Genetically modified mesenchymal stem cells expressing an immune response-stimulating cytokine to attract and/or activate immune cells

Abstract

A genetically modified mesenchymal stem cell (MSC) and medical use thereof in the treatment of tumors, the MSC including one or more exogenous nucleic acid molecule(s), wherein the exogenous nucleic acid molecule(s) include a region encoding one or more immune response-stimulating or immune response-modulating cytokine(s) operably linked to a promoter or promoter/enhancer combination. The invention encompasses the use of the cells in modulating the tumor microenvironment in order to attract immune effector cells and facilitate their activation and/or adoption of a memory phenotype. One aspect of the invention relates to the use of the cells in anti-tumor treatment including combined administration of the mesenchymal stem cells with anti-tumor immunotherapies, such as checkpoint inhibitors, immune cells, for example T cells, such as T cells with artificial T cell receptors, for example a chimeric antigen receptor (CAR-Ts) or exogenous T-Cell Receptor (TCR) transduced cells, NK cells or macrophages/monocytes, or a cancer vaccine.

1 . A method of treating a tumor in a subject comprising administering a genetically modified mesenchymal stem cell (MSC) and an anti-tumor immunotherapy to the subject, wherein said MSC comprises one or more exogenous nucleic acid molecule(s), wherein said exogenous nucleic acid molecule(s) comprise a region encoding one or more immune response-stimulating cytokine(s) operably linked to a promoter or promoter/enhancer combination. 
     
     
         2 . The method according to  claim 1 , wherein the promoter or promoter/enhancer combination yields constitutive expression of the exogenous nucleic acid. 
     
     
         3 . The method according to  claim 2 , wherein the promoter yielding constitutive expression is an EFlalpha promoter, a PGK promoter, a CMV promoter, an SV40 promoters, a GAG promoter or a UBC promoter. 
     
     
         4 . The method according to  claim 1 , wherein the promoter or promoter/enhancer combination is induced when the genetically modified mesenchymal stem cell comes into proximity with a tumor tissue or a tumor stromal tissue, or wherein the promoter or promoter/enhancer combination is induced upon differentiation of said cell, post-administration. 
     
     
         5 . The method according to  claim 1 , wherein the promoter is the RANTES promoter, the HSP70 promoter or the Tie2 promoter. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . The method according to  claim 1 , wherein the immune response-stimulating cytokine maintains or enhances the activity, survival and/or number of immune cells within and/or in proximity to a tumor tissue. 
     
     
         10 . The method according to  claim 1 , wherein the one or more immune response-stimulating cytokine(s) comprise IL-2, IL-7, IL-12, IL-15 and/or IL-21. 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . The method according to  claim 1 , wherein the one or more immune response-stimulating cytokine(s) comprise IFN gamma and/or IFN beta. 
     
     
         16 . (canceled) 
     
     
         17 . The method according to  claim 1 , wherein the exogenous nucleic acid molecule comprises a region encoding an immune stimulatory molecule that induces T-cell proliferation and/or differentiation operably linked to a promoter or promoter/enhancer combination. 
     
     
         18 . The method according to  claim 17 , wherein the immune stimulatory molecule that induces T-cell proliferation and/or differentiation is CD28. 
     
     
         19 . The method according to  claim 1 , wherein the one or more immune response-stimulating cytokine is/are a chemokine. 
     
     
         20 . The method according to  claim 19 , wherein the chemokine has chemotactic properties for attracting T cells. 
     
     
         21 . The method according to  claim 1 , wherein at least one of the one or more immune response-stimulating cytokine(s) is selected from the group consisting of chemokine (C-C motif) ligand 1 (CCL1, CCL2, CCL4, CCL17, CCL19, CCL22, CCL23, and stromal cell-derived factor 1 (SDF-1). 
     
     
         22 . The method according to  claim 1 , wherein the anti-tumor immunotherapy comprises the administration of an immune cell. 
     
     
         23 . The method according to  claim 22 , wherein the mesenchymal stem cell and the immune cell are autologous to the subject of medical treatment. 
     
     
         24 . The method according to  claim 22 , wherein the immune cell is a T cell. 
     
     
         25 . The method according to  claim 22 , wherein the immune cell is a T cell comprising an artificial T cell receptor, wherein said T cell receptor binds specifically to a tumor antigen. 
     
     
         26 . The method according to  claim 22 , wherein the immune cell is a macrophage. 
     
     
         27 . The method according to  claim 1 , wherein the anti-tumor immunotherapy comprises the administration of one or more checkpoint inhibitors. 
     
     
         28 . The method according to  claim 27 , wherein said checkpoint inhibitor is a PD-L1 inhibitor, PD-1 inhibitor and/or CTLA-4 inhibitor. 
     
     
         29 . The method according to  claim 1 , wherein the anti-tumour immunotherapy comprises the administration of tumor antigens or patient-derived tumor material. 
     
     
         30 . (canceled) 
     
     
         31 . The method according to  claim 1 , wherein the anti-tumor immunotherapy comprises the administration of an antibody or antibody fragment targeted to a tumor specific antigen. 
     
     
         32 . A genetically modified mesenchymal stem cell (MSC), wherein said MSC comprises one or more exogenous nucleic acid molecule(s), wherein said exogenous nucleic acid molecule(s) comprises one or more regions encoding two or more immune response-stimulating cytokines operably linked to one or more promoters or promoter/enhancer combinations. 
     
     
         33 . The genetically modified mesenchymal stem cell according to  claim 32 , wherein at least one of said two or more immune response-stimulating cytokines is selected from the group consisting of IL-2, IL-7, IL-12, IL-15, IL21, IFN gamma and IFN beta. 
     
     
         34 . The genetically modified mesenchymal stem cell according to  claim 32 , wherein the two or more immune response-stimulating cytokines comprise at least IL-12, and one or more of IL-2, IL-7, IL-15, and/or IL-21. 
     
     
         35 . The genetically modified mesenchymal stem cell according to  claim 32 , wherein the two or more immune response-stimulating cytokines comprise at least IL-7 and IL-21. 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . (canceled) 
     
     
         39 . The method according to  claim 25 , wherein the artificial T cell receptor is a chimeric antigen receptor (CAR). 
     
     
         40 . The method according to  claim 1 , wherein said exogenous nucleic acid molecule(s) comprise a region encoding two or more immune response-stimulating cytokine(s), selected from the group consisting of IL-2, IL-7, IL-12, IL-15 and IL-21. 
     
     
         41 . The method according to  claim 40 , wherein the two or more immune response-stimulating cytokines comprise at least IL-7 and IL-21.