Chimeric antigen receptor (CAR) T cells are engineered to express receptors that enable the targeting of specific proteins, namely those found on the surfaces of tumor cells.
CAR T cells contain three distinct regions:
THE ECTODOMAIN: Comprised of three components; a signal peptide, an antigen-recognizing region, and a spacer. The ectodomain lies outside the cytoplasm, interacts with the extracellular space and is the part that initiates the CAR T cell’s immune response.
THE TRANSMEMBRANE DOMAIN: This membrane-spanning, hydrophobic, α-helical structure serves the purpose of stabilizing the CAR T cell receptor.
THE ENDODOMAIN: Predominantly comprised of three immunoreceptor tyrosine-based activation motifs (ITAMs) of the cytoplasmic portion of the CD3 ζ chain, as well as co-stimulatory regions. The endodomain is responsible for transmission of intracellular activation.
When the engineered receptor binds to the target protein on another cell’s surface, the endodomain clusters and transmits an activating signal to the T lymphocyte. In turn, this signaling triggers the T cell’s effector functions against the target cell, leading to the target cell’s destruction.
An advantage of tumor-specific T cells that are generated via this mechanism is that they respond to the antigen in a non-MHC-restricted manner. This feature allows the use of CAR T cells in patients with different haplotypes while circumventing tumor escape due to MHC down-regulation.
Furthermore, unlike conventional T cell receptors (TCRs), which are restricted to protein antigens, the range of antigens that can be targeted by single-chain, variable fragment (scFv)-based chimeric receptors also extends to non-classical T cell targets, such as carbohydrate tumor-associated antigens (TAAs).
CAR T-cell therapy has been studied most comprehensively in patients with B cell malignancies and has shown some encouraging early results with success rates ranging from 69% to 90% in pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL).
To date, the FDA has approved two CAR T-cell therapies, Kymriah (Novartis) and Yescarta (Kite Pharma). However, with more than 380 CAR T cell-based clinical trials currently in progress, the potential for the approval of additional CAR T-cell therapies seems quite likely.
NOTE: PeproTech products support CAR T-Cell research; however, PeproTech itself does not conduct research relating to CAR T-Cells. This information is based on a collection of references and cumulative information provided by professional researchers.
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