Cell-based vehicles for potentiation of viral therapy

Abstract

Provided herein are carrier cells and virus combinations and methods for treatment of cancers. Also provided are modified carrier cells for such treatment, and methods of selecting carrier cells that are matched to subjects for such treatment.

1 . A carrier cell, comprising an oncolytic virus, wherein:
 the virus can replicate in the cell;   the cell can be administered to a human subject;   the cell has been treated or modified or both to enhance the immunosuppressive properties or immunoprivileged properties of the cell for administration to a human subject; and   optionally, the cell has been treated or modified to enhance amplification of the virus in the cell.   
     
     
         2 . The carrier cell of  claim 1 , wherein the cell has been treated or modified to enhance amplification of the virus in the cell. 
     
     
         3 . The carrier cell of  claim 1  that has been treated or modified to achieve or enhance or improve one or more of: virus amplification in the cell, blocking of the induction of an anti-viral state in a subject or in the tumor microenvironment, immune suppression or immune evasion, protection against allogeneic inactivation/rejection determinants, and protection against complement or inhibition of complement activation. 
     
     
         4 . The carrier cell of  claim 1  that has been pretreated or loaded with a growth factor and/or cytokine to enhance amplification of the virus in the cell. 
     
     
         5 . The carrier cell of  claim 4  that has been pre-treated to load the cell with one or more of IL-10, TGFβ, VEGF, FGF-2, PDGF, HGF, IL-6, GM-CSF, a RTK/mTOR agonist, a Wnt protein ligand, and a GSK3 inhibitor/antagonist. 
     
     
         6 . The carrier cell of  claim 1  that is selected from among a treated or modified stem cell, immune cell, and tumor cell. 
     
     
         7 . The carrier cell of  claim 1  that is a stem cell. 
     
     
         8 . The carrier cell of  claim 7 , wherein the stem cell is selected from among a mesenchymal, neural, totipotent, pluripotent, induced pluripotent, multipotent, oligopotent, unipotent, adipose stromal, endothelial, bone marrow, cord blood, adult peripheral blood, myoblast, small juvenile, epithelial, embryonic epithelial, and fibroblast stem cell. 
     
     
         9 . The carrier cell of  claim 7 , wherein the stem cell is a mesenchymal stem cell selected from among mesenchymal cells from adult bone marrow, adipose tissue, blood, dental pulp, neonatal umbilical cord, cord blood, placenta, placenta-derived adherent stromal cells, placenta-derived decidual stromal cells, endometrial regenerative cells, placental bipotent endothelial/mesenchymal progenitor cells, amniotic membrane or fluid mesenchymal stem cells, amniotic fluid derived progenitors, Wharton's Jelly mesenchymal stem cells, pelvic girdle stem cells, Chorionic Villus Mesenchymal Stromal cells, subcutaneous white adipose mesenchymal stem cells, pericytes, adventitial reticular stem cells, hair follicle-derived stem cells, hematopoietic stem cells, periosteum-derived mesenchymal stem cells, lateral plate mesenchymal stem cells, exfoliated deciduous teeth stem cells, periodontal ligament stem cells, dental follicle progenitor cells, stem cells from apical papilla, and muscle satellite cells. 
     
     
         10 . The carrier cell of  claim 6  that is an immune cell selected from among granulocytes, mast cells, monocytes, dendritic cells, natural killer cells, lymphocytes, T-cell receptor (TCR) transgenic cells targeting tumor-specific antigens, and CAR-T cells targeting tumor-specific antigens. 
     
     
         11 . The carrier cell of  claim 1  that is a tumor cell or tumor cell line. 
     
     
         12 . The carrier cell of  claim 11  that is a tumor cell line selected from among a human leukemia, T-cell leukemia, myelomonocytic leukemia, lymphoma, non-Hodgkin's lymphoma, Burkitt lymphoma, diffuse large B cell lymphoma, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), erythroleukemia, myelomonoblastic leukemia, malignant non-Hodgkin's NK Lymphoma, myeloma/plasmacytoma, multiple myeloma and a macrophage cell line. 
     
     
         13 . The carrier cell of  claim 11  that is a modified or treated cell from a human tumor cell line selected from an NCI-60 panel, a fibrosarcoma, a hepatocarcinoma, a prostate cancer, a breast cancer, a head and neck cancer, a lung cancer, a pancreatic cancer, an ovarian cancer, a colon cancer, a gastric cancer, a gynecological cancer, a sarcoma, a melanoma, a squamous cell carcinoma, a hepatocellular carcinoma, a bladder cancer, a renal cell carcinoma, an embryonal carcinoma, a testicular teratoma, a glioblastoma, an astrocytoma, a thyroid carcinoma or a mesothelioma cell line. 
     
