Immunological detection of altered cells

Abstract

Disclosed are methods, compositions of matter, and protocols useful for the detection of altered cells in a patient. Immune cells capable of clonal expansion are engineered to produce a soluble signal upon activation and/or clonal expansion. The cells may possess a suicide gene, inducible upon administration pharmacological or light/radiation activatable, so as to eliminate the cells from body when desired. In another embodiment, immune cells produce a localized marker, the marker being visible with imaging technology. In other embodiments cells capable of non-clonal expansion are utilized. The disclosure provides means of utilizing the immunosurveillance properties of immune cells to diagnose and localize diseases associated with alteration of host cells.

1 . A method of detecting an altered cell in an individual comprising the steps of:
 obtaining a delivery vehicle, wherein the delivery vehicle is capable of activation subsequent to binding to one or a plurality of antigens on the altered cell;   labeling the delivery vehicle with a label capable of producing a detectable signal;   administering to the individual the labeled delivery vehicle; and   detecting the altered cell with the labeled delivery vehicle in vivo.   
     
     
         2 . The method of  claim 1 , wherein the delivery vehicle is one or more of B cells, T cells, innate lymphoid cells, natural killer cells, natural killer T cells, gamma delta T cells, T regulatory cells, macrophages, monocytes, dendritic cells, neutrophils, myeloid derived suppressor cells, mast cells, hematopoietic stem cells, fibroblasts, stromal vascular fraction, exosomes, endothelial progenitor cells, mesenchymal stem cells, pluripotent cell lines, or engineered nanoparticles. 
     
     
         3 . The method of  claim 1 , wherein the label is a fluorescent label, a radioactive label, a magnetic label, or a sonographic label. 
     
     
         4 . The method of  claim 1 , wherein the altered cell is one or more of a preneoplastic cell, a neoplastic cell, a bacterially infected cell, a virally infected cell, a stressed cell, a diseased cell, or an autoimmune cell. 
     
     
         5 . The method of  claim 1 , wherein the antigen is one or more of CA19-9, CA125, CLPP, 707-AP, AFP, ART-4, BAGE family, BING-4, CAGE, MAGE family, GAGE family, SAGE family, b-catenin/m, bcr-abl, Calcium-activated chloride channel 2, CTL-recognized antigen on melanoma (CAMEL), CAP-1, CEA, CASP-8, CDK/4, CDC-27, Cyp-B, Cyclin-B1, DAM-8, DAM-10, ecto vimentin EGFR, ELV-M2, ep-CAM, EphA3, ETV6, G250, Gp100, HAGE, HER-2/neu, HPV E6/E7, Immature laminin receptor, Mesothelin, EPV-E6, LAGE, hTERT, SAP-1, survivin, iCE, MART-1, tyrosinase, MUC-1, MC1-R, NY-ESO-1, PRAME, SSX-2, PSA, PSMA, SSEA, TAG-72, Ig, TCR, TEL/AML, XAGE family, IDH1 mutation, IDH2 mutation, IL13Rα2 mutation, epCAM or WT-1. 
     
     
         6 . The method of  claim 1 , wherein the label capable of producing a detectable signal is a gene element encoding a molecule or series of molecules that are secreted and can be detected in systemic circulation of the individual. 
     
     
         7 . A method of in vivo labeling a cell in an individual having cancer, the method comprising the steps of:
 obtaining a population of lymphocytes capable of activation subsequent to binding to an antigen on the cell;   labeling the population of lymphocytes with a label capable of producing a detectable signal;   administering to the individual the labeled population of lymphocytes; and   detecting the cell with the labeled population of lymphocytes in vivo.   
     
     
         8 . The method of  claim 7 , wherein the population of lymphocytes is autologous or allogeneic to the individual. 
     
     
         9 . The method of  claim 7 , wherein the antigen on the cell is an antigen associated with the cancer. 
     
     
         10 . The method of  claim 7 , wherein the label is a reporter gene selected from the group consisting of neomycin, phosphoro-transferase, chloramphenicol acetyl transferase, thymidine kinase, β-glucuronidase, aminoglycoside, phosphotransferase, hygromycin B, xanthine-guanine phosphoribosyl, luciferase, DHFR/methotrexate, β-galactosidase, alkaline phosphatase, turbo and tagRFP, or nuclear targeted versions of the same. 
     
     
         11 . The method of  claim 7 , wherein the population of lymphocytes is immortalized. 
     
     
         12 . The method of  claim 7 , wherein the population of lymphocytes is tagged ex vivo with an agent allowing for in vivo localization. 
     
     
         13 . The method of  claim 12 , wherein the agent is a radiolabel imaging agent, therapeutic agent, or diagnostic agent selected from the group consisting of  110 In,  111 In,  177 Lu,  18 F,  52 Fe,  62 Cu,  64 Cu,  67 Cu,  67 Ga,  68 Ga,  86 Y,  90 Y,  89 Zr,  94 Tc,  94 Tc,  99m Tc,  120 I,  123 I,  124 I,  125 I,  131 I,  154 Gd,  155 Gd,  156 Gd,  157 Gd,  158 Gd,  32 P,  11 C,  13 N,  15 O,  186 Re,  188 Re,  51 Mn,  52m Mn,  55 Co,  72 As,  75 Br,  76 Br,  82m Rb, or  83 Sr, or one or a plurality of quantum dots. 
     
     
         14 . The method of  claim 7 , wherein the label is a fluorescent label selected from the group consisting of green fluorescent protein (GFP), blue fluorescent protein (BFP), yellow fluorescent protein (YFP), red fluorescent protein (RFP), cyan fluorescent protein (CFP), or orange fluorescent protein (OFP). 
     
     
         15 . The method of  claim 7 , wherein the label is a microbubble, radiation activatable nanoparticle, or scintillator nanocrystal linked to a chemical agent moiety. 
     
     
         16 . The method of  claim 7 , wherein the labelled population of lymphocytes localizes to cells by binding to an antigen thereon. 
     
     
         17 . The method of  claim 7 , wherein detecting comprises measuring the detectable label using an imaging device. 
     
     
         18 . A composition for detecting an altered cell comprising a labeled delivery vehicle capable of activation subsequent to binding to one or a plurality of antigens on the altered cell. 
     
     
         19 . The composition of  claim 15 , wherein the labeled delivery vehicle is a labeled B cell, T cell, innate lymphoid cell, natural killer cell, natural killer T cell, gamma delta T cell, T regulatory cell, macrophage, monocyte, dendritic cell, neutrophil, myeloid derived suppressor cell, mast cell, hematopoietic stem cell, fibroblast, stromal vascular fraction, exosome, endothelial progenitor cell, mesenchymal stem cell, pluripotent cell line, or engineered nanoparticle. 
     
     
         20 . The composition of  claim 15 , wherein the labeled delivery vehicle is labeled with a fluorescent label, a radioactive label, a magnetic label, or a sonographic label.