Introduction to TCR
The TCR-T technology works by genetically modifying T cells to redirect their cytotoxic activity towards tumor associated antigens (TAA). This modification features enhanced T cell to target cell affinity as well as specificity, therefore also being called “Affinity-Enhanced TCR”.
TCR is composed of two subunits TCRα and TCRβ. Each TCR subunit contains an antigen-recognition domain. When a TCR recognizes a compatible peptide-MHC complex presented by a target cell, it elicits activation signals to T cells and initiates target cell killing.
Mechanism of TCR-T
Proteins inside cancer cells can undergo degradation, processing and antigen presentation and finally display on cell surface. The MHC presented cancer antigen can therefore be recognized by TCR-T cells, which secrete cytolytic components to mediate cancer cell clearance.
Advantages of TCR-T therapy
Broad selection of cancer-specific antigens
Although CAR-T therapy demonstrated tremendous success in hematopoietic cancers, its efficacy in solid cancers remain elusive. One prominent drawback of CAR-T cells is the lack of target antigens. TCR-T cells can be engineered to target majority of TAAs, especially ones located intracellularly. Thus, the application of TCR-T therapy outcompetes antibody therapy and CAR-T therapy. TCR-T cells are also capable of distinguishing mutated antigens, which enables extraordinary selectivity towards tumor tissues while sparing normal tissues.
Humanized for long-term protection
Typically, therapeutic antibody or the chimeric receptors in CAR-T cells are derived from rodent immunization. Direct use of these antibodies often lead to the development of anti-drug-antibodies in patients, which limits the duration of antibody or CAR-T cells. The TCR constructs in TCR-T cells, however, are derived from patients’ autologous TCR repertoire. They are fully humanized and do not lead to rejection responses, which allows for long-term protection by TCR-T cells.
Disadvantages of CAR-T Advantages of TCR-T
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