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transposable system carrying the CD19 CAR gene. These nanoparticles were injected
into a mice model. Appreciably, they selectively and quickly edit T cells to specifically
target leukemic cells. The antitumor efficacy was comparable to conventional CAR-T
cell therapies [122].
5. Universal/SUPRA CAR-T cells
Researchers have been exploring various other possibilities that would pave the
way for the next generation. One of which is split, Universal Programmable
(SUPRA) CAR-T cells. The promise and opportunity that the universal allogeneic
T cells hold are enormous. These engineered cells have the capability of targeting multiple antigens and control the level of T cell activation with a possibility to manage toxicity. To prevent graft-versus-host disease in SUPRA CAR-T cells, the expression of
genes expressing TCR and HLA class I are experimentally removed. The disruption
of these two genes in animal models resulted in successful prevention of the graft-versushost-disease [18].
Currently, CAR-T cells are designed to target and bind one or two antigens, but
other interesting strategies are being explored to design novel universal CARs to reach
a near-infinite antigen specificity. One example is avidin-linked CARs in conjugation
with biotinylated antibodies. This ingenious system is designed not only to control
the CAR-T cell activity with a safety switch, but also to target multiple antigens, either
simultaneously or sequentially [42].
SUPRA CARs are receptors composed of two components: a universal receptor
(zipCAR) expressed in T cells and a tumor-targeting scFv adaptor (zipFv) located on
the surface of T cells. Further, the zipCAR universal receptor is a combination of intracellular signaling domains and a leucine zipper as the extracellular domain. The fusion
between a cognate leucine antigen and an scFv forms the zipFv. The advantage of
SUPRA CARs over the conventional CAR lies in its ability to target multiple antigens
without further genetic manipulations [123].
23Engineering solutions to design CAR-T cells
6. Critical aspects for clinical development
The current CAR-T cell therapy uses patient-specific autologous T cells requiring
an individualized manufacturing process. This approach has changed the therapeutic
landscape, particularly in hematological malignancies. Initiatives are currently underway
to explore the possibility of “off-the-shelf” allogeneic CAR-T cells that can be made
immediately available for the patients.
The transfer of the desired fraction of the genetic material is key to the production
of CAR-T cells. Severa l companies and research labs use viral vectors for the development of these cells. Few academic and industrial facilities have the capability of
24 Irene Uboldi et al.
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manufacturing CAR-T cells via transduction with viral vectors [77].Thishasled
researchers to look for a nonviral methods of transfection such as electroporation or
an improved form called n ucleofection. Electroporation uses an electric pulse to
permeabilize the cell membrane and move the molecule of interest into t he cell. While
Nucleofection, particularly Neucleofector is an improved electroporation technology.
The efficiency of using the latter in transfecting primary cells, stem cells, neurons, and
other cell lines are far greater than the tradit ional nonviral method. Integration vectors
such as transposons and CRISPR-CAS9 can greatly reduce the cos t of transfection and
the overall cost of production [124]. The improvement in the transfection using the
nonviral method has widened the possibilities for developing novel cell and gene therapies of the future.
Nevertheless, few challenges limit the expansion of the CAR-T cells therapy to the
extended population. First, the high cost of production of these types of therapies, for
example, Kimriah and Yescarta, renders it difficult to make these treatments widely available. In fact, the cost for a single dose of the treatment is roughly is about four to five
hundred thousand US dollars. The cost of production of CAR-T cells is high, so are
the closed or functionally closed facilities that are needed for production. These costs
are expected to decrease once process-related efficiencies are achieved.
The choice of the antigen target and its volume of response is a crucial consideration
during the clinical development of the CAR-T cells. It is of fundamental importance that
the target receptor is present just on tumor cells and not in healthy tissue to avoid the
destruction of healthy cells.
The patient may often require multiple infusions of CAR-T cell therapy. Another
consideration is that, because autologous CAR-T cells, unlike off-the-shelf treatment
options, are made on-demand, the time required for the production of CAR-T cells
needs to be taken into account by the team treating the patient. Generally, from the time
the patient material is received at the manufacturing site, it can take between 7 and
22 days to complete the manufacturing process. Followed by often cryopreserved
shipping.
6.1 CAR-T cells produced with an automated process
Automated equipment can reduce the burden of the operators and can efficiently handle core steps in the manufacturing process. This advantage translates to the reduced
time taken at each step in the process and elimination of any error or variance that
may result from manual operation. Thus, increasing the reliability of the GMP
manufacturing process. Notably the ability to control the whole manufacturing process
with minimal human interventions will further provide sterility assurance and standardize the manufacturing process. Continuous in-process quality control
measurements will still be required to ensure that the final product continually meets
specifications [125].
Some of the current automated solutions available are CliniMACS Prodigy System,
Ambr 250, Aastrom Replicell System, and Lonza’s automated cell processing system
Cocoon. Two of these systems are described.
6.1.1 CliniMACS prodigy system to produce CAR-T cells
CliniMACS Prodigy is a system commercialized by Miltenyi Biotech. It allows the cell
activation, transduction, amplification, and final harvesting through unit operations
[125]. It is also designed to handle automatic washing and fractionation. Single-use cham-
bers which form a part of the prodigy tubing sets are used. The magnetic cell separation
unit is capable of separation of any type of cells [126].
6.1.2 Cocoon system
The Cocoon System is a production solution that can be used for bench scale to commercial manufacture. It is designed to be compact and thereby utilize minimal cleanroom
space. This is perfectly suited for a centralized and decentralized manufacturing model.
Designed by Octane Biotech Inc., this technology is now fully owned by Lonza [127].It
is a fully closed automated system with a single chamber. A cluster of chambers can be
added for different protocols and products. This machine once loaded with the protocol
can performing: cell seeding, expansion, perfusion, digesting/harvesting, concentration,
washing, and formulation [125]. It offers great potential for manufacturing cell and gene
therapy products, including CAR-T cells. Cocoon’s Software monitors and controls the
environment for healthy cell growth. It can also monitor pH in real-time and automatically adjust the process when needed.
25Engineering solutions to design CAR-T cells
7. Conclusion
CAR-T cell therapy has already exhibited its potential in the treatment of tumor
malignancies. Two therapies, Tisangencleucel and Axicabtagene ciloleucel, were
approved by FDA in 2017 and are already on the market for the treatment of certain types
of B-cell lymphoma and B-cell precursor acute lymphoblastic leukemia (ALL).
There are still few challenges that need to be overcome to ensure therapeutic success.
First, the side effects resulting from the administration of CAR-T cells, notably cytokine
release syndrome. Secondly, not all patients respond to the therapy in the same way,
though remission rates are rising. Relapse has also been seen several months after the first
CAR-T cell administration. Another, challenge in CAR-T cell therapy is the “ontarget-off-tumor,” which could cause serious toxicity.
But the landscape of this emerging treatment strategy is rapidly changing. Improved
efficiencies in the production process complemented with the exploration of new
26 Irene Uboldi et al.
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strategies to engineer CAR-T cells is certainly promising. These approaches attempt to
increase CAR-T cells efficacy, augment its persistence and enrich its specificity. For
example, CAR-T cells have been designed to secrete matrix-degrading enzymes, BiTEs,
antibodies, oncolytic viruses, antibodies for a stronger antitumor activity. Logic gates
have been implemented to more precisely target tumor cells.
Currently also new ways to transfect CAR-T cells using alternatives to viral vectors,
such as transposon systems, TALEN, ZFN, and CRISPR/Cas9 are being explored.
Future initiatives will see the development of universal CAR-T cells, that could be
administered to any patient and the realization of a universal CAR receptor that could
target every type of antigen. This will make this therapeutic strategy more affordable and
immediately available for treatment.
It would not be surprising to see CAR-T cells replacing traditional pharmacological
therapies for the treatment of a variety of difficult-to-treat conditions. The current teething issues must be seen only as a part of the evolution process in developing the next
generation of novel and revolutionary medicines. Once these challenges are overcome,
the benefit for the patient and the field of medicine will be far greater than the sacrifices
done to master this therapy.
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31Engineering solutions to design CAR-T cells
CHAPTER TWO
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
Engineered microbes for cancer
immunotherapy
Aoife M. Brennan, Anna Sokolovska, Ning Li, and Vincent M. Isabella
Synlogic Operating Company, Inc., Cambridge, MA, United States
Contents
1. Microbes as tumor immunotherapy 33
1.1 History of microbes as tumor immunotherapy 34
1.2 Mechanistic underpinnings 34
2. Application of synthetic biology to therapeutics 38
2.1 History of synthetic biology 38
2.2 Sense and respond 39
2.3 The intersection of synthetic biology and therapeutics 41
2.4 Chassis selection 41
3. Synthetic biology techniques to engineer safety and control growth 43
3.1 Biocontainment of genetically modified live biotherapeutic products 43
3.2 Genetic stability 43
3.3 Auxotrophies as a mechanism to control growth 44
3.4 Kill switches as biocontainment mechanisms 44
4. Application of synthetic biology to engineer microbial therapeutics for cancer 46
4.1 Engineering effector functions 46
4.2 Enzymatic and metabolic conversion 47
4.3 Cytotoxic agents 47
4.4 Microbial antitumor vaccines 49
4.5 Cytokine delivery 50
4.6 Innate immune effectors 51
4.7 Engineering safety and tumor targeting 52
5. Regulatory considerations in the development of engineered bacteria as therapeutics 54
6. Conclusion 56
References 56
1. Microbes as tumor immunotherapy
Bacteria and human health share a close and complex relationship, which is particularly noteworthy within the context of bacteria and cancer. Bacterial infection stimulates the development of stomach and gallbladder cancer [1], tumors exhibit their own
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