Therapy Comparison: Chimeric Antigen Receptor and T-Cell Receptor
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Therapy Comparison: CAR (Chimeric Antigen Receptor) and TCR (T-Cell Receptor)
Therapy Comparison: Chimeric Antigen Receptor and T-Cell Receptor. In ACT, TCR and CAR-T therapies, modified T cells are successfully used as clinical immunotherapy for the treatment of solid tumors (Figure 1).
CAR T cells are designed to transfer any specificity to immune effector cells, such as T cells, which specifically eliminate tumor cells carrying antigens.
CAR has scFv derived from antibody, CD3ζ, and transmembrane domain (so-called first-generation CAR). In this way, the engineered CAR can recognize specific tumor-associated antigens.
Therefore, CAR can bind to unprocessed tumor surface antigens without MHC processing, while TCR binds to tumor cell intracellular and surface antigen peptides embedded in MHC (Table 1).
Generally, CAR scFv domains are used to bind to cell surface antigens. The scFv fragment can guide the constitutive activation and proliferation of T cells through an antigen-dependent mechanism.
Figure 1 Comparison of TCR, CAR and transgenic T cells in immunotherapy. The cancer-targeted receptors TCR and CAR are introduced into activated T cells, enabling them to resist specific types of cancer. The ζ subunit of CD3 on the surface of T cells is essential for triggering the signal cascade of T cells. Unlike TCR, which needs to be activated by endogenous CD3, CAR is a hybrid receptor made from a single-chain variable fragment (scFv) linked to the CD3ζ subunit. Both the introduction and endogenous TCR can recognize HLA peptides on cancer cells. In contrast, CAR does not directly recognize HLA, which triggers the T cell signaling cascade in a way that is independent of TCR.
Table 1 Comparison characteristics of TCR and CAR.
The first generation of CARs T cells showed limited expansion and relatively short persistence, which failed to stimulate strong anti-tumor activity in clinical studies. The clinical activity of “second-generation” CARs can be induced by the insertion of the CD3ζ domain, namely the costimulatory receptors CD28 (28ζ), 4-1BB/CD137 (BBζ) and OX40 (OX40ζ) CAR.
CD28 or CD137/4-1BB is added to the CD3ζ domain of CAR-T cells, which then promotes a stronger and lasting T cell response.
In addition, these second-generation CARs targeting CD19 antigen (CD19-specific scFv) are highly active against B-cell malignancies and have good clinical benefits.
In order to overcome the limitations of each single costimulatory domain, the third-generation CAR is proposed to combine two costimulatory signals (CD28 and 4-1BB) at the same time. Compared with the second-generation, it has better scalability and longer Persistence.
The TCR is an α/β heterodimer that binds to the MHC binding antigen (Figure 1). As mentioned above, compared with TCR, CAR recognizes tumor antigens that cause T cell activation and has different functions.
CAR-T cell therapy has certain disadvantages when targeting tumor-specific antigens, such as extra-tumor toxicity.
Compared with CARs, TCRs have several structural advantages in T cell-based therapies, because their receptor structure has more subunits (10 subunits vs. 1 subunit) and larger immune receptors. Tyrosine activation motifs (ITAMs) (10 vs. 3), less dependent on antigen (1 vs. 100), and more costimulatory receptors (CD3, CD4, CD28, etc.).
TCRs with a low MHC interaction affinity range (104-106M-1) have been suggested for effective T cell stimulation. In contrast, CARs have a higher affinity range (106-109M-1) and dissociation rate to recognize cell surface antigens.
In order to maintain high antigen sensitivity and recognize pMHC, the use of monomeric TCR-CD3 complexes has been suggested. In contrast, CAR-mediated cell sensitivity requires a higher density of cell surface antigens.
In addition, the T cell/antigen interaction is initiated in the immune synapse (IS) structure, in which TCR presents a circular area with peripheral LFA-1 adhesion, while CAR shows diffuse LFA-1 distribution in an acyclic area .
Therefore, TCR-IS initiates a slower but longer lasting signal than CAR-IS. At the same time, CAR-T cells show faster killing function and transfer to the next tumor target (continuous killing), which is in sharp contrast with the prolonged signal and longer killing time of TCR-T cells.
Clinical trials involving TCR and CAR therapy may inhibit tumor progression. CARs cannot effectively inhibit the malignant cells of certain solid tumors. This is due to the existence of various types of antigens, their expression levels, immunosuppressive environment and the construction of CARs.
However, TCR-T cell transfer therapy has effectively treated some solid tumors and hematological tumors.
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