     
         14 . The carrier cell of  claim 1  that is a modified or treated cell from a GM-CSF whole tumor cell vaccine (GVAX). 
     
     
         15 . The carrier cell of  claim 1 , wherein the oncolytic virus is selected from among new castle disease virus, parvovirus, measles virus, reovirus, vesicular stomatitis virus (VSV), adenovirus, poliovirus, herpes simplex virus (HSV), a poxvirus, coxsackie virus (CXV) and Seneca Valley virus (SVV). 
     
     
         16 . The carrier cell of  claim 15 , wherein the oncolytic virus is a poxvirus that is a vaccinia virus. 
     
     
         17 . The carrier cell of  claim 16 , wherein the vaccinia virus is selected from among a Lister strain, Western Reserve (WR) strain, Copenhagen (Cop) strain, Bern strain, Paris strain, Tashkent strain, Tian Tan strain, Wyeth strain (DRYVAX), IHD-J strain, IHD-W strain, Brighton strain, Ankara strain, CVA382 strain, Dairen I strain, LC16m8 strain, LC16 M0 strain, modified vaccinia Ankara (MVA) strain, ACAM strain, WR 65-16 strain, Connaught strain, New York City Board of Health (NYCBH) strain, EM-63 strain, NYVAC strain, Lister strain LIVP, JX-594 strain, GL-ONC1 strain, a vvDD TK mutant strain with deletions in VGF and TK, ACAM2000, and ACAM1000. 
     
     
         18 . The carrier cell of  claim 1  that has been treated to enhance or improve virus amplification or to block induction of an anti-viral state in the subject or in the tumor microenvironment. 
     
     
         19 . The carrier cell of  claim 1  that is treated to inhibit, or is modified to express an inhibitor of, interferon-γ and/or interferon-β. 
     
     
         20 . The carrier cell of  claim 1  that has been treated to enhance virus amplification by pre-treatment or treatment to load the cell with one or more of IL-10, TGFβ, VEGF, FGF-2, PDGF, HGF, IL-6, GM-CSF, a RTK/mTOR agonist, a Wnt protein ligand, and a GSK3 inhibitor/antagonist. 
     
     
         21 . The carrier cell of  claim 18  that has been treated to block induction of an anti-viral state by pre-treatment with or treatment to load the cell with one or more small molecule or protein inhibitors that interfere with IFN Type I/Type II receptors, interfere with downstream signaling, interfere with IFNAR1/IFNAR2 signaling, interfere with IFNGR1/IFNGR2 signaling, interfere with STAT1/2 signaling, interfere with Jak1 signaling, interfere with Jak2 signaling, interfere with IRF3 signaling, interfere with IRF7 signaling, interfere with IRF9 signaling, interfere with TYK2 signaling, interfere with TBK1 signaling, or interfere with other signaling pathways that effect an immune response against the oncolytic virus in the cell or subject. 
     
     
         22 . The carrier cell of  claim 18  that has been sensitized to block induction of an anti-viral state by pre-treatment or treatment to load the cell with one or more HDAC inhibitors for interfering with/deregulating IFN signaling/responsiveness. 
     
     
         23 . The carrier cell of  claim 18  that has been sensitized to block induction of an anti-viral state or enhance virus amplification by pre-treatment or treatment to load the cell with antagonists of virus sensing and/or anti-virus defense pathways. 
     
     
         24 . The carrier cell of  claim 23 , wherein the virus sensing and/or defense pathway(s) is/are mediated by one or more of STING, PKR, RIG-1, MDA-5, OAS-1/2/3, AIM2, MAVS, RIP-1/3, and DAI (ZBP1). 
     
     
         25 . The carrier cell of  claim 24 , wherein the antagonists is/are selected from one or more of K1, E3L, and K3L vaccinia proteins; NS1/NS2 influenza proteins; hepatitis C NS3-4A; arenavirus NP and Z proteins; Ebola virus VP35; HSV US11, ICP34.5 and ICP0; MCMV M45; and Borna disease virus X protein. 
     
     
         26 . The carrier cell of  claim 1  that has been sensitized to protect against inactivation/rejection determinants. 
     
     
         27 . The carrier cell of  claim 26 , wherein the cell has been sensitized to protect against inactivation/rejection determinants by pre-treatment or treatment to load the cell with one or more viral major histocompatibility complex (MEW) antagonists. 
     
