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Combination therapy for treating cancer with a recombinant poxvirus expressing a tumor antigen and an immune checkpoint molecule antagonist or agonist

A technology of immune checkpoints and tumor-associated antigens, applied in the direction of anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, anti-animal/human immunoglobulin, cancer antigen components, etc., can solve the problem of cancer treatment Meeting medical needs and other issues

Pending Publication Date: 2017-02-22
BAVARIAN NORDIC AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] There is a clear unmet medical need for additional cancer treatments, including active immunotherapies and cancer vaccines

Method used

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  • Combination therapy for treating cancer with a recombinant poxvirus expressing a tumor antigen and an immune checkpoint molecule antagonist or agonist
  • Combination therapy for treating cancer with a recombinant poxvirus expressing a tumor antigen and an immune checkpoint molecule antagonist or agonist
  • Combination therapy for treating cancer with a recombinant poxvirus expressing a tumor antigen and an immune checkpoint molecule antagonist or agonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0312] Construction of MVA-BN-mHER2

[0313] Simultaneous infection and transfection of cultures allows homologous recombination between the viral genome and the recombinant plasmid. Insert-carrying viruses are isolated, characterized, and virus stocks are prepared.

[0314] Plasmid pBN146 contains sequences that are also present in MVA-BN (14L and 15L open reading frames). The mHER2 sequence was inserted between the MVA-BN sequences to allow recombination into the MVA-BN viral genome. Therefore, a plasmid containing the mHER2 sequence downstream of a poxvirus promoter, in particular the vaccinia type A inclusion body gene promoter, was constructed. This plasmid also contains a selection cassette containing a synthetic vaccinia virus promoter (Ps), a drug resistance gene (guanine-xanthine phosphoribosyltransferase; Ecogpt), an internal ribosome entry site (IRES), and enhanced green fluorescence protein. Two selection genes (gpt and EGFP) are encoded by a single bicistronic...

Embodiment 2

[0331] Increased IFNγ due to treatment with MVA-BN-mHER2 and anti-CTLA4

[0332] Female BALB / c mice (6-8 weeks old, approximately 20 g) were purchased from Simonsen Laboratories, Gilroy, CA. For the experimental lung metastasis model, mice were vein grafted on day 1 with 5.0 × 10 4 CT26-HER-2 cells forming tumors in the lungs in 300 μL DPBS.

[0333] The following antibodies were purchased from Bio X Cell (West, Lebanon, NH): anti-ICOS agonistic antibody (clone 17G9), anti-CTLA-4 (9D9), anti-PD-1 (RMP1-14) and anti-LAG-3 ( C9B7W). All antibodies were injected intraperitoneally at 200 μg per mouse in 100 μL PBS on days 3 and 17 unless otherwise indicated. For virus treatment, unless otherwise indicated, 7.1 μL of 1.0 × 10 7 Infection units of MVA-BN-HER2-treated mice.

[0334] On day 25, whole blood, tumor / lung or spleen (4 mice / group) were pooled for flow cytometry analysis. Splenocytes were prepared by pressing the spleen between two frosted glass slides and lysing red ...

Embodiment 3

[0342] Increased IFNγ and cytokine production due to treatment with MVA-BN-mHER2 and anti-CTLA4

[0343] Treatment with MVA-BN-HER2 increased the quantity and quality of tumor antigen- and virus-specific T cells in the spleen. As described in Example 2, mice were implanted with 5 × 10 4 CT26-HER-2 cells were treated with MVA-BN-HER2 and anti-CTLA4. On day 25, tumor / lung or spleen (4 mice / group) were pooled and restimulated overnight as described in Example 2 to measure virus and tumor antigen specific responses.

[0344] result in figure 2 Shown in , A) Pie charts are area weighted to reflect the number of IFNγ+ cells per million CD8+ T-cells. B) IFNγMFI increases with tumor antigen-specific (HER2p63) multifunctional T cells with combination therapy.

[0345] In both Examples 2 and 3, the number and quality of antigen- and virus-specific T cells increased as a result of combined treatment with MVA-BN-HER2 and anti-CTLA-4. Furthermore, combination treatment increased the ...

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Abstract

The invention relates to compositions, kits, and methods for cancer therapy using recombinant poxviruses encoding a tumor-associated antigen in combination with antagonists or agonists of immune checkpoint inhibitors.

Description

[0001] field of invention [0002] The present invention relates to cancer therapy using recombinant poxviruses encoding tumor antigens in combination with one or more agonists or antagonists of immune checkpoint molecules. [0003] Background of the invention [0004] Recombinant poxviruses have been used as vaccines against infectious organisms and more recently against tumors. Mastrangelo et al. J Clin Invest. 2000;105(8):1031-1034. Two of these poxvirus classes, fowlpoxviruses and orthopoxviruses, have been shown to be effective in combating tumors and have been implicated in potential cancer therapy. Ditto. [0005] Fowlpox, an exemplary fowlpox virus species, has been shown to be a safe vehicle for human administration because fowlpox virus enters mammalian cells and expresses proteins, but fails to replicate. Skinner et al. Expert Rev Vaccines. 2005 Feb;4(1):63-76. Additionally, the use of fowlpox virus as a vector for expression is being evaluated in numerous clinic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/39A61P35/00
CPCA61K39/39A61K2039/5254A61K39/464406A61K39/461A61K39/464411A61P35/00A61P37/04A61P43/00Y02A50/30A61K39/275A61K39/395C07K2317/76C12N2710/24041C12N2710/24141A61K2039/5256A61K39/0011A61K39/00117A61K39/001106A61K39/001182A61K39/001193A61K39/00115A61K39/001194A61K35/76C07K16/2818C07K16/30C12N7/00
Inventor S·福伊斯蒂法尼·曼德尔瑞安·朗特里A·弗兰祖斯奥夫
Owner BAVARIAN NORDIC AS
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