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.

What is claimed is: 
     
         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 . The method of  claim 6 , wherein the gene element is activated by a promoter associated with activation of the immune cell, wherein the promoter is activated as a consequence of T cell receptor signal transduction when the immune cell is a T cell, as a consequence of B cell receptor signal transduction when the immune cell is a B cell, as a consequence of NK activator receptor when the immune cell is a NK cell, as a consequence of NKG2D when the immune cell is a NK cell, as a consequence activation of a receptor of a danger associated molecular pattern (DAMP), or as a consequence activation of a pathogen associated molecular pattern (PAMP) 
     
     
         8 . The method of  claim 7 , wherein the DAMP receptor is one or more of a toll like receptor (TLR), a receptor for advanced glycation end products (RAGE), a siglec receptor, a stimulator of interferon genes (STING), a retinoic acid-inducible gene I (RIG-I), a melanoma differentiation-associated gene 5 (MDA5), or a Toll-interleukin 1 receptor domain (TIR)-containing adapter molecule 1 (TICAM-1). 
     
     
         9 . The method of  claim 7 , wherein the PAMP receptor is one or more of a toll like receptor (TLR), a receptor for advanced glycation end products (RAGE), a siglec receptor, a stimulator of interferon genes (STING), retinoic acid-inducible gene I (RIG-I), a melanoma differentiation-associated gene 5 (MDA5), or a Toll-interleukin 1 receptor domain (TIR)-containing adapter molecule 1 (TICAM-1). 
     
     
         10 . A method for treating a subject suffering from a disease, comprising:
 generating an ex vivo cell comprising:
 culturing a sample comprising cells; 
 transducing the cells with a retroviral vector; and 
 culturing the transduced cells with an induction agent; and 
   administering the generated cell to the subject.   
     
     
         11 . The method of  claim 10 , wherein the generated cell is a chimeric antigen receptor (CAR) T cell or a tumor infiltrating leukocyte (TIL). 
     
     
         12 . The method of  claim 10 , wherein the induction agent is a IL-2. 
     
     
         13 . The method of  claim 10 , wherein administering the generated cells comprises intravenous administration of generated cells. 
     
     
         14 . The method of  claim 10 , wherein treating the subject is performed in a closed system, wherein the sample is obtained from the subject, the cells are transduced extracorporeally, and the generated cells are reintroduced to the subject. 
     
     
         15 . 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. 
     
     
         16 . 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. 
     
     
         17 . 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. 
     
     
         18 . A nucleic acid encoding a fusion protein, the nucleic acid comprising:
 a first sequence, wherein the first sequence encodes a protein for detection of altered cells;   a second sequence, wherein the second sequence encodes a protein that produces a detectable signal, wherein the protein is luciferase; and   a third sequence, wherein the third sequence encodes a promoter.   
     
     
         19 . A cell for fusion protein secretion, the cell comprising the nucleic acid of  claim 18 .