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Monocyte and macrophage for expressing chemokine receptor with solid tumor directional chemotactic ability, and preparation and application thereof

A technology of chemokine receptors and monocyte-macrophages, which is applied in the field of monocytes and macrophages, can solve the problem of difficult delivery of immune cells, improve the efficiency and utilization of specific killing, and reduce non-specificity Immune to attack effects

Active Publication Date: 2021-08-31
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For example, glioblastoma (GBM) is located inside the brain of the body and is hindered by the blood-brain barrier and extracellular dense matrix. Traditional adoptive transplantation of immune cells is often difficult to deliver to the tumor lesion

Method used

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  • Monocyte and macrophage for expressing chemokine receptor with solid tumor directional chemotactic ability, and preparation and application thereof
  • Monocyte and macrophage for expressing chemokine receptor with solid tumor directional chemotactic ability, and preparation and application thereof
  • Monocyte and macrophage for expressing chemokine receptor with solid tumor directional chemotactic ability, and preparation and application thereof

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preparation example Construction

[0053] In a second aspect, the present invention provides a method for preparing macrophages, comprising the steps of: constructing a lentiviral expression system containing chemokine receptor genes, and integrating the chemokine receptor genes into multiple macrophages using the lentiviral expression system. Macrophages are prepared after induced differentiation from competent stem cells or mononuclear macrophages;

[0054] Preferably, the pluripotent stem cells are firstly induced to differentiate into monocytes, and then differentiated into macrophages.

[0055] The strategy of stably expressing the receptor CCR2B, which recognizes the chemokine CCL2 secreted by solid tumor cells, in adoptive transplantation iMAC / Macrophage through a lentiviral expression system can endow the immune cells with three abilities in clinical treatment: 1. Significantly improve its The ability to chemotaxis and migrate to GBM and other solid tumors that can secrete chemokines, thereby enhancing ...

Embodiment 1

[0067] Example 1 Secretion of Chemokine CCL2 in Different Solid Tumor Cells

[0068] Analysis of data from the tumor cell database CCLE (Cancer Cell Line Encyclopedia) showed that solid tumors, including GBM, mesothelioma, and renal carcinoma, secreted higher levels of the chemokine CCL2.

[0069] Further data mining and comparison of the database, the results are as follows figure 1 As shown in A, the level of CCL2 secreted by GBM was found to be significantly higher than that of normal brain tissue.

[0070] GBM cell lines (U87MG, U251 and LN229), ovarian cancer cell lines (OVCAR8 and HO-8910) and blood mononuclear macrophages (THP1) were cultured in vitro, and ELISA experiments were performed on the above cells, and the results were as follows: figure 1 As shown in B, it can be seen that GBM cell lines (U87MG, U251 and LN229) highly express chemokine CCL2, and its expression level is significantly higher than that of ovarian cancer cell lines (OVCAR8 and HO-8910), and bloo...

Embodiment 2

[0082] Inject 1×10 subcutaneously in the ventral side of immunodeficient NSG mice 6 A U87MG cell carrying the luciferase gene. After tumor formation, inject 1×10 6 iMACs and T lymphocytes with fluorescent dyes. After 5 days, in vivo imaging of mice showed that both iMAC and T lymphocytes that did not express chemokine receptor CCR2B were concentrated in the mouse liver, and neither had the ability to migrate to the GBM site ( figure 2 ).

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Abstract

The invention provides a monocyte and a macrophage for expressing a chemokine receptor with solid tumor directional chemotactic ability, and preparation and application thereof, and relates to the field of biotechnology. The invention provides a macrophage, the macrophage overexpresses the chemokine receptor, the macrophage has the ability of chemotactic migration to a solid tumor and remarkable effects of chemotactic migration to the tumor and infiltration, the specific killing efficiency and utilization rate of adoptively transplanted macrophage can be improved, and non-specific immune attack to normal tissues is reduced. The invention provides a preparation method of macrophages, which comprises the following steps: constructing a lentivirus expression system containing a chemokine receptor gene, integrating the chemokine receptor gene into pluripotent stem cells or mononuclear macrophages by using the lentivirus expression system, performing induced differentiation to obtain the macrophages, and the macrophages can stably overexpress the chemokine receptor for a long time.

Description

technical field [0001] The invention relates to the field of biotechnology, in particular to monocytes and macrophages expressing chemokine receptors and capable of directional chemotaxis to solid tumors, as well as their preparation and application. Background technique [0002] CAR-T is a new type of precise targeted therapy for the treatment of tumors. It has a good therapeutic effect in hematological tumors. Still not ideal. Therefore, it is urgent to find more effective and safe substitutes for immunotherapy against solid tumors. Because Macrophage plays a central role in the interaction between the adoptive immune system and the innate immune system, and has the characteristics of strong plasticity and long-term residence in tumor tissues, it is becoming a new method for immune cell therapy of solid tumors. choose. In addition, existing studies have tried to deliver CAR-T and other immune cells to tumor foci through intracranial injection in order to achieve the pur...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/10C12N15/12C12N15/867A61K39/00A61P35/00
CPCC07K14/7158C12N15/86C12N5/0645A61K39/0011A61P35/00C12N2506/115C12N2510/00C12N2740/15043A61K2039/80A61K2039/884A61K2039/812A61K2039/82A61K2039/86
Inventor 张进雷安华朱萌濛
Owner ZHEJIANG UNIV
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