Use of a combination of myxoma virus and rapamycin for therapeutic treatment

a technology which is applied in the field of therapeutic use of myxoma virus and rapamycin, can solve the problems of inability to achieve effective cancer treatment, inability to effectively treat various types of cancer, and inability to work effectively. achieve the effect of improving safety and increasing containmen

Inactive Publication Date: 2009-02-05
THE JOHN P ROBARTS RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022]The present invention is further based on the unexpected discovery that rabbit Myxoma virus protein M135R is involved in eliciting an immune response in rabbits and that a Myxoma virus strain that does not express functional M135R can kill cells in vitro, but does not cause myxomatosis disease in animals. Such a viral strain can be used to treat cells having a deficient innate anti-viral response, including those that are non-responsive to interferon, and including treatments given in combination with the drug rapamycin, without the need for increased containment of the virus, leading to improved safety.

Problems solved by technology

Current treatments used to treat various types of cancer tend to work by poisoning or killing the cancerous cell.
Unfortunately, treatments that are toxic to cancer cells typically tend to be toxic to healthy cells as well.
Moreover, the heterogenous nature of tumours is one of the primary reasons that effective treatments for cancer remain elusive.
These types of therapies are considered blunt tools that have limited applicability due to the varying types of tumour cells and the limited window in which these treatments can be administered.
Since the replication selective oncolytic virus does not replicate efficiently in normal cells, toxicity to the patient should be low, particularly in comparison to traditional therapies such as radiation or chemotherapy.
However, it is unknown which viruses will best fulfill the oncolytic goals of sustained replication, specificity and potent lytic activity.
Clinical work has shown that current oncolytic viruses are indeed safe, but are not potent enough as monotherapies to be completely clinically effective.
However, the application of such a common human pathogen is limited, as it is likely that the general population has been exposed and acquired an immune response to this virus, which would attenuate the lytic effect of the virus.
HSV can also cause serious side effects or a potentially fatal disease.
However, Reovirus is difficult to genetically manipulate and its viral replication cannot be easily shut off.
However, VSV suffers from the same problems as the Reovirus in that it is difficult to genetically manipulate and its viral replication cannot be easily shut off.

Method used

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  • Use of a combination of myxoma virus and rapamycin for therapeutic treatment
  • Use of a combination of myxoma virus and rapamycin for therapeutic treatment
  • Use of a combination of myxoma virus and rapamycin for therapeutic treatment

Examples

Experimental program
Comparison scheme
Effect test

example 1

Infection of Mouse and Human Cell Lines with Myxoma Virus

Virus Strains

[0157]Viral strains used include wildtype MV, MV modified to express either green fluorescence protein (“GFP”) or β-galactosidase (“LacZ”), and killed (“dead”) MV. Viruses were prepped and titred using standard techniques.

Cell Strains

[0158]Mouse experiments were performed using mouse embryo fibroblasts (“MEFs”) derived from a wild-type mouse, and from the following mouse knockouts: IFNα / β receptor homozygous knockout; STAT1 homozygous knockout; PKR heterozygous; RNaseL heterozygous knockout; Mx1 heterozygous knockout; triple PKR / RNaseL / Mx1 homozygous knockout.

[0159]Human experiments were performed on BGMK control cells and human tumour cell lines HT29, HOP92, OVCAR4, OVCAR5, SK-MEL3, SK-MEL28, M14, SKOV3, PC3, DU145, CAKI-1, 786-0, T47D, MDAMB 435, SF04, U87, A172, U373, Daoy and D384 as described in Stojdl et al., Cancer Cell (2003) 4: 263-275.

Methods

[0160]Generally, assays and experiments were performed as descr...

example 2

Effect of Rapamycin on the Kinetics of Myxoma Virus Replication in Restrictive Cell Lines

Virus Strains

[0180]Viral strains used include wildtype MV (“vMyxLac”), and MV modified to have the MT-5 gene knocked out (“vMyxLacT5-”). Viruses were prepped and titred using standard techniques.

Cell Strains

[0181]Human experiments were performed on BGMK primate control cells, RK-13 rabbit control cells and normal human fibroblasts A9, restrictive human tumour cell lines 786-0 (renal), ACHN (renal), HCT116 (colon), MCF-7 (breast), MDA-MB-435 (breast), M14 (melanoma) and COL0205 (colon).

Methods

[0182]Generally, assays and experiments were performed as described in Lalani et al. Virology (1999) 256: 233-245; Johnston et al. J Virology (2003) 77(13): 7682-7688; and Sypula et al. Gen Ther Mol Biol (2004) 8: 103.

[0183]For viral growth curves, cells were grown in vitro in a monolayer, and pretreated with 20 nM rapamycin or a control (1:5000 dilution of DMSO) prior to infection with virus.

[0184]Samples o...

example 3

Molecular Consequences of Inhibiting mTOR in the Context of Myxoma Virus Infection

[0205]Western Blot analysis (FIG. 43) was performed using cell lysates from 786-0 cells, a Type II cancer cell line where rapamycin enhances myxoma virus infection. Lysates were collected 16 hours post infection with either vMyxLac or vMyxT5KO at an MOI of 3, or without virus infection. Indicated lanes contain protein from cells that were pretreated with 20 nM rapamycin (designated R) or appropriate vehicle control (1:5000 dilution of DMSO, designated D) for 6 hours before infection. The blots were probed using primary antibodies directed against the indicated proteins.

[0206]As demonstrated, myxoma virus infection affects many of the signaling pathways that converge on mTOR, the physiologic target of rapamycin. In the context of infection with either wild type (vMyxLac) or MT-5 deficient (vMyxT5KO) virus, where rapamycin has a beneficial effect on virus replication, global effects are observed in many ...

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Abstract

The present invention relates to therapeutic use of a combination of Myxoma virus, including in combination with rapamycin. Treatment with rapamycin enhances the ability of Myxoma virus to selectively infect cells that have a deficient innate anti-viral response, including cells that are not responsive to interferon. The combination of rapamycin and Myxoma virus can be used to treat diseases characterized by the presence of such cells, including cancer. The invention also relates to therapeutic use of Myxoma virus that does not express functional M135R.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims benefit and priority from U.S. provisional patent application No. 60 / 658,816, filed on Mar. 7, 2005, the contents of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates generally to therapeutic use of Myxoma virus and rapamycin.BACKGROUND OF THE INVENTION[0003]Current treatments used to treat various types of cancer tend to work by poisoning or killing the cancerous cell. Unfortunately, treatments that are toxic to cancer cells typically tend to be toxic to healthy cells as well. Moreover, the heterogenous nature of tumours is one of the primary reasons that effective treatments for cancer remain elusive. Current mainstream therapies such as chemotherapy and radiotherapy tend to be used within a narrow therapeutic window of toxicity. These types of therapies are considered blunt tools that have limited applicability due to the varying types of tumour cells and the lim...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/76C12N7/00C12Q1/70A61P31/00A61K35/768
CPCA61K31/436C12N2710/24032A61K35/768A61K2300/00A61P31/00A61P31/12A61P35/00A61P43/00C12N7/02A61K39/275A61K35/76C12Q1/04
Inventor MCFADDEN, GRANTBARRETT, JOHNSTANFORD, MARIANNE
Owner THE JOHN P ROBARTS RES INST
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