Methods and compositions concerning poxviruses and cancer

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 ...

AI Technical Summary

Benefits of technology

[0014] The mechanism by which viruses of the invention can be considered oncolytic and have enhanced safety and / or accelerated clearance from normal tissues involves the extent to which normal cells as opposed to non-normal cells (such as cancer cells or tissues) are capable of exhibiting an antiviral response (i.e., mounting, responding and / or inducing an immune response). Normal cells or tissues have such an ability, while cancer cells or tissues often do not express or have reduced levels of cellular proteins that induce or are involved in the antiviral response. Such cellular proteins include interferons, TNF, chemokines, cytokines, and other factors. 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. The basis for some embodiments of the invention is that the viruses discussed herein are an improved form of therapy, such as by enhanced safety and reduced toxicity on normal cells, as they will have less effect on normal, in contrast to non-normal, cells. Thus, the attenuated virus will preferentially replicate and express genes in cancer cells in which the induction or response to interferon, for example, is reduced or absent.

[0020] A TNF-modulating polypeptide refers to a poxvirus polypeptide that has an activity that affects a cell's immune and inflammatory response that is activated via TNF receptors. This response may involve inducing apoptotic cell death. Poxviruses express these TNF-modulating polypeptides as a way to counteract the TNF-mediated clearance of virus and / or virus-infected cells. These polypeptides have function in which they specifically bind and sequester extracellular TNF, resulting in the inhibition of viral clearance. It is specifically contemplated that these polypeptides may suppress, diminish, or eliminate this particular anti-viral reaction. These TNF-modulating polypeptides modulate, affect, interfere with, inhibit, reduce, alter, or eliminate the activity or function of this mechanism directly or indirectly. Thus, allowing the viral infection to proceed and viral virulence to be increased. TNF modulatory polypeptides include, but are not limited to, A53R and B28R of vaccinia virus, and other polypeptides with similar activities or properties.

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.

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