Methods and compositions concerning poxviruses and cancer

a technology of poxvirus and cancer, applied in the field of poxviruses, can solve the problems of ineffective clearing of attenuated virus, reduced antiviral response, inability to counter, etc., and achieve the effect of increasing the antitumoral efficacy of attenuated vaccinia virus and increasing the antitumoral efficacy

Inactive Publication Date: 2006-05-11
JENNEREX BIOTHERAPEUTICS ULC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0076] In still further embodiments of the invention, there are methods of treating cancer in a cancer patient involving contacting a tumor site with a therapeutically effective amount of a composition comprising an attenuated vaccinia virus and an agent that increases antitumoral efficacy of the attenuated vaccinia virus, so as to effect treatment of the cancer. The agent that increases the antitumoral efficacy of the attenuated vaccinia virus can be an interferon, proteinase, peptidase, microtubule stabilizing agent, chemotherapy, radiotherapy, gene therapy, immunotherapy, or immunomodulatory therapy.

Problems solved by technology

In normal cells or tissues, viruses that were attenuated and less able to counter an anti-viral immune response are readily cleared; however, in non-normal cells and / or tissues, the anti-viral response is reduced and thus, even the attenuated virus is not as efficiently cleared.

Method used

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  • Methods and compositions concerning poxviruses and cancer
  • Methods and compositions concerning poxviruses and cancer
  • Methods and compositions concerning poxviruses and cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

Vaccinia Virus Propagation in Cell Lines

[0354] A panel of 16 different routinely available vaccinia virus laboratory strains / available mutants (and rabbitpox, and other poxviruses) was evaluated: Copenhagen, Dairen, Evans, USSR, Tashkent, Tian Tan, WR, IHD-J, IHD-W, Lister, NYCBOH, Patwadangar, King, and WR mutants B8R, B18R and B13R Replication was assessed in both cancer cells and in normal cells. A preferred virus would have relatively high replication in the cancer cells and reduced replication in normal cells (i.e., a larger therapeutic ratio or index between tumor and normal cells). Two human tumor cell lines were tested: A2780 colon carcinoma and HCT116 colon carcinoma (American Type Culture Collection). Normal cells included normal human bronchial epithelial (NHBE) cells. For cytopathic effect assays using proliferating cells, cells were grown to 70% confluence (DMEM with 2% FBS) at which time cells were infected with multiplicities of infection (MOI) of 0.001 to 10. Five t...

example 2

Vaccinia Virus in Combination with Paclitaxel

[0356] Although viruses such as adenovirus and HSV have been tested in combination with chemotherapy, vaccinia viruses have not (including the Copenhagen strain). VV has been engineered to express prodrug-activating enzymes (e.g. thymide kinase) have been tested in combination with relatively non-toxic prodrugs that become toxic following activation by the prodrug-activating gene product (Puhlhann et al., 2000).

[0357] Synergy between standard cytotoxic chemotherapeutics that are approved for the treatment of cancer patients and Vaccinia viruses would be an favorable feature for a poxvirus, including vaccinia and specifically Copenhagen strain. Paclitaxel (a.k.a taxol) is approved for use in cancer patients in the U.S. and Europe. VV Copenhagen were tested in combination with Taxol in both HCT116 and LNCaP cancer cell lines. Isobologram generation and analysis has shown synergy of VV in combination with Taxol (FIG. 5). Isobolograms were ...

example 3

Tumor Regression Results from Vaccinia Virus Administration

[0359] Subcutaneous murine tumor xenografts were formed by injecting 5×105 CMT-64 cells or 106 CMT-93 cells (murine rectal carcinoma) suspended in 100 μl PBS subcutaneously into the flanks of C57B / 6 mice. In the first experiment, W WR strain mutants in B8R and B18R were injected into subcutaneous CMT-93 tumors (estimated baseline tumor sizes 40-100 μl) in the flanks of immunocompetent C57 / B6 mice at doses of 104 to 108 particles suspended in 40 μl per day on days 1, 3 and 5. A single needle puncture was made in the center of the tumor and four needle tracts were made out into each tumor quadrant. Approximately one-fourth of the solution was injected into each tract as the needle was being withdrawn. Controls received identical treatment with psoralen-UV inactivated virus or PBS. Bidimensional tumor measurements were performed biweekly and the tumor volume established by the following formula: (length)(width)(width)(3.14 / 6)....

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Abstract

The present invention concerns methods and compositions for the treatment of cancer and cancer cells using altered poxviruses, including a vaccinia virus that has been altered to generate a more effective therapeutic agent. Such poxviruses are engineered to be attenuated or weakened in their ability to affect normal cells. In some embodiments, methods and compositions involve poxviruses that possess mutations that result in poxviruses with diminished or eliminated capability to implement an antiviral response in a host. Poxviruses with these mutations in combination with other mutations can be employed for more effective treatment of cancer.

Description

BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] The present invention relates generally to the fields of oncology and virology. More particularly, it concerns poxviruses, specifically including vaccinia viruses, that comprise one or more mutations rendering them particularly suitable for the treatment of cancer. [0003] 2. Description of Related Art [0004] Normal tissue homeostasis is a highly regulated process of cell proliferation and cell death. An imbalance of either cell proliferation or cell death can develop into a cancerous state (Solyanik et al., 1995; Stokke et al., 1997; Mumby and Walter, 1991; Natoli et al., 1998; Magi-Galluzzi et al., 1998). For example, cervical, kidney, lung, pancreatic, colorectal and brain cancer are just a few examples of the many cancers that can result (Erlandsson, 1998; Kolmel, 1998; Mangray and King, 1998; Gertig and Hunter, 1997; Mougin et al., 1998). In fact, the occurrence of cancer is so high that over 500,000 deaths per ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/12A61KA61K35/76A61K35/768A61K38/00A61K38/21A61K38/48A61K39/285A61P35/00C12N5/08C12N7/00C12N7/01C12N7/04C12N15/863C12Q1/70
CPCA61K48/00A61K45/06C12N15/86C12N2710/24121C12N2710/24132C12N2710/24143C12N2710/24161C12N2710/24162A61K38/21A61K35/768C12N7/00A61K2300/00A61P35/00A61P37/04
Inventor KIRN, DAVID
Owner JENNEREX BIOTHERAPEUTICS ULC
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