Combination Therapy with Gold Controlled Transgenes

Abstract

Control Devices are disclosed including RNA destabilizing elements (RDE) combined with transgenes, including Chimeric Antigen Receptors (CARs) in eukaryotic cells. These RDEs can be used to optimize expression of transgenes, e.g., CARs, in the eukaryotic cells so that, for example, effector function is optimized. CARs and transgene payloads can also be engineered into eukaryotic cells so that the transgene payload is expressed and delivered at desired times from the eukaryotic cell. Such CAR T-cells with transgene payloads can be combined with the administrstion of other molecules, e.g., other therapeutics such as anticancer therapies.

What is claimed is: 
     
         1 . A method for delivering a payload, comprising the steps of: exposing a cancer cell to a therapeutic agent; obtaining a primary T-cell comprising a chimeric antigen receptor, and a heterologous nucleic acid comprising a promoter operably linked to a polynucleotide encoding the payload that is operably linked to a polynucleotide encoding a RNA degradation element (RDE), wherein the RDE is an AU rich element, wherein the heterologous nucleic acid is transcribed to make a transcript encoding the transgene operably linked to the RDE; exposing the primary T-cell to a ligand for the chimeric antigen receptor wherein the ligand is associated with the cancer cell, and wherein binding of the ligand by the receptor activates the primary T-cell; and expressing the transgene wherein the amount of polypeptide made from the transgene is increased after the primary T-cell is activated. 
     
     
         2 . The method of  claim 1 , wherein the therapeutic agent is an unconjugated antibody, an immunoconjugate, a gene therapy, a chemotherapeutic agent, a therapeutic peptide, a cytokine, a localized radiation therapy, a radioconjugate, a surgery, an interference RNA, a drug, or a toxin. 
     
     
         3 . The method of  claim 2 , wherein the therapeutic agent is an immunoconjugate and wherein the immunoconjugate binds to the same ligand as the chimeric antigen receptor. 
     
     
         4 . The method of  claim 2 , wherein the therapeutic agent is an immunoconjugate and wherein the immunoconjugate binds to a different ligand as the chimeric antigen receptor. 
     
     
         5 . The method of  claim 2 , wherein the chemotherapeutic agent is a mitotic inhibitor, an antitumor antibiotic, a plant alkaloid, an alkylating agent, an antimetabolite, and/or a radionuclide. 
     
     
         6 . The method of  claim 1  wherein the transgene encodes a cytokine, a FasL, an antibody, a growth factor, a chemokine, an enzyme that cleaves a polypeptide or a polysaccharide, a granzyme, a perforin, or a checkpoint inhibitor. 
     
     
         7 . The method of  claim 1 , wherein the transgene encodes an IL-2, and IL-12, an IL-15, an IL-18, an IFNg, a CD40L, or a TNF-α. 
     
     
         8 . The method of  claim 1 , wherein the chimeric antigen receptor is an anti-DLL3 chimeric antigen receptor. 
     
     
         9 . The method of  claim 8 , wherein the ligand is a DLL3 found on a tumor cell. 
     
     
         10 . The method of  claim 9 , wherein the tumor cell is an IDH1mut glioma cell, a melanoma cell, or a small cell lung cancer cell. 
     
     
         11 . The method of  claim 10 , wherein the transgene encodes a cytokine, a FasL, an antibody, a growth factor, a chemokine, an enzyme that cleaves a polypeptide or a polysaccharide, a granzyme, a perforin, or a checkpoint inhibitor. 
     
     
         12 . The method of  claim 11 , wherein the wherein therapeutic agent is an unconjugated antibody, an immunoconjugate, a gene therapy, a chemotherapeutic agent, a therapeutic peptide, a cytokine, a localized radiation therapy, a surgery, an interference RNA, a drug, or a toxin. 
     
     
         13 . The method of  claim 11 , wherein the therapeutic agent is an immunoconjugate and wherein the immunoconjugate binds to a DLL3. 
     
     
         14 . The method of  claim 1 , wherein the chimeric antigen receptor is an anti-TnMUC1 chimeric antigen receptor. 
     
     
         15 . The method of  claim 14 , wherein the ligand is a TnMUC1 found on a tumor cell. 
     
     
         16 . The method of  claim 15 , wherein the tumor cell is a breast cancer cell or a pancreatic cancer cell. 
     
     
         17 . The method of  claim 15 , wherein the transgene encodes a cytokine, a FasL, an antibody, a growth factor, a chemokine, an enzyme that cleaves a polypeptide or a polysaccharide, a granzyme, a perforin, or a checkpoint inhibitor, and wherein the wherein therapeutic agent is an unconjugated antibody, an immunoconjugate, a gene therapy, a chemotherapeutic agent, a therapeutic peptide, a cytokine, a localized radiation therapy, a surgery, an interference RNA, a drug, or a toxin. 
     
     
         18 . The method of  claim 1 , wherein exposing the cancer cell to a therapeutic agent is performed before exposing the primary T-cell to a ligand for the chimeric antigen receptor. 
     
     
         19 . The method of  claim 1 , wherein exposing the primary T-cell to a ligand for the chimeric antigen receptor is performed before exposing the cancer cell to a therapeutic agent. 
     
     
         20 . The method of  claim 1 , wherein exposing the cancer cell to a therapeutic agent is performed at the same time as exposing the primary T-cell to a ligand for the chimeric antigen receptor.