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Composition for removing tumor immunosuppression and application thereof

A technology of immunosuppression and composition, applied in the fields of immunology and medicine, can solve the problems of unsatisfactory clinical effect, failure of DC vaccine to induce anti-tumor T cells, bankruptcy, etc.

Active Publication Date: 2020-01-31
BEIJING TRICISIONBIO THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, after Sipuleucel-T went on the market, sales have been poor, and the original manufacturer, Dendreon Corporation, declared bankruptcy
Moreover, several other large-scale DC cell-based tumor vaccines have failed in phase III clinical trials
For example, Merck’s Stimuvax (targeting MUC1, renamed tecemotide in 2013) failed twice in phase III studies, and GlaxoSmithKline’s GSK1572932A (targeting MAGEA3) also stopped in clinical phase III. These data show that alone The use of DC vaccines usually does not lead to the expected improvement in the effect of immunotherapy, and satisfactory clinical results cannot be obtained
This may be due to the influence of various immunosuppressive factors, resulting in the failure of DC vaccine to induce enough anti-tumor T cells, which leads to clinical failure.

Method used

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  • Composition for removing tumor immunosuppression and application thereof
  • Composition for removing tumor immunosuppression and application thereof
  • Composition for removing tumor immunosuppression and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0064] [Preparation method of engineered antigen-presenting cells]

[0065] The third aspect of the present invention provides a method for preparing engineered antigen-presenting cells, the engineered antigen-presenting cells are used to relieve tumor immunosuppression, which includes introducing the composition described in the first aspect into the antigen-presenting cells, Thereby engineering antigen-presenting cells.

[0066] In certain embodiments, the methods of the invention comprise the steps of:

[0067] (1) constructing a nucleic acid capable of producing components (a) to (e);

[0068] (2) isolate peripheral blood mononuclear cells from venous blood, and induce differentiation to obtain antigen-presenting cells; and

[0069] (3) introducing the nucleic acid of step (1) into the antigen-presenting cell of step (2), and culturing the antigen-presenting cell under conditions suitable for expression of the nucleic acid.

[0070] In a preferred embodiment, the method...

preparation example

[0074] This preparation example is for the preparation of DNA and mRNA encoding antigens and immune checkpoint inhibitors

[0075] 1. Preparation of DNA and mRNA Constructs

[0076] The DNA sequences used to produce the mRNAs encoding IL12, IL15, IL15Rα and TGF-β regulatory peptides and PD1-CD80 of the present invention were respectively constructed, and used for subsequent in vitro transcription reactions. Following the coding sequence is a polyadenosine segment. The DNA sequence information is shown in Table 1 below.

[0077] In addition, the coding sequence of human tumor antigen GPC3 for in vitro sensitization is constructed. The coding sequence of GPC3 in the present invention consists of the sequence shown in SEQ ID No.11, and the amino acid sequence consists of the sequence shown in SEQ ID No.12. The sequence of GPC3 is available through the Genebank database. In this example, the antigen disclosed in CN107583042A was used.

[0078] Table-1 DNA sequence list

[007...

Embodiment 1

[0083] This example is used to study the effect of the composition of the present invention on T cell response.

[0084] 1. Induction culture of DC cells in vitro

[0085] Aseptically extract 50ml of venous blood from patients with hepatocellular carcinoma, separate peripheral blood mononuclear cells with lymphocyte separation medium in an ultra-clean workbench, add mononuclear cells to AIM-V medium, and place them in 37°C, 5% CO 2 Incubate in an incubator to allow monocytes to adhere to the wall. After 2h, the non-adherent cells were removed, and the adherent cells were added to iDC medium (GM-CSF with a final concentration of 800U / mL and IL-4 at 500U / mL were added to the AIM-V medium), and placed at 37°C for 5 %CO 2 Cultured in the incubator for 6 days. Transfer half of the cell culture medium to a centrifuge tube, collect the cells by centrifugation at 500g, remove the supernatant, and add an equal volume of fresh mDC medium (configuration of fresh medium for mDC: add AI...

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Abstract

The invention discloses a composition for removing tumor immunosuppression and application thereof. The composition provided by the invention comprises following (a) to (e) components or coded nucleicacid thereof: (a) IL-15, a mutant thereof or functional fragments thereof; (b) an IL-15 receptor alpha, a mutant thereof or functional fragments thereof; (c) IL-12, a mutant thereof or functional fragments thereof; (d) TGF-beta regulatory peptide, a mutant thereof or functional fragments thereof; and (e) PD1-CD80 fusion protein, a mutant thereof or functional fragments thereof. According to the composition provided by the invention, the immune response of T lymphocytes can be improved synergistically.

Description

technical field [0001] The invention relates to the fields of immunology and medicine, in particular to a composition for releasing tumor immunosuppression and its application. Background technique [0002] Traditionally, tumor cell immunotherapy mainly stimulates the immune system through vaccination or adoptive cell immunotherapy, thereby triggering an immune response. This approach is based on the assumption that tumor-specific antigens are expressed by tumor cells and presented on the tumor cell surface by the major histocompatibility complex (MHC), while antitumor T cells are not sufficiently activated. Therefore, to address this issue, attempts have been made to either stimulate key positive co-immune and innate immune pathways such as CD28, CD40L (CD154) and various TLR receptors, or inhibit negative immunosuppressive pathways such as CTLA-4 The receptor, PD-1 receptor, increases the recognition of these antigens. [0003] Existing studies have shown that the expres...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61K38/20A61K38/17C12N5/10C12N15/87A61P35/00
CPCA61K38/1709A61K38/1774A61K38/1793A61K38/208A61K38/2086A61K39/001111A61K2039/5154A61P35/00C12N5/0639C12N15/87C12N2510/00A61K2300/00
Inventor 孙圣楠林鑫文高柳吴斐然
Owner BEIJING TRICISIONBIO THERAPEUTICS INC
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