     
         28 . The carrier cell of  claim 27 , wherein the MEW antagonist is selected from among one or more of A40R MHCI antagonist from vaccinia; Nef and TAT from HIV; E3-19K from adenovirus; ICP47 from HSV 1 and HSV2; CPXV012 and CPXV203 from Cowpox; ORF66 from varicella zoster virus (VZV); EBNA1, BNLF2a, BGLF5, and BILF1 from Epstein Barr virus (EBV); US2/gp24, US3/gp23, US6/gp21, US10, and US11/gp33 from human cytomegalovirus (hCMV); Rh178/VIHCE from rhesus CMV (RhCMV); U21 from human herpes virus (HHV) 6 or HHV7; LANA1, ORF37/SOX, kK3/MIR1, and kK5/MIR2 from Kaposi's sarcoma associated herpes virus (KSHV); mK3 from mouse hepatitis virus-68 (MHV-68); UL41/vhs from alpha-herpesvirus, herpes simplex virus (HSV), bovine herpes virus-2 (BHV-1), and pseudorabies virus (PRV); UL49.5 from Varicellovirus, BHV-1, equine herpes virus 1 and 4 (EHV-1/4) and PRV; and m4/gp34, m6/gp48, m27, and m152/gp40 from murine CMV (mCMV). 
     
     
         29 . The carrier cell of  claim 26 , wherein the cell has been sensitized to protect against inactivation/rejection determinants by pre-treatment or treatment to load the cell with antagonists of human MHC class I chain related genes MIC-A and MIC-B or with beta-2 microglobulin (B2 M) antagonists of viral origin. 
     
     
         30 . The carrier cell of  claim 1 , wherein the cell has been sensitized to enhance immune suppression/immune evasion by pre-treatment or treatment to load the cell with immunosuppressing factors of viral origin. 
     
     
         31 . The carrier cell of  claim 30 , wherein the immunosuppressing factor is selected from among one or more of an inhibitor of immune FAS/TNF/granzyme B-induced apoptosis; an IL-1/NFκB/IRF3 antagonist; an IL-1 and toll-like receptor (TLR) antagonist; an IL-1β antagonist; a TNFα blocker; an IFNα/β blocker; and an IFNγ blocker. 
     
     
         32 . The carrier cell of  claim 30 , wherein the cell has been sensitized to enhance immune suppression/immune evasion by pre-treatment or treatment to load the cell with one or more small molecule inhibitor(s) of one or more of antigen peptide transporter-1/2 (TAP-1 and TAP-2) and tapasin. 
     
     
         33 . The carrier cell of  claim 1  that is engineered for improved viral amplification and/or immunomodulation by one or more of:
 a) engineering to prevent or to be unresponsive to an interferon-induced antiviral state; 
 b) engineering to express immunosuppressive factors of human or viral origin to prevent/inhibit allogeneic anti-carrier cell or anti-viral immune responses; and 
 c) engineering to express cancer or stem cell-derived factors that facilitate viral infection of otherwise non-permissive carrier cells and/or tumor cells. 
 
     
     
         34 . The carrier cell of  claim 33  that is a) engineered to be unresponsive to an interferon-induced antiviral state by transient or permanent suppression of Type I/Type II IFN receptors and/or downstream signaling, wherein permanent suppression can be effected by deleting the locus that is suppressed. 
     
     
         35 . The carrier cell of  claim 34 , wherein suppression is effected by suppression of one or more of Type I/Type II interferon receptor expression, IFN α/β receptor expression, IFNγ receptor expression, IFNAR1/IFNAR2 expression, IFNGR1/IFNGR2 expression, STAT1/2 receptor expression, Jak1/2 receptor expression, IRF3 receptor expression, IRF7 receptor expression, IRF9 receptor expression, TYK2 kinase expression, and TBK1 kinase expression. 
     
     
         36 . The carrier cell of  claim 33  that is a) engineered to be unresponsive to an interferon-induced antiviral state by transient or permanent suppression of elements of the cytosolic viral DNA/RNA-sensing and anti-viral defense machinery. 
     
     
         37 . The carrier cell of  claim 33  that is a) engineered to prevent or to be unresponsive to an interferon-induced antiviral state by transient or permanent expression of antagonists of virus-sensing and anti-viral defense pathways mediated by STING, PKR, RIG-1, MDA-5, OAS-1/2/3, AIM2, MAVS, RIP-1/3, and DAI (ZBP1). 
     
     
         38 . The carrier cell of  claim 37 , wherein the antagonist(s) is/are selected from one or more of K1, E3L, and K3L vaccinia proteins; NS1/NS2 influenza A proteins; hepatitis C NS3-4A; arenavirus NP and Z proteins; Ebola virus VP35; HSV US11, ICP34.5 and ICP0; MCMV M45; and Borna disease virus X protein. 
     
     
         39 . The carrier cell of  claim 33  that is b) engineered to express immunosuppressive factors to prevent/inhibit allogeneic anti-carrier cell or anti-viral immune responses. 
     
     
         40 . The carrier cell of  claim 33  that is b) engineered to express immunosuppressive factors to prevent/inhibit allogeneic anti-cell carrier or anti-viral immune responses selected from factors of human origin. 
     
     
         41 . The carrier cell of  claim 40 , wherein the factors of human origin are selected from among one or more of: IDO, Arginase, TRAIL, iNOS, IL-10, TGFβ, VEGF, FGF-2, PDGF, HGF, IL-6, sMICA, sMICB, sHLA-G, HLA-E, PD-L1, FAS-L, B7-H4, and single-chain antibodies (scFv) that target or deplete NK and/or NKT cells, and/or γδ T cells. 
     
     
         42 . The carrier cell of  claim 39 , wherein the factors of viral origin are selected from among one or more of: ectromelia/vaccinia virus SPI-2/CrmA (inhibitor of immune FAS/TNF/Granzyme B induced apoptosis), Vaccinia Virus encoded N1 (IL-1/NFkB/IRF3 antagonist), HA (NCR antagonists targeting NKp30, NKp44, NKp46), IL-18 binding protein, A40R, A46R, A52R, B15R/B16R, TNFα blockers, IFN α/β blockers, IFNγ blockers, and other IL-1/IL-1β/NFκB/IRF3/NCR/MHCI/TLR/NKG2D antagonists. 
     
     
         43 . The carrier cell of  claim 33  that is c) engineered to express cancer or stem cell-derived factors that facilitate viral infection of otherwise impermissive carrier cells and/or tumor cells. 
     
     
         44 . The carrier cell of  claim 33  that is c) engineered to express cancer or stem cell-derived factors that facilitate viral infection of otherwise impermissive carrier cells and/or tumor cells, wherein the factors are selected from among one or more growth factors and cytokines that facilitate viral infection. 
     
     
         45 . The carrier cell of  claim 33  that is c) engineered to express cancer or stem cell-derived factors that facilitate viral infection of otherwise impermissive carrier cells and/or tumor cells, wherein the factors are selected from among one or more of cancer associated antigens, oncofetal antigens, oncogene/tumor suppressors, differentiation antigens, GM-CSF, IL-10, TGFβ, VEGF, FGF-2, PDGF, HGF, IL-6, RTK/mTOR agonists and Wnt protein ligands. 
     
     
         46 . A method of treatment of cancer, comprising administering the carrier cell of  claim 1  to a subject who has cancer. 
     
     
         47 . The method of  claim 46 , wherein the cancer comprises a solid tumor or a hematologic malignancy. 
     
     
         48 . The method of  claim 46 , wherein the carrier cell is allogeneic to the subject. 
     
     
         49 . The method of  claim 46 , wherein the carrier cell is autologous to the subject. 
     
     
         50 . The method of  claim 46 , wherein the carrier cells are treated or modified to have improved viral amplification properties and/or to have enhanced immunosuppressive or immune privileged properties; and/or the carrier cells are sensitized by pre-treatment with factors that promote viral amplification and/or enhance the immunosuppressive or immune privileged properties of the carrier cells. 
     
     
         51 . The method of  claim 46 , wherein the cancer is selected from among leukemias, lymphomas, melanomas, carcinomas, sarcomas, myelomas, and neuroblastomas. 
     
     
         52 . The method of  claim 46 , where in the cancer is selected from among pancreatic cancer, lung cancer, ovarian cancer, breast cancer, cervical cancer, bladder cancer, prostate cancer, brain cancer, central nervous system cancer, adenocarcinomas, liver cancer, skin cancer, hematological cancers, biliary tract cancer, bone cancer, choriocarcinoma, colon and rectal cancers, connective tissue cancer, cancer of the digestive system, endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, gastric cancer, intra-epithelial neoplasm, kidney cancer, larynx cancer, oral cavity cancer, retinoblastoma, rhabdomyosarcoma, cancer of the respiratory system, stomach cancer, testicular cancer, thyroid cancer, uterine cancer and urinary system cancers. 
     
     
         53 . The method of  claim 46 , wherein a carrier cell without virus is pretreated with IFN-gamma, and is administered prior to administration of the carrier cell comprising virus, or is administered concurrently with the carrier cell comprising virus. 
     
     
         54 . The method of  claim 46 , wherein the cell/virus combination is matched to the subject.