnered with GSK last year, is, on the other hand, more focused on TCR based therapies for a number of solid tumours. Unfortunately, as target antigens are also expressed by heathy cells in vital organs, the risk of potentially lethal side effects is not negligible. While research groups try to create low-affinity CAR-T cells or other approach to reduce side effects, developers and investors wonder:
Will the industry be able to deliver and cope with the manufacturing
demand?
Although one might argue that promising clinical data are
the real drive, these new “living drugs” might not even reach the patients on
large scale if they come with an astronomical price tag and investors might
walk away from a technology that requires huge investment to be made
commercially viable. Moreover, in the optimistic scenario where all the T-cell
based immunotherapies currently in development will prove clinical effective,
only who managed to engineer down costs, while maintain safety and
effectiveness, will win the race. As T-based immunotherapies are mainly
patient-specific drugs, where 1 batch is equal to 1 patient, manufacturing
costs are currently very high. Other than cost-effectiveness, there are also a
number of challenges which still need to be overcome, as shown in the following
diagram.
Will automated manufacturing directly in the
clinical facility be really the answer?
According to Dr Robert
Preti (President of PCT and CSO at Neostem), the only way to successfully
achieve scalability and sustainability for patient specific cell therapies at
commercial scale is an industry-wide effort of innovation and engineering to
rebuilt unit operations and move processes from a cleanroom focus towards
production spaces more suited to “high-volume” production3. Perhaps
this will drive the development of the new system for commercial-scale
manufacturing that Neostem aims to develop with Invetech. The push towards new facility design for cell
therapy products at commercial stage is also echoed by GE Healthcare which is working
towards a closed, digitally integrated, automated ecosystem capable of
manufacturing patient-specific cell therapy products and distribute them
worldwide in a regulatory complainant manner. New generation GMP facilities will
have to be designed.
How will a Future Factory for commercial
cell-based products manufacturing look like?
In the meantime, CDMOs worldwide continue to increase their
capacity to cope with the increasing manufacturing demand. Examples are Wuxi
App Tec (US), MEDINET (Japan), Nikon (Japan), PharmaBIO (Japan). While
automated platforms might be developed by customizing and importing technology
already available; more knowledge of the “living” drug product is needed to
develop analytics, potency assays and release testing for T-cell based
therapies. There is also who, to the
troubles that come with patient-specific products, prefers striving to develop
a universal “off-the-shelf” T-cells therapy where the cells are modified to
avoid immune rejection in the recipient patient. It is the French company
Cellectis which announced a strategic alliance with MD Anderson Cancer Center
on clinical development of their allogeneic CART cell therapies.
After the clinical wave, a manufacturing wave of promising
enabling technologies might be on its way for cell-based immunotherapy.
Fabio D’Agostino is a passionate life sciences professional with experience in both the medical device and biopharmaceutical industry. An active member of the PDA Cell and Gene Task Force, he has contributed to a number of conferences in the cell and gene therapy industries. He was also instrumental in the launch of the new journal: Cell and Gene Therapy Insights.
After graduating with Honours from the Polytechnic University of Turin (Italy) with a BSc and a Master’s in Biomedical Engineering, he started his career at LivaNova (formerly Sorin Group) before moving to Newcastle University to take an Engineering Doctorate in Biopharmaceutical Process Development. He currently holds a research position at the Institute of Genetic Medicine (Newcastle University) where he is responsible for the development of an innovative platform for modular tissue engineering.
References
[1] “Towards a commercial process for the manufacture of
genetically modified T cells for therapy”, A D Kaiser, M Assenmacher, B
Schröder, M Meyer, R Orentas, U Bethke and B Dropulic. Cancer Gene Therapy
(2015) 22, 72–78
[2] “Rethinking clinical delivery of adult stem cell
therapies”, Nuala Trainor, Alexis Pietak,
Tim Smith, Nature Biotechnology 32, 729–735 (2014)
[3] “Guest Commentary: Building a problem or a solution?”,Robert
Preti, DDNews , September 2015, VOL. 11, NO. 9
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