EGFR (epidermal growth factor receptor)-specific chimeric antigen receptor and application thereof

Abstract

The invention discloses an EGFR (epidermal growth factor receptor)-specific chimeric antigen receptor and application thereof. The EGFR-specific chimeric antigen receptor comprises a transmembrane signal region, an extracellular recognition region, a hinge region, a transmembrane region and an intracellular signal transduction region, which are connected in sequence. A CAR-T with the surface modified by the EGFR-specific chimeric antigen receptor has a strong tumor-specific antigen activation effect, a cytokine secretion function and a tumor-killing ability for triple negative breast cancer; the in-vitro killing efficiency is more than 90% under a low effector-to-target ratio; animal experiments verify the remarkable effective inhibitory effect of the CAR-T, the CAR-T has a remarkable tumor suppressive effect in in-vivo experiments, and accordingly, it is indicated that the CAR-T of the EGFR-specific chimeric antigen receptor has high applicability to the triple negative breast cancer.

Description

technical field [0001] The invention belongs to the technical fields of molecular biology and immunology, and specifically relates to an EGFR-specific chimeric antigen receptor and its application. Background technique [0002] In 2014, the National Cancer Center reported that the incidence of breast cancer among Chinese women was 41.82 per 100,000 people (Cancer incidence and mortality in China, 2014. Chinese Journal of Cancer Research, 2018, 30(1): 1- 12.), ranking first among female malignant tumors. At present, the annual incidence of breast cancer in China exceeds 160,000, and it is still increasing at a rate of 3% to 4%. Statistics show that the incidence of breast cancer in major cities in China has increased by 37% in 10 years, and the death rate has increased by 38.9%. Therefore, the prevention and treatment of breast cancer has a huge medical and health demand in our country. Among them, triple negative breast cancer (TNBC) accounts for 12-17% of all types of br...

AI Technical Summary

Problems solved by technology

CN104087607A discloses a CAR-T that specifically recognizes human EGFR. Under the same effect-to-target ratio, the in vitro killing rate of EGFR-overexpressing glioma cells U87 is as high as 98%. The in vitro killing rate of cell CFPAC-1 is only 40%. CN103113470A also discloses a CAR-T targeting human EGFR. The in vitro killing rate of cell A431 is still only about 50%

When differentiated into exhausted T cells, their ability to proliferate and secrete cytokines is greatly reduced, while the expression level of inhibitory receptors is increased, which ultimately limits their anti-tumor effects

The modification of CAR structure usually endows T cells with the effector function of mediating powerful tumor cell killing, but the excessive activation of T cells will drive the exhaustion of T cells, so it may also limit the persistence of T cells in turn, so the existing CAR- Although T is mostly effective, it often faces the dilemma of strong depletion and poor treatment effect

The results of clinical application of EGFR-specific CAR-T in the treatment of non-small cell lung cancer showed that 2 out of 11 patients with non-small cell lung cancer had a partial response, and 5 cases were in stable condition, but the duration was only 2-8 months. Subsequently, the disease progressed (NCT01869166), which shows that the current application of EGFR-specific CAR-T needs to further improve the persistence and reduce the exhaustion rate.

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