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An oncolytic virus vaccine and its drug combined with immune cells to treat tumors

A technology for oncolytic viruses and vaccines, which is applied to anti-tumor drugs, medical raw materials derived from viruses/bacteriophages, viruses, etc. It can solve the problems of poor oncolytic effect, inability to successfully package, and ineffective improvement of effects, etc.

Active Publication Date: 2020-10-27
JOINT BIOSCIENCES (SH) LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, when using VSV and TCR-T in combination for tumor immunotherapy, there are still at least the following problems: (1) The cure rate is not high when the wild strain or attenuated strain of VSV is directly used in combination with TCR-T, which is different from using one alone. (2) Wild-type VSV still has certain safety risks, and it is currently known to have strong neurotoxicity to rodents. For clinical use, it needs to be genetically modified to further Reduce the risk of disease; (3) random gene modification may lead to poor oncolytic effect, or may not be successfully packaged, and recombinant virus cannot be prepared at all

Method used

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  • An oncolytic virus vaccine and its drug combined with immune cells to treat tumors
  • An oncolytic virus vaccine and its drug combined with immune cells to treat tumors
  • An oncolytic virus vaccine and its drug combined with immune cells to treat tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1: Construction and effect display of attenuated strains with site-directed mutation

[0059] 1. According to the manner in Table 1, site-directed mutation was performed on the Indiana strain of vesicular stomatitis virus, and three groups of mutated attenuated strains were obtained. The group number without gene mutation is: JBS000, as a control.

[0060] Table 1 The mutation status of each group

[0061]

[0062] The specific construction method of the attenuated strain is a conventional technique in the art, which is briefly described as follows:

[0063] (1) Construct the plasmid. Using the pVSV-XN2 plasmid as a template, the PCR method was used to introduce different mutation sites as described in Table 1. PCR was performed on the plasmid and primers for each mutation site, and then the PCR product was subjected to 1% agarose gel electrophoresis, and then the gel recovery kit was used for gel recovery to obtain plasmids with different mutations in the...

Embodiment 2

[0084] Example 2: Construction and effect display of oncolytic virus vaccine

[0085] 1. On the basis of each attenuated strain and wild-type virus prepared in Example 1, insert the NY-ESO-1 gene to construct an oncolytic virus vaccine. The construction schematic diagram is as follows Figure 5 shown. The insert fragments of each group are shown in Table 2.

[0086] Table 2 Display table of insert fragments in each group

[0087]

[0088] The specific preparation methods of JBS004-JBS007 are conventional techniques in the field, and are briefly described as follows. It should be noted that the following description does not limit JBS004 to JBS007 to be carried out according to the following method, but gives an example.

[0089] (1) Construction of attenuated strain plasmid. Artificially synthesized linking sequences with restriction enzyme sites Xho I and Mlu I, using biological technology and gene recombination technology, insert it into the non-coding between the G p...

Embodiment 3

[0102] Example 3: The pharmacokinetics and acute toxicity test results of JBS004

[0103] 1. Pharmacokinetic experiment. Select C57BL / 6 mice and subcutaneously inoculate 2×10 5 LLC cells, about 9 days after inoculation, the transplanted tumor grows to 100mm 3 Left and right, the LLC xenograft tumor model was established. Single intratumoral injection of 10 8 pfu / JBS004, tumor tissue samples were taken at 0 min (+15min), 6h, 12h, 48h, 96h, 120h and 14 days (repeat 3 times), the tissue was broken with a fully automatic grinder, and the tumor was extracted with Trizol The total RNA of the tissue is finally analyzed for the copy number of viral nucleic acid by quantitative PCR (fluorescent probe method). The result is as Figure 19 , 20 shown. The results showed that the amount of virus in the tumor reached its peak at 6 hours after infection, which was about 500 times more than the initial dose; 48 hours after infection, the amount of virus began to be lower than the init...

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Abstract

The invention belongs to the field of biotechnology, and in particular relates to an oncolytic virus vaccine and a drug for treating tumors in combination with immune cells. The present invention provides a brand-new attenuated strain of oncolytic virus by performing site-directed mutation on the matrix protein M of the VSV wild-type virus, and its matrix protein M gene sequence is shown in SEQ ID NO 3. The attenuated strain can be used alone as a drug to treat tumors, and its safety and cure rate are superior to wild-type virus and other known attenuated strains. Based on the attenuated strain of oncolytic virus, the present invention also provides a vaccine applicable to tumor treatment by inserting NY-ESO-1 into the attenuated strain. The vaccine has a high cure rate and high biological safety. On the basis of the vaccine, the present invention also uses the vaccine in combination with TCR-T cells to provide a drug that can efficiently treat multiple types of tumors; on a mouse lung cancer model, the cure rate can reach 95%.

Description

technical field [0001] The invention belongs to the field of biotechnology, and in particular relates to an oncolytic virus vaccine and a drug for treating tumors in combination with immune cells. Background technique [0002] According to the national cancer statistics released by the National Cancer Center in January 2019, there were about 3.929 million cancer cases and 2.338 million deaths in 2015. On average, more than 10,000 people are diagnosed with cancer every day, and 7.5 people are diagnosed with cancer every minute. Solid tumors such as liver cancer, colorectal cancer, and female breast cancer are still the main malignant tumors in my country. Malignant tumors (cancers) have become one of the major public health problems that seriously threaten the health of the Chinese population. Although the current cancer treatment has made great progress in multidisciplinary comprehensive treatment such as surgery, chemotherapy, radiotherapy and molecular targeted therapy, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N7/01C12N7/04A61K39/00A61K48/00A61K35/76A61K47/46A61K47/69A61P35/00A61K35/17
CPCC12N7/00A61K39/0011A61K48/0008A61K47/46A61K35/76A61K35/17A61P35/00A61K47/6901C12N2760/20221C12N2760/20234C12N2760/20243A61K2039/5254A61K2300/00C12N2760/20232C12N15/86A61K35/766Y02A50/30A61K2039/545A61K2039/54A61K39/001188C12N2740/15043A61K39/4611A61K39/4622A61K39/4634A61K2239/59A61K2039/70A61K35/15A61K39/4613A61K39/4614A61K39/461A61K39/4644A61K39/4631A61K39/4632A61K2039/5256A61K2239/46A61P37/04A61K39/464499A61K39/145A61K45/06
Inventor 周国庆张苏宏张凡
Owner JOINT BIOSCIENCES (SH) LTD
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