CAR-T CELL-BASED IMMUNOTHERAPY BASIC PRINCIPLES
The basic design of CAR includes a tumor-associated antigen (TAA) binding region (usually scFv), an extracellular hinge region, a transmembrane region and an intracellular signal. The first chimeric TCR was constructed by replacing the Vα and Vβ extracellular domains of the TCR chains. Single chain antibody links the CD3ζ for the first generation. Costimulatory molecule, such as CD28, has been engineered to the signal transduction region for the second generation. Another costimulatory molecule based on the second generation for the third generation has been engineered to the signal transduction region. The cytokines based on the second generation for the fourth generation has been engineered to the signal transduction region. A dual CAR T cell expresses two separate CARs with different ligand binding targets. Dual CAR T cell activation requires co‑expression of both targets on the tumour. A conditional CAR T cell is by default unresponsive until the addition of a small molecule to complete the circuit. A tandem CAR T cell expresses a single CAR consisting of two linked scFvs that have different affinities. The physiological CAR consists of an antigen receptor and a CD3ζ intracellular signaling domain with/without a transmembrane and a spacer region. The universal CAR utilizes biotin or anti-FITC scFv as targeting region fused with the transmembrane domain. Marked CAR T cells express a CAR plus a tumour epitope to which an existing monoclonal antibody agent binds.
Creative Biolabs CAR/TCR-related Products & Services
Structural and Functional Basis of CAR
1
VL Antigen-binding region (scFv)
VH
Monoclonal antibody
Hinge region Transmembrane region
TCR-CD3 complex γ ε
α β
ε δ
T cell
Seminal research
1993
1989
1st-generation
Tumor cell
Cell activation Cytotoxicity induction Cytokine production Cell survival Cell proliferation
Signal transduction region
ζ ζ
Evolution of CAR
2
VH
Tumor antigen
Anti-tumor signal
2nd-generation 1998
2003
4th-generation
2007 2004
3rd-generation
2009
VL
γ ε α β ε δ ζ ζ
CD3ζ
CD8α
CD4
CD28
4-1BB
Hinge
IgG1 sequences
Transgene 3
Classic CAR
1
2
＋
Dual CAR
1
＋
Cytokine Co-stimulating ligand
New CAR Models and Concepts Conditional CAR
2
Additional small molecule
1
Receptor & ligand
＋
2
Tandem CAR
1
Physiological CAR
2
1
＋
Avidin/anti-FITC labeled scFv
Universal CAR
Biotin/FITC
2
＋
Marked CAR
1
2
＋
Selection marker
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