The Complete Guide to CAR Design & Construction

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The Complete Guide to CAR Design Construction
www.creative-biolabs.com/car-t/
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CAR-T technology
CAR-T refers to Chimeric Antigen Receptor T-Cell
Immunotherapy, which is a modification of the
conventional T cell receptor TCR via a chimeric
antigen receptor and is generally engineered into
a monoclonal antibody antigen-binding domain. In
the scFV segment, the modified CAR-T cells can
specifically recognize tumor-associated antigens,
and are not limited by MHC, so that the
targeting, killing activity, and persistence of
effector T cells are improved compared with
conventional immune cells. CAR-T technology
generally selects cytotoxic T lymphocytes (CTLs)
for modification because CTLs recognize tumor
antigens and release granzymes and perforin to
kill tumors.
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CAR T generation
In 1989, the first CAR T generation was reported
on the PNAS. The basic design of the
first-generation CAR included a tumor-associated
antigen-binding region (usually derived from the
scFV region of the monoclonal antibody
antigen-binding region), an extracellular hinge
region, a transmembrane region, and a steroid
chain in the TCR complex as the intracellular
signal area. The first generation of CAR can only
cause transient T cell proliferation and lower
cytokine secretion, but it can not provide long
time T cell expansion signals and sustained in
vivo anti-tumor effects. Due to the lack of
co-stimulatory signals and the poor proliferating
ability, CAR-T cells have eady become apoptotic
before it meets a large number of tumor cells.
The second-generation CAR assembles the necessary
second signal molecule (usually CD28, CD134 or
CD137 molecule) for the complete activation and
survival of T cells, which can increase the
immune memory and killing ability of CAR-T cells.
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As the expectation of more antitumor efficacy,
the 3rd-generation of CARs combined multiple
signaling domains (eg, CD3 ?-CD28-41BB, CD3
?-CD28-OX40) to acquire further enhanced
activation signals, proliferation, production of
cytokines and effective function. For instance,
the a-CD19-CD3 ?-4-1BB CAR-Ts for chronic
lymphocyte leukemia showed complete remission to
infiltrate and lyse cancer tissue. Even better, a
fraction of CAR-Ts functioned as a memory
phenotype for preventing tumor relapses. Despite
the significant therapeutic effect, the emerging
uncontrollable activity with more antitumor
efficacy caused life-threatening lysis activity
as the most critical adverse effect or fluency
clinically significant exit of pro-inflammatory
cytokines, pulmonary toxicity, multi-organ
failure, and eventual Death.
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CAR T therapy
At the 2015 annual meeting of the American
Society of Clinical Oncology (ASCO), the first
successful clinical trial was demonstrated to use
CAR-T therapy for solid tumors of pancreatic
cancer. Six patients with refractory pancreatic
cancer were treated 4 patients developed disease
progression and 2 patients were stable (3.7
months and 5.3 months) including one patient
without metastatic disease. The researchers, from
the University of Pennsylvania in Philadelphia,
used a special CAR-T (mesothelin costimulatory
molecule 4-1BB) cell, which was specifically
infiltrated into the patient's tumor site.
Mesothelin (MSLN) is a membrane-anchored protein
that is commonly seen in mesothelial cells but is
overexpressed in all pancreatic cancer tissues.
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As a global company, we have more than 200
talented and well-trained scientists located in
different continents working closely with
partners from the entire world to develop and
produce medicines of tomorrow. Specifically, we
are the established leading expert in TCR and CAR
TNK cell immune therapy development, as we offer
the one-stop custom services that cover the
entire new drug development pipeline.
Creative Biolabs
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Email marketing_at_creative-biolabs.com
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Thank you
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www.creative-biolabs.com/car-t/