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Chimeric broad-spectrum oncolytic adenovirus for multi-mechanism synergistic immunotherapy and application thereof in tumor therapy

An oncolytic adenovirus and immunotherapy technology, applied to broad-spectrum chimeric oncolytic adenovirus and its application in tumor treatment, can solve problems such as poor effect, and achieve long-term survival protection and good anti-cancer effect , improve safety and effectiveness

Pending Publication Date: 2021-08-13
VONCOLYTIC THERAPEUTICS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is to solve the problem that the existing tumor immunotherapy has poor effect on solid tumors, and to provide a multi-mechanism synergistic anti-cancer agent that can be used as an immune checkpoint inhibitor and CAR-T / CAR-NK cell therapy synergist Chimeric broad-spectrum oncolytic adenovirus and its application in tumor therapy

Method used

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  • Chimeric broad-spectrum oncolytic adenovirus for multi-mechanism synergistic immunotherapy and application thereof in tumor therapy
  • Chimeric broad-spectrum oncolytic adenovirus for multi-mechanism synergistic immunotherapy and application thereof in tumor therapy
  • Chimeric broad-spectrum oncolytic adenovirus for multi-mechanism synergistic immunotherapy and application thereof in tumor therapy

Examples

Experimental program
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Effect test

Embodiment 1

[0056] Example 1 Development of a chimeric broad-spectrum oncolytic adenovirus VirRon, a multi-mechanism synergistic and synergistic immunotherapy of the present invention

[0057] A chimeric broad-spectrum oncolytic adenovirus VirRon, a multi-mechanism synergistic and synergistic immunotherapy described in the present invention, is recombined from an adenovirus right-arm plasmid, an adenovirus left-arm plasmid and an exogenous gene shuttle plasmid. The three plasmids and the recombination process are now introduced, as follows:

[0058] (1) Adenovirus right arm backbone plasmid

[0059]Adenovirus right arm backbone plasmid pPE3F11bH48-RC(+) was rebuilt from pBHGlox(delta)E13Cre plasmid (Catalog no.PD-01-40) and pBHGE3 plasmid (Catalog no.PD-01-12) provided by Microbix Biosystems, Canada Come. Insert the SpeI+NotI fragment of pBHGE3 containing part of the E3 region sequence and the synthetic ADP gene sequence (as shown in the 30901-31182bp of SEQ ID NO:3) into the SpeI+PacI ...

Embodiment 2

[0066] Example 2 Cytological experiment of chimeric broad-spectrum oncolytic adenovirus VirRon, a multi-mechanism synergistic and synergistic immunotherapy of the present invention

[0067] A chimeric broad-spectrum oncolytic adenovirus VirRon, a multi-mechanism synergistic and synergistic immunotherapy described in the present invention, can specifically proliferate and replicate in tumor cells, mediate the high-efficiency expression of anti-cancer genes, and finally destroy or inhibit tumor cells.

[0068] (1) Specific proliferation and replication of oncolytic adenovirus VirRon

[0069] Collect solid tumor cell lines and normal cell lines in the logarithmic growth phase, spread 96-well plates, 1×10 4 After the cells adhered to the wall, replace with serum-free medium; add VirRon at MOI=5pfu / cell to infect the cells. After 2 hours of virus infection, change the 5% serum culture medium, continue to cultivate for 0h, 48h, and 96h, collect cells and supernatants at 0h, 48h, a...

Embodiment 3

[0080]Example 3 Animal experiments of a chimeric broad-spectrum oncolytic adenovirus VirRon, a multi-mechanism synergistic and synergistic immunotherapy of the present invention

[0081] (1) Animal model experiment of VirRon against liver cancer

[0082] Thirty healthy purebred BALB / C nude mice, 4 weeks old, male, were provided by Shanghai Chengqin Biotechnology Co., Ltd., certificate number SCXK (Shanghai) 2012-0002. The HCCLM3 cell suspension in the logarithmic growth phase was injected into the right armpit of nude mice, 5×10 6 Cell number / 100μl / only. Twelve days after inoculation, the tumor formation rate was 100%, and the maximum and minimum diameters of transplanted tumors were about 5.0 mm on average. They were randomly divided into 3 groups (VirRon group, AdSVP-H48-DsRed group, blank control group), 10 rats in each group. In each group, one mouse with the largest tumor and one mouse with the smallest tumor were removed first, and the remaining 8 mice entered the exp...

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Abstract

The invention relates to a chimeric broad-spectrum oncolytic adenovirus for multi-mechanism synergistic immunotherapy and an application thereof in tumor treatment. The oncolytic adenovirus has the characteristics of triple tumor targeting regulation mechanism, modification of three virus structure genes, chimeric combination of three serum type adenoviruses and loading of three types of anti-cancer immune genes, and can activate the inherent anti-cancer activity of various virus structure proteins; the tumor cell infection capability is improved while the situation that viruses escape from interception of pre-stored neutralizing antibodies of organisms and adhesion and uptake of hepatocytes can be guaranteed; and the effect of killing cancer cells is improved and enhanced through three types of anticancer immunomodulatory genes. According to the key technology, the design concept of mutual cooperation of multiple mechanisms is ingeniously preset in a genome, the immunosuppression barrier of a tumor microenvironment can be broken, and an obvious synergistic effect is achieved on immune checkpoint inhibitor treatment and immune cell treatment. The oncolytic adenovirus disclosed by the invention belongs to a brand new type of oncolytic adenovirus, realizes real multi-mechanism synergistic interaction, is good in targeting property and strong in anticancer activity, has broad spectrum, and can be independently or auxiliarily used for treating cancers, especially solid tumors.

Description

technical field [0001] The invention belongs to the fields of life science and biomedicine, and specifically relates to a broad-spectrum chimeric oncolytic adenovirus for multi-mechanism synergistic and synergistic immunotherapy applied to tumor treatment and its application in tumor treatment. Background technique [0002] Oncolytic virus-mediated gene therapy has high tumor cell killing efficiency, good specificity, high safety, few side effects, and low cost, making it a new option after the three conventional treatment methods (surgery, radiotherapy, and chemotherapy) and immunotherapy. Another important emerging tumor treatment model. The biggest challenge of oncolytic virus therapy is how to improve the safety and effectiveness of the product. Through some safety regulation mechanisms, it can ensure that the oncolytic virus replicates in tumor cells to a large extent, but does not replicate in normal cells, the targeting specificity of tumors is improved, and its safe...

Claims

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Application Information

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IPC IPC(8): C12N7/01C12N15/24C12N15/23C12N15/19C12N15/34A61K35/761A61K38/20A61K38/21A61K38/19A61K48/00A61P35/00A61P35/04C12R1/93
CPCC12N7/00C07K14/005C07K14/5434C07K14/57C07K14/521A61K35/761A61K38/208A61K38/217A61K38/195A61K48/005A61K48/0008A61P35/00A61P35/04C12N2710/10021C12N2710/10022C12N2710/10032A61K2300/00
Inventor 黎江苏英晗
Owner VONCOLYTIC THERAPEUTICS CO LTD
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