CAR-T cell is currently the most promising technology in the field of oncology, which has been pinned on by the majority of clinicians and cancer patients, and has great clinical transformation value, and is also a hot spot in the medical research community. Today, Xiao Heng will take you to know this **.
In physiological conditions, most tumor cells express certain tumor-specific or associated antigens (TSA or TAA), which are engulfed and degraded by antigen-presenting cells (APCs) into small peptides, some of which bind to histocompatibility complexes (MHC molecules) and present them on the membrane surface of APCs. When the TCR of a certain T cell is just able to bind to the MHC-antigen complex presented on the surface of APC cells, T cells are activated and proliferated by the combined action of costimulatory receptor ligands (e.g., B7-CD28).Activated T cells, on the other hand, carry the TCR that recognizes tumor antigens, so they can directly recognize tumor antigens on the surface of tumor cells and kill tumor cells.
Traditional immune cells** are cultured in vitro and infused back into the body in order to kill tumor cells. However, the traditional ** immune cells are dominated by cytokine-induced killer cells (CIK), which have poor efficacy due to lack of targeting, and increasing the ability of immune cells to recognize tumors is the key to improving the ability of immune cells to kill tumors. CAR-T cells are remodeled in this direction.
CAR-T cell** (Chimeric AntigenReceptor T-Cell Immunotherapy): Chimeric Antigen Receptor T-Cell Immunity** By stably expressing an artificially designed CAR molecule in T cells, the T cells are endowed with a new targeted activation function of tumor cells, and then the modified CAR-T cells are infused back into the patient, and these engineered CAR-T cells are no longer MHC-restricted, and can be activated only by binding to the targeted antigen, so as to efficiently kill tumor cells. The antigen recognition region of the antibody that can recognize the tumor antigen and the original element that can promote the proliferation of T cells are conjugated together to form a chimeric antigen receptor, which is then transfected into the patient's T cells by gene transduction to express the chimeric antigen receptor (CAR). After the patient's T cells are "recoded", a large number of tumor-specific CAR-T cells can be generated after contact with the target cells, and the specific killing of tumor cells can be achieved.
The key to CAR-T is the design of the CAR molecule, which is an artificially engineered receptor molecule that can give immune cells the specificity to be activated by a specific target, thereby enhancing the cell's ability to recognize antigen signals and activate. The extracellular domain is the single-chain variable fragment (SCFV) and hinge domain of monoclonal antibodies. SCFV is responsible for recognizing and binding relevant antigens (TAAs) on the surface of tumor cells. Hinge is responsible for linking SCFV to the transmembrane domain (TM). The transmembrane domain is responsible for anchoring the CAR structure to the T cell membrane and has a stabilizing effect on the CAR structure, and there is evidence that it can also enhance the activation of T cells. The intracellular domain consists of two parts, a signaling domain and one or more co-stimulatory domains. The signaling activation domain is responsible for activating T cells, and this structure is usually CD3. The process of T cell activation relies on phosphorylation of the activation motif (ITAM) of the immune receptor tyrosine in CD3. In addition to CD3, some studies have used the FC receptor of the immunoglobulin (Ig)E- domain as the signaling activation domain of CAR, but this structure has been found to be suboptimal. However, relying solely on CD3 in the signaling activation domain is not sufficient to activate T cells to a certain level and sustain CAR-T cell proliferation. The costimulatory domain (which is lacking in the first generation of CAR-T) usually originates from the signaling subunit of T cells, such as from the CD28 receptor family (CD28, ICOS) or the tumor necrosis factor receptor family (4-1BB, OX40, CD27), etc., and its function is to transmit extracellular binding signals to T cells, initiate downstream signaling cascade reactions, provide a second signal for T cell activation, enable T cells to continue to proliferate and release cytokines, and improve the anti-tumor ability of T cells.
Today, with the continuous innovation of CAR's technology, CAR has developed to the fifth generation, and its transformation direction has been to reduce toxicity and non-specific antigen recognition, improve the safety of the first generation, improve efficiency by stimulating the proliferation, activation and production of memory phenotypes in CAR-T cells, and provide immune regulation for the optimal role of CAR-T cells
References: 1] Yang, Kailin et al “antigen presentation in cancer - mechanisms and clinical implications for immunotherapy.” nature reviews. clinical oncology vol. 20,9 (2023): 604-623.
2] cartellieri, marc et al. “chimeric antigen receptor-engineered t cells for immunotherapy of cancer.” journal of biomedicine & biotechnology vol. 2010 (2010): 956304.
3] depil, s et al. “'off-the-shelf' allogeneic car t cells: development and challenges.” nature reviews. drug discovery vol. 19,3 (2020): 185-199.