By Fabio D'Agostino
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.
An increasing number of companies worldwide are betting on
closed and automated system to tackle many of these challenges. Dr Andrew
Kaiser shared his vision in a recent paper1. He explains how a
“device-based manufacturing” could enable to scale out production of patient
specific cellular products while considerably reducing costs in terms of labour
and facility. Devices like the CliniMACS Prodigy (Miltenyi Biotec), which are
capable of performing automatically all steps of a conventional manufacturing
process for gene-modified T-cell product, could be run in a room where an
operator could oversee several units at the same time. Another interesting
platform is the one developed by Octane (Canada). Octane’s automation platform
consists of Cocoon, which acts as the control system, and a disposable
pre-sterilized cassette, where the cell manipulations occur. Each cassette can
be easily customized to the unit operations of the manufacturing process. As
the process parameters are monitored and controlled, each Cocoon is able to react
accordingly to sensors’ feedback to accommodate natural variation in starting
cellular material from each patient. Lonza recently announced an exclusive
technology evaluation of the Octane Cocoon™ cell production platform with the
goal of a global deployment of this groundbreaking innovation. Dr Nuala Trainor
(Director of Biological Programs at Octane Medical Group) explained how their “GMP-in-a-box”
production system could solve many of the issues linked to the manufacturing of
patient-specific cell-products by enabling production within the clinical
facility. She even envisions a “franchising model” where the manufacturer of
the automation system would be responsible for providing all elements of
support required for routine implementation and all operational supplies2.
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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