Self-antigen specific t-cells as vaccines for augmenting engraftment and stability of autologous transfer

Abstract

Disclosed are compositions and methods relating to genetically modified cells for the long-term expression of an antigen of interest.

1 . A genetically modified T cell, wherein the T cell has been modified to express an T cell receptor specific for an antigen of interest and wherein the T cell comprises a vector encoding the antigen of interest or therapeutic peptide. 
     
     
         2 . The genetically modified T cell of  claim 1 , wherein the antigen of interest is a tumor antigen, a viral antigen, or a bacterial antigen. 
     
     
         3 . The genetically modified T cell of  claim 2 , wherein the tumor antigen is selected from the group consisting of ALK, BAGE proteins, BIRC5 (survivin), BIRC7, CA9, CALR, CCR5, CD19, CD20 (MS4A1), CD22, CD27, CD30, CD33, CD38, CD40, CD44, CD52, CD56, CD79, CDK4, CEACAM3, CEACAM5, CLEC12A, DEPDC1, EGFR, EGFR variant III, ERBB2 (HER2), ERBB3, ERBB4, EPCAM, EPHA2, EPHA3, FCRL5, FLT3, FOLR1, GAGE proteins, GD2, GD3, GPNMB, GM3, GPR112, IL3RA, KIT, KRAS, LGR5, EBV-derived LMP2, L1CAM, MAGE proteins, MLANA, MSLN, MUC1, MUC2, MUC3, MUC4, MUC5, MUC16, MUM1, ANKRD30A, NY-ESO1 (CTAG1B), OX40, PAP, PAX3, PAX5, PLAC1, PRLR, PMEL, PRAME, PSMA (FOLH1), RAGE proteins, RET, RGS5, ROR1, ROS1, SART1, SART3, SLAMF7, SLC39A6 (LIV1), STEAP1, STEAP2, TERT, TMPRSS2, Thompson-nouvelle antigen, TNFRSF17, TYR, UPK3A, VTCN1, WT1, gp72, p53, the ras oncogene product, HPV E7, telomerase, and melanoma gangliosides. 
     
     
         4 . (canceled) 
     
     
         5 . The genetically modified T cell of  claim 2 , wherein the viral antigen is from a virus selected from the group consisting of Herpes Simplex virus-1, Herpes Simplex virus-2, Varicella-Zoster virus, Epstein-Barr virus, Cytomegalovirus, Human Herpes virus-6, Variola virus, Vesicular stomatitis virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D virus, Hepatitis E virus, Rhinovirus, Coronavirus, Influenza virus A, Influenza virus B, Measles virus, Polyomavirus, Human Papilomavirus, Respiratory syncytial virus, Adenovirus, Coxsackie virus, Dengue virus, Mumps virus, Poliovirus, Rabies virus, Rous sarcoma virus, Reovirus, Yellow fever virus, Ebola virus, Marburg virus, Zika virus, Lassa fever virus, Eastern Equine Encephalitis virus, Japanese Encephalitis virus, St. Louis Encephalitis virus, Murray Valley fever virus, West Nile virus, Lymphocytic choriomeningitis virus, Rift Valley fever virus, Rotavirus A, Rotavirus B, Rotavirus C, Sindbis virus, Simian Immunodeficiency virus, Human T-cell Leukemia virus type-1, Hantavirus, Rubella virus, Simian Immunodeficiency virus, Human Immunodeficiency virus type-1, Human Immunodeficiency virus type-2; echovirus; parvovirus; vaccinia virus; molluscum virus; JC virus; and arboviral encephalitis virus antigen. 
     
     
         6 . (canceled) 
     
     
         7 . The genetically modified T cell of  claim 2 , wherein the bacterial antigen is an antigen selected from a bacterium from the group consisting of  M. tuberculosis, M. bovis, M. bovis  strain BCG, BCG substrains,  M. avium, M. intracellulare, M. africanum, M. kansasii, M. marinum, M. ulcerans, M. avium  subspecies paratuberculosis,  Nocardia asteroides, Legionella pneumophila, Salmonella typhi, Shigella species, Yersinia pestis, Pasteurella haemolytica, Pasteurella multocida, Actinobacillus pleuropneumoniae, Listeria monocytogenes, Listeria ivanovii, Brucella abortus, Cowdria ruminantium, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydia psittaci, Coxiella burnetti, Ehrlichia species, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus agalactiae, Bacillus anthracis, Escherichia coli, Vibrio cholerae, Campylobacter  species,  Neiserria meningitidis, Neiserria gonorrhea, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus ducreyi, Clostridium tetani, Clostridium botulinum, Yersinia enterolitica , meningococci,  klebsiella, proteus, serratia , diphtheria, bacilli, leptospira, and Lyme disease bacterial antigen. 
     
     
         8 . The genetically modified T cell of  claim 1 , wherein the therapeutic peptide is a peptide hormone, selected from the group consisting of erythropoietin, insulin, and glucagon. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The genetically modified T cell of  claim 1 , wherein the antigen of interest or therapeutic peptide is operably linked to an inducible promoter or tissue specific promoter. 
     
     
         12 . The genetically modified T cell of  claim 1 , wherein the T cell further comprises an inducible knockout system for reducing transgene expression. 
     
     
         13 . The genetically modified T cell of  claim 1 , wherein the T cell further comprises a second antigen of interest. 
     
     
         14 . The genetically modified T cell of  claim 13 , wherein the second antigen of interest is encoded on a vector. 
     
     
         15 . (canceled) 
     
     
         16 . A method of providing long-term delivery of an antigen to a subject comprising administering to a subject the modified T cell of  claim 1 . 
     
     
         17 . (canceled) 
     
     
         18 . A method of providing long-term delivery of an antigen to a subject comprising administering to a subject a genetically modified T cell wherein the T cell has been modified to express a vector encoding the antigen of interest. 
     
     
         19 . The method of  claim 18 , wherein the T cell is a memory T cell. 
     
     
         20 . A method of treating, inhibiting, reducing, or preventing cancer comprising administering to a subject with a cancer the genetically modified T cell of  claim 1  wherein the T cell has been modified to express an T cell receptor specific for a tumor antigen of interest and wherein the T cell comprises a vector encoding the tumor antigen of interest. 
     
     
         21 . (canceled) 
     
     
         22 . A method of treating chronic kidney disease comprising administering to a subject with chronic kidney disease the genetically modified T cell of  claim 1  wherein the T cell has been modified to express a T cell receptor specific for EPO and wherein the T cell comprises a vector encoding EPO. 
     
     
         23 . A method of treating diabetes comprising administering to a subject with diabetes the genetically modified T cell of  claim 1 , wherein the T cell has been modified to express a T cell receptor specific for insulin and wherein the T cell comprises a vector encoding insulin. 
     
     
         24 . A method of treating, inhibiting, reducing, or preventing a viral or bacterial infection in a subject comprising administering to a subject in risk of said infection the genetically modified T cell of  claim 1  (a first genetically modified T cell, wherein the first T cell has been modified to express a T cell receptor specific for a bacterial or viral antigen of interest; wherein the antigen of interest is an antigen from the bacterium or virus from which immunological protection is sought; and wherein the T cell further comprises a vector encoding the antigen of interest. 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 24 , further comprising administering to the subject a second modified T cell, wherein the second modified T cell comprises a T cell receptor specific for the bacterial or viral antigen of interest expressed on the first modified T cell. 
     
     
         30 . The method of  claim 29 , wherein the second modified T cell further comprises at least one antigen of interest expressed by the first modified T cell.