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Tumor vaccine combining exosome with immune checkpoint blocker and preparation method thereof

A technology of immune checkpoints and tumor vaccines, applied in the field of tumor vaccines combined with immune checkpoint blockers and its preparation, can solve the problems of unsatisfactory therapeutic effects of tumor vaccines

Pending Publication Date: 2020-10-30
HEBEI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to provide a tumor vaccine combined with exosomes and immune checkpoint blockers and its preparation method to solve the problem of unsatisfactory therapeutic effects of existing tumor immunotherapy methods and tumor vaccines

Method used

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  • Tumor vaccine combining exosome with immune checkpoint blocker and preparation method thereof
  • Tumor vaccine combining exosome with immune checkpoint blocker and preparation method thereof
  • Tumor vaccine combining exosome with immune checkpoint blocker and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Taking OVA, a widely used antigen model, as an example, the preparation method of Exo-OVA-aPD-L1 is described in detail below, such as figure 1 shown, including the following steps:

[0041] (1) Culture primary dendritic cells (DC)

[0042] After the C57BL / 6 female mice were killed by neck dislocation, they were soaked in 75% alcohol for 5-10 min for preliminary disinfection. In the ultra-clean workbench, use instruments such as scissors and tweezers after cleaning and sterilization to conduct experiments. The leg bones of the mouse limbs were taken out under aseptic conditions, soaked in PBS containing 10% penicillin & streptomycin (double antibody), and the muscles and connective tissue on the surface of the leg bones were removed as much as possible with a scalpel. The treated leg bones were placed in incomplete medium RPMI1640, the joints at both ends of the leg bones were cut off, and bone marrow cells (Bone Marrow Cell, BMC) were exposed. Using the prepared 1 m...

Embodiment 2

[0054] The anti-tumor effect of Exo-OVA-aPD-L1 was studied, and the results are as follows:

[0055] (1) Evaluation of the immune activation ability of Exo-OVA-aPD-L1 in vitro

[0056] By isolating mouse spleen lymphocytes and detecting the number of proliferation and differentiation of lymphocytes, the ability of the material to activate immunity in vitro was verified. After incubation of mouse splenic lymphocytes with Exo, Exo-OVA, Exo-OVA-aPD-L1, the cells were resuspended in PBS by centrifugation, and T cells, DCs, B cells and macrophages were labeled with fluorescent antibodies respectively. As detected by flow cytometry, the results were as follows Figure 6 As shown, the first column in Figure a is CD8+ T cells, and the second column is CD4+ T cells. Figure b shows dendritic cells, picture c shows macrophages, and picture d shows B cells. The results showed that Exo was basically the same as the control group, without the ability to activate the immune system. Both ...

Embodiment 3

[0067] The anti-tumor effect of cross-linked Exo-OVA-aPD-L1 combined with pure exosome Exo-OVA and immune checkpoint drug aPD-L1 was studied. The results are as follows: Figure 14 and Figure 15 shown.

[0068] Through the anti-tumor effect in mice and local tumor immunohistochemical analysis, it can be proved that the cross-linked material is more effective in activating immunity, enhancing local immune cell infiltration in tumor, and effectively inhibiting tumor growth than simple drug combination therapy.

[0069] 1. DC cells are antigen-presenting cells, which express PD-L1 themselves, and exosomes secreted by them also express PD-L1. During antigen presentation, they form an immunosuppressive pathway with PD-1 on the surface of T cells, which will affect DC and Efficiency of exosomes in activating immune cells. By modifying the PD-L1 antibody, we can block its own PD-L1, and at the same time modify the surface of the PD-L1 antibody to enhance antigen presentation and i...

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Abstract

The invention provides a tumor vaccine combining exosome with an immune checkpoint blocker and a preparation method thereof. The tumor vaccine takes an exosome Exo-Ag of a dendritic cell activated bya specific tumor antigen Ag as a carrier; the aPD-L1 modified tumor vaccine Exo-Ag-aPD-L1 is obtained by taking phospholipid-polyethylene glycol-succinimide ester DSPE-PEG-NHS as a cross-linking agentand modifying the surface of exosome Exo-Ag with a PD-L1 antibody. The dendritic cell exosome is used as a carrier to realize efficient lymph node enrichment and remarkable immune activation effect of the tumor vaccine, and meanwhile, by blocking an immune checkpoint pathway, the'braking 'effect of the tumor vaccine on immune response is relieved so that the effect that one plus one is greater than two is achieved. The dendritic cell exosome is used as a carrier to be effectively combined with the immune checkpoint blocker to synergistically remove tumors and prevent tumor metastasis and recurrence.

Description

technical field [0001] The invention relates to the technical field of tumor immunotherapy drugs, in particular to a tumor vaccine combined with exosomes and immune checkpoint blockers and a preparation method thereof. Background technique [0002] At present, tumor immunotherapy methods include chimeric antigen receptor (CAR) T cell therapy, immune checkpoint blockade (ICB) therapy and tumor vaccines, etc. These immunotherapy methods act on different stages of the tumor immune cycle to improve immune response Efficiency, significant improvement in patient survival has been achieved in clinical trials. However, the single immunotherapy approaches in current studies have their own limitations. [0003] CAR-T cells can be stimulated to proliferate exponentially, resulting in a highly amplified T-cell response to clear tumor cells within weeks. However, extensive studies have revealed the limitations of CAR-T cell immunotherapy. First, CAR-T cells can recognize and act on no...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61K39/395A61K45/06A61K47/46A61P35/00
CPCA61K39/001186A61K39/0011A61K39/00119A61K39/39558A61K45/06A61K47/46A61P35/00A61K2039/5154A61K2039/5156
Inventor 李振华戴欣悦张金超
Owner HEBEI UNIVERSITY
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