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CXCL9 modified chimeric antigen receptor T (CAR-T) structure and application thereof

A specific structure, meso-car-cxcl9 technology, applied to medical preparations containing active ingredients, polypeptides containing positioning/targeting motifs, anti-animal/human immunoglobulins, etc., can solve the problem of unseen combination Application and other issues

Active Publication Date: 2021-04-09
THE FIRST AFFILIATED HOSPITAL OF ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there have been no reports on the combined application of CXCL9 and CAR-T technology

Method used

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  • CXCL9 modified chimeric antigen receptor T (CAR-T) structure and application thereof
  • CXCL9 modified chimeric antigen receptor T (CAR-T) structure and application thereof
  • CXCL9 modified chimeric antigen receptor T (CAR-T) structure and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] This application uses CXCL9 to modify and transform CAR-T cells. Taking a lung cancer model as an example, a chimeric antigen receptor is designed based on the mesothelin target, and CXCL9 is used to modify and transform CAR-T cells. First, a specific CAR structure is designed. Then the T cells are labeled, the specific process is as follows.

[0050] (1) CAR structure design

[0051] Based on the structure of the second-generation CAR, the mesothelin-targeting CAR (meso-CAR) was designed, specifically connected in sequence: human CD8a molecule signal peptide (CD8a), scFv derived from human mesothelin antibody, human CD28 molecule transmembrane region and Intracellular region of CD28 molecule, intracellular region of human CD3z molecule (CD3Zeta), namely: CD8a-meso-CD28-CD3Zeta (CD3ζ);

[0052] That is to say, the CAR (meso-CAR-CXCL9) structure after modification of CXCL9 is: human CD8a molecular signal peptide (CD8a), scFv derived from human mesothelin antibody, human C...

Embodiment 2

[0089] Using the CAR-T cells prepared in Example 1, the inventors further carried out relevant cell experiments and animal experiment analysis, and the relevant experimental items and experimental results are introduced and analyzed as follows.

[0090] (1) Expression analysis of chemokine CXCL9

[0091] First, T cells were collected 5 days after virus infection, and the expression of CXCL9 in the cytoplasm of T cells was detected by flow cytometry.

[0092] The result is as figure 1 As shown in C, it can be seen from the analysis that:

[0093] The expression of CXCL9 in untransduced T cells (UTD) and CARTmeso cells was 10%-16%, while the expression of CXCL9 in CARTmeso-CXCL9 cells reached 30%-50%, indicating that the modified CARTmeso-CXCL9 cells successfully overexpressed CXCL9.

[0094] Subsequently, the secretion level of the T cell chemokine CXCL9 was determined. The specific operation: the supernatants of UTD cells, CARTmeso or CARTmeso-CXCL9 cells were collected resp...

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Abstract

The invention belongs to the technical field of tumor immunotherapy, and particularly relates to a CXCL9 modified chimeric antigen receptor T (CAR-T) structure and application patent application matter thereof. The CXCL9 modified CAR-T structure meso-CAR-CXCL9 has a specific structure: CD8a-meso-CD28-CD3Zeta-P2A-CXCL9. In the application, inventors obtain CAR-T-CXCL9 cells based on mesothelin design by taking a lung cancer model as an example. Preliminary experiment results show that, compared with conventional CAR-T cells, the modified cells have higher cytokine secretion and cytotoxicity capacities, can obviously increase immune cell infiltration of a tumor site, and inhibit angiogenesis, and further, the modified CAR-T-CXCL9 cell therapy slows down tumor growth, increases the survival rate of mice, and shows excellent anti-tumor activity.

Description

technical field [0001] This application belongs to the technical field of tumor immunotherapy, and specifically relates to a CXCL9-modified CAR-T structure and its application. Background technique [0002] In tumor immunotherapy, CAR-T (Chimeric Antigen Receptor T, Chimeric Antigen Receptor T) immunotherapy has shown good clinical efficacy in the treatment of hematological malignancies, among which CAR-T cells targeting CD19 have been approved For the treatment of CD19 positive lymphoma or leukemia. However, CAR-T cell therapy for solid tumors is hindered by various challenges and has not yet achieved the expected efficacy. The main reason is that the migration and accumulation of T cells in tumor sites is the first step to realize their effector functions, but the hidden location and complex microenvironment of solid tumors make it difficult for immune cells to enter. Therefore, how to improve the effect of intratumoral T cell infiltration in solid tumors is an important...

Claims

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Application Information

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IPC IPC(8): C07K19/00A61K38/19A61K39/00A61P35/00
CPCC07K14/7051C07K14/521C07K16/30A61K39/001111A61K38/195A61P35/00C07K2319/02C07K2319/03A61K2039/5156A61K2300/00
Inventor 张毅田永贵
Owner THE FIRST AFFILIATED HOSPITAL OF ZHENGZHOU UNIV
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