CAR (chimeric antigen receptor) carrying truncated or non-truncated natural cytotoxic receptor signal structure and application of CAR

Abstract

The invention discloses a CAR (chimeric antigen receptor). The CAR comprises an antigen binding structural domain (scfv) and a signal conducting domain, wherein the signal conducting domain comprisesa first conducting domain and a second conducting domain, and the antigen binding structural domain is connected in series between the first conducting domain and the second conducting domain. When the CAR structure is stimulated by antigen, the level of secreted cytokines is extremely low, and safety of clinical application can be well ensured and is higher; killing capacity of antigen positive tumor cells in vitro is higher, and anti-tumor activity is better.

Description

technical field [0001] The invention relates to the technical field of tumor immunotherapy, in particular to a chimeric antigen receptor carrying a truncated or non-truncated natural cytotoxicity receptor signal structure and an application thereof. Background technique [0002] Chimeric antigen receptor (CAR) is the core component of CAR-T. Using the ligand-binding domain properties, CAR can redirect the specificity and reactivity of selected immune cells, thus endowing T cells with an HLA-independent manner. The ability to recognize tumor antigens, which allows CAR-engineered T cells to recognize a wider range of targets than natural T-cell surface receptors TCR. The basic design of CAR includes a tumor-associated antigen (tumor-associated antigen, TAA) binding region (usually derived from the scFV segment of the antigen-binding region of a monoclonal antibody), an extracellular hinge region, a transmembrane region and an intracellular signal Area. [0003] The current t...

AI Technical Summary

Problems solved by technology

In terms of effectiveness, first of all, the tumor stroma composed of solid tumor-associated fibroblasts (CAFs) provides a physical barrier for the infiltration of CAR-T cells, and CAFs also secrete extracellular matrix proteins to separate T cells from cancer cells. Second, the metabolic environment of the tumor microenvironment of solid tumors is not conducive to the persistence of traditional CAR-T cells, because once tumor formation is activated, tumor cells stop producing ATP through oxidative phosphorylation and switch to aerobic glycosylation The solution causes the tumor environment to become acidic, which is the so-called "Warburg effect". The pH value drops from 7.4 to 6.5; finally, the tumor microenvironment causes hypoxia to further produce immune suppression, and tumor cells in a hypoxic environment produce a HIF1 -ɑ molecule, which weakens the anti-tumor function of traditional CAR-T cells by attracting regulatory T cells (Tregs) to the tumor site. Tregs suppress the immune response, thus limiting the therapeutic effect of traditional CAR-T on solid tumors

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