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Compositions and methods for cancer therapy with dengue virus and dendritic cells

A technology of dendritic cells and dengue virus, applied in biochemical equipment and methods, medical raw materials derived from viruses/bacteriophages, viruses, etc., can solve problems such as unsatisfactory results, low ability of complete response, and limited success

Inactive Publication Date: 2020-04-10
PRIMEVAX IMMUNO ONCOLOGY INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These attempts have had limited success due to the self-identity of the peptides selected as targets for immunotherapy, lack of immune activation, adverse events, and / or tumor immune evasion mechanisms
[0006] Current cellular therapies such as dendritic cell therapy have a low ability to induce durable complete responses in advanced cancer patients (5-10% in most immunogenic cancer types and lower in others)
Typically, dendritic cell therapy results from low activation (eg, not enough immune cells to completely kill all cancer cells), poor targeting (eg, healthy cells are killed and / or tumor cells are not killed), or immunosuppression Tumor microenvironment limits drug efficacy leading to suboptimal outcomes

Method used

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  • Compositions and methods for cancer therapy with dengue virus and dendritic cells
  • Compositions and methods for cancer therapy with dengue virus and dendritic cells
  • Compositions and methods for cancer therapy with dengue virus and dendritic cells

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0155] Example 1. Generation and pulse treatment of murine dendritic cells (DC)

[0156] Mature DCs were generated from mouse bone marrow using the method as described by Lutz M. et al. (J. Immunol. Methods 223:77-92, 1999). The bone marrow suspension was incubated in culture dishes for 10 days in medium supplemented with recombinant murine GM-CSF. Non-adherent cells were collected, centrifuged, and resuspended in medium containing GM-CSF and lipopolysaccharide. Two days later, DCs were harvested and their viability was determined by trypan blue exclusion. Purity of DCs was determined by flow cytometry analysis. DCs were pulsed with 10 μg / ml of synthetic peptide for 18 hours. After 18 hours of incubation, DCs were harvested, washed twice in HBSS, and resuspended in HESS for additional analysis (see Examples 2 and 3).

Embodiment 2

[0157] Example 2. Dengue virus and dendritic cells for the treatment of melanoma in a first mouse model

[0158] Mouse model experiments using dengue virus (DV) strains and tumor antigen-primed dendritic cells (DCs) were performed to observe the results of combined targeting of cancer cells. DV C57BL / 6 mice were inoculated with 0.05 ml of 1x10 via tail base injection 6 or 1x10 7 Dengue virus (DEN-2 strain #1710) in pfu / ml. 2,000 ( rIL-2) and 500 IU (rIFN-γ) administered recombinant murine IL-2 (Genzyme) and IFN-γ (Sigma Pharmaceuticals). Seven days after dengue virus administration, C57BL / 6 mice were immunized intravenously with mouse DCs incubated separately with the two peptides. Synthetic peptides. An H-2b-restricted peptide from ovalbumin (OVA-8), SIINFEKL (SEQ ID NO: 7), was used as a control. Using B16 melanoma-associated H-2b-restricted peptide (EGSRNQDWL (SEQ ID NO: 1 )) derived from antigen gp100 / pme117 and B16 melanoma-associated H-2b-restricted peptide derived...

Embodiment 3

[0162] Example 3. Dengue virus and dendritic cells for the treatment of melanoma in a second mouse model

[0163] Mouse model experiments were performed using DCs primed with dengue virus (DV) strains and tumor antigens to observe the results of combined targeting of cancer cells. Cytokines were administered to mice to parallel the response to DV observed in humans.

[0164] Tumors were established in mice using the H-2b-restricted B16 mouse melanoma cell line (ATCC #CRL-6322). Peptides (derived from antigen gp100 / pme117 and B16 melanoma-associated H-2b-restricted peptide derived from TRP-1 / gp75) for pulsed dendritic cells were synthesized. Dendritic cells were generated from mouse bone marrow according to the method described by Lutz et al. (J. Immunol. Methods 223:77-92, 1999).

[0165] On day 0, mice received 5x10 4live B16 melanoma cells to establish lung metastases. On day 7, mice were inoculated with 0.05 ml of 1x10 by injection at the base of the tail 6 or 1x10 7 ...

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Abstract

Described herein are compositions and methods for treating a disease, particularly a melanoma, with a Dengue Virus and, optionally, primed dendritic cells recognizing a tumor antigen. Lysis protocolsare described where the lysis does not result in complete or less than complete lysis of cells in order to provide cell surface molecules maintained in a cell surface-embedded state. Non-lethal Denguevirus strains are also provided for therapeutic purposes.

Description

[0001] cross reference [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 520,345, filed June 15, 2017, which is hereby incorporated by reference in its entirety. [0003] sequence listing [0004] This application contains a Sequence Listing, which has been filed electronically in ASCII format, and is hereby incorporated by reference in its entirety. Said ASCII copy, created on June 14, 2018, is named 48253-707_601_SL.txt and is 45,748 bytes in size. Background technique [0005] Unlike cytotoxic drugs, radiation and surgery, immunotherapy stimulates the immune system to recognize and kill tumor cells. Many attempts have been made to stimulate the immune system to recognize and destroy tumor cells. These attempts have had limited success due to the self-identity of the peptides selected as targets for immunotherapy, lack of immune activation, adverse events and / or tumor immune evasion mechanisms. [0006] Current cellular therapies such...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/12A61K35/15A61P35/00
CPCA61K35/76A61K39/12A61P35/00C12N5/0639C12N7/00C12N2770/24121C12N2770/24133A61K39/4615A61K39/464456A61K2239/57A61K2239/31A61K39/464492A61K39/4622A61K2239/38A61K2300/00Y02A50/30A61K35/15
Inventor 布鲁斯·W·里戴托尼·陈
Owner PRIMEVAX IMMUNO ONCOLOGY INC