US2017015976A1PendingUtilityA1

Genetically modified mesenchymal stem cells that express an exogenous cytotoxic protein

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Assignee: APCETH GMBH & CO KGPriority: Apr 13, 2009Filed: Aug 31, 2016Published: Jan 19, 2017
Est. expiryApr 13, 2029(~2.7 yrs left)· nominal 20-yr term from priority
Inventors:Peter J. Nelson
C12N 2510/00A61P 35/00A61P 35/04C12N 5/0663C12N 2830/002C12N 2740/15043C12N 15/86A61K 2035/124A61K 35/28A61K 35/12C12N 5/10C12N 5/0662
44
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Claims

Abstract

This invention provides a method for treating a subject afflicted with a tumor using genetically modified mesenchymal stem cells, wherein each genetically modified mesenchymal stem cell contains an exogenous nucleic acid comprising (i) a cytotoxic protein-encoding region operably linked to (ii) a promoter or promoter/enhancer combination, whereby the cytotoxic protein is selectively expressed when the genetically modified mesenchymal stem cells come into proximity with the tumor's stromal tissue. This invention further provides genetically modified mesenchymal stem cells for use in this method.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method for treating a subject afflicted with a tumor comprising introducing into the subject's bloodstream a therapeutically effective number of genetically modified mesenchymal stem cells, wherein each genetically modified mesenchymal stem cell comprises an exogenous nucleic acid comprising (i) a cytotoxic protein-encoding region operably linked to (ii) a promoter or promoter/enhancer combination, wherein the promoter or promoter/enhancer combination is inducible by inflammatory mediators. 
     
     
         2 . The method of  claim 1 , wherein the promoter or promoter/enhancer combination is inducible by cytokines. 
     
     
         3 . The method of  claim 1 , wherein the inflammatory mediator is selected from the group consisting of TNF-alpha, IFN-gamma, IL-6, TGF-beta, IL-10, M-CSF and IL1β. 
     
     
         4 . The method of  claim 1 , wherein the promoter or promoter/enhancer combination comprises an NF-kβ-responsive element or a Smad-binding element. 
     
     
         5 . The method of  claim 1 , wherein the promoter is the RANTES promoter. 
     
     
         6 . The method of  claim 1 , wherein the subject is human. 
     
     
         7 . The method of  claim 1 , wherein the genetically modified mesenchymal stem cells are CD34 −  stem cells. 
     
     
         8 . The method of  claim 1 , wherein the genetically modified mesenchymal stem cells are allogenic with respect to the subject. 
     
     
         9 . The method of  claim 1 , wherein the genetically modified mesenchymal stem cells are autologous with respect to the subject. 
     
     
         10 . The method of  claim 1 , wherein the tumor is selected from the group consisting of a prostate tumor, a breast tumor, a pancreatic tumor, a squamous cell carcinoma, a breast tumor, a melanoma, a basal cell carcinoma, a hepatocellular carcinoma, testicular cancer, a neuroblastoma, a glioma or a malignant astrocytic tumor, a glioblastoma multiforme, a colorectal tumor, an endometrial carcinoma, a lung carcinoma, an ovarian tumor, a cervical tumor, an osteosarcoma, a rhabdo/leiomyosarcoma, a synovial sarcoma, an angiosarcoma, an Ewing sarcoma/PNET and a malignant lymphoma. 
     
     
         11 . The method of  claim 1 , wherein the cytotoxic protein is Herpes simplex viral thymidine kinase, and the subject is treated with ganciclovir in a manner permitting the Herpes simplex viral thymidine kinase to render the ganciclovir cytotoxic. 
     
     
         12 . The method of  claim 1 , wherein the therapeutically effective number of genetically modified mesenchymal stem cells is from 1×10 5  to 1×10 9  cells/kg body weight. 
     
     
         13 . The method of  claim 1 , wherein the therapeutically effective number of genetically modified mesenchymal stem cells is from 1×10 6  to 1×10 8  cells/kg body weight. 
     
     
         14 . A genetically modified mesenchymal stem cell comprising an exogenous nucleic acid comprising (i) a cytotoxic protein-encoding region operably linked to (ii) a promoter or promoter/enhancer combination, wherein the promoter or promoter/enhancer combination is inducible by inflammatory mediators. 
     
     
         15 . The genetically modified mesenchymal stem cell of  claim 14 , wherein the promoter or promoter/enhancer combination is inducible by cytokines. 
     
     
         16 . The genetically modified mesenchymal stem cell of  claim 14 , wherein the inflammatory mediator is selected from the group consisting of TNF-alpha, IFN-gamma, IL-6, TGF-beta, IL-10, M-CSF and IL1β. 
     
     
         17 . The genetically modified mesenchymal stem cell of  claim 14 , wherein the promoter or promoter/enhancer combination comprises an NF-kβ-responsive element or a Smad-binding element. 
     
     
         18 . The genetically modified mesenchymal stem cell of  claim 14 , wherein the promoter is the RANTES promoter. 
     
     
         19 . The genetically modified mesenchymal stem cell of  claim 14 , wherein the stem cell is a human stem cell. 
     
     
         20 . The genetically modified mesenchymal stem cell of  claim 14 , wherein the stem cell is a CD34 −  stem cell. 
     
     
         21 . The genetically modified mesenchymal stem cell of  claim 14 , further comprising a (iii) selection marker gene operably linked to (iv) a constitutive promoter or promoter/enhancer combination. 
     
     
         22 . The genetically modified mesenchymal stem cell of  claim 21 , wherein the cytotoxic protein-encoding region operably linked to the promoter or promoter/enhancer combination and the selection marker gene operably linked to the constitutive promoter or promoter/enhancer combination are a part of a proviral sequence integrated into the stem cell genome. 
     
     
         23 . The genetically modified mesenchymal stem cell of  claim 22 , wherein the proviral sequence is a lentiviral, alpha-retroviral or gamma-retroviral sequence. 
     
     
         24 . The genetically modified mesenchymal stem cell of  claim 14 , wherein the cytotoxic protein is Herpes simplex viral thymidine kinase or cytosine deaminase. 
     
     
         25 . A retroviral packaging cell comprising:
 a. a retroviral vector including (i) a cytotoxic protein-encoding region operably linked to (ii) a promoter or promoter/enhancer combination, wherein the promoter or promoter/enhancer combination is inducible by inflammatory mediators, and   b. a gene encoding a viral surface protein providing a tropism for mesenchymal or CD34− stem cells.   
     
     
         26 . The retroviral packaging cell according to  claim 25 , wherein the promoter or promoter/enhancer combination is inducible by cytokines. 
     
     
         27 . The retroviral packaging cell according to  claim 25 , wherein the inflammatory mediator is selected from the group consisting of TNF-alpha, IFN-gamma, IL-6, TGF-beta, IL-10, M-CSF and IL1β. 
     
     
         28 . The retroviral packaging cell according to  claim 25 , wherein the promoter or promoter/enhancer combination comprises an NF-kβ-responsive element or a Smad-binding element. 
     
     
         29 . The retroviral packaging cell according to  claim 25 , wherein the promoter is the RANTES promoter.

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