Immune cell trapping devices and methods for making and using the same

Abstract

Embodiments herein described provide devices for identifying and collecting rare cells or cells which occur at low frequency in the body of a subject, such as, antigen-specific cells or disease-specific cells. More specifically, the devices are useful for trapping immune cells and the devices contain a physiologically-compatible porous polymer scaffold, a plurality of antigens, and an immune cell-recruiting agent, wherein the plurality of antigens and the immune cell recruiting agent attract and trap the immune cell in the device