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Immunotherapy of targeted transportation of chemotactic factor and cytokine via mesenchymal stem cell

A technology of mesenchymal stem cells and chemokines, which is applied in the field of immunotherapy for mesenchymal stem cells to target and transport chemokines and cytokines, which can solve the problems of side effects, loss, and low infiltration activity of T cells.

Active Publication Date: 2020-10-30
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the therapeutic effect of antibodies is usually limited by many factors, such as low infiltration of T cells in solid tumors and loss of activity
In addition, systemic use of immunotherapy drugs such as interferon-α, interleukin-2 or PD-1 antibodies may cause serious side effects

Method used

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  • Immunotherapy of targeted transportation of chemotactic factor and cytokine via mesenchymal stem cell
  • Immunotherapy of targeted transportation of chemotactic factor and cytokine via mesenchymal stem cell
  • Immunotherapy of targeted transportation of chemotactic factor and cytokine via mesenchymal stem cell

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0152] Example 1 Characteristics of Adipose-derived Mesenchymal Stem Cells Migrating to Tumors

[0153] The mesenchymal stem cells were extracted from the subcutaneous fat of mice. After flow cytometry detection, these cells expressed specific mesenchymal stem cell marker molecules, and did not express marker molecules of other cell types ( figure 1 A), confirming the purity of the adipose-derived mesenchymal stem cells used in the experiment. Adipose-derived mesenchymal stem cells were transfected with lentivirus to express GFP, and then 5×10 5 The cells were injected into the tumor-bearing mice (CT26 intestinal cancer subcutaneous tumor) through the tail vein, and the tumor and other organs were immunofluorescence stained on tissue sections after 7 days, and the results showed that GFP-positive mesenchymal stem cells only resided in the tumor. It was not found in other organs such as liver, spleen and kidney ( figure 1 B). GFP-positive mesenchymal stem cells in the tumor ...

Embodiment 2

[0154] Example 2 Anti-tumor properties of CXCL9 and OX40L

[0155] In order to explore immune-activating therapeutic molecules with high efficacy, chemokines and cytokines with potential anti-tumor functions were selected, and the genes were cloned into lentiviral vectors to package lentiviruses carrying these genes. The CT26 intestinal cancer cell line transduced with these genes or blank control lentiviruses was subjected to a subcutaneous xenograft tumor experiment to detect the antitumor efficacy of these molecules. Chemokines CCL3 and CXCL9 with potential antitumor efficacy were overexpressed in CT26 ( figure 2 A) After that, the in vitro proliferation of cells was not affected ( figure 2 B), while the growth of subcutaneous xenografts in vivo was significantly inhibited ( figure 2 C), indicating that these chemokines may inhibit tumor growth through the action of the immune system in vivo. Among them, CXCL9 has the most significant anti-tumor effect. Detecting the...

Embodiment 3

[0157] Example 3 Anti-tumor efficacy of mesenchymal stem cells overexpressing chemokine CXCL9 and cytokine OX40L

[0158] Adipose-derived mesenchymal stem cell system overexpressing CXCL9 and OX40L was established by lentivirus infection. The successful expression and secretion of CXCL9 was identified by Western blot and ELISA ( Figure 4 A&B), Western blot and flow cytometry confirmed the successful expression of OX40L on the cell membrane ( Figure 4 C&D). Mesenchymal stem cells overexpressing OX40L can also stimulate the proliferation of T cells after co-cultured with T cells ( Figure 4 E), demonstrating its biological activity. Afterwards, MSCs overexpressing CXCL9 and OX40L were established ( Figure 5 A&B) In the CT26 subcutaneous xenograft tumor model, mice were injected with 5×10 5 Mesenchymal stem cells or PBS were treated three times at intervals of four days, and the mesenchymal stem cells carrying CXCL9 and OX40L showed the strongest anti-tumor effect ( Fig...

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Abstract

The invention provides immunotherapy for targeted transportation of a chemotactic factor and a cytokine via a mesenchymal stem cell. Specifically, the invention provides the mesenchymal stem cell. Themesenchymal stem cell expresses an immunostimulatory factor, wherein the immunostimulatory factor is selected from the group consisting of CCL3, CCL19, CCL21, XCL1, CXCL9, OX40L, 4-1BBL, GITRL, CD40L, and combinations of the above immunostimulatory factors. The mesenchymal stem cell disclosed by the invention can specifically attract and activate immune cells for killing tumor tissues at a tumorpart, and the mesenchymal stem cell and chemotactic factor and / or cytokine have a synergistic effect, so the mesenchymal stem cell has an immune curative effect which is more efficient and low in sideeffect and is remarkably enhanced in tumor tissue killing capability, especially colorectal cancer cell killing capability.

Description

technical field [0001] The present invention belongs to, specifically, the present invention relates to the immunotherapy of targeted transport of chemokines and cytokines by mesenchymal stem cells. Background technique [0002] The rapid development of immunotherapy has brought a new dawn to cancer, especially Chimeric Antigen Receptor T cell immunotherapy (CAR-T) and immune regulatory checkpoint blockade are currently two cutting-edge cancer immunotherapies. CAR-T cell therapy has shown certain curative effect in some types of cancer, but it also encounters the low efficiency of T cells reaching the solid tumor site and the short duration of action, the number of existing immune cells in the tumor site is small, and the systemic drug brings The bottleneck of the side effects and so on. The use of antibodies targeting T cell inhibitory receptors PD-1 or CTLA-4 can produce very significant anti-tumor effects. However, the therapeutic effect of antibodies is usually limited...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/10A61K35/28A61K45/06A61P35/00A61P35/02A61P35/04
CPCC12N5/0667C12N5/0665A61K35/28A61K45/06A61P35/00A61P35/02A61P35/04C12N2510/02A61K2300/00
Inventor 高维强马斌印盼
Owner SHANGHAI JIAO TONG UNIV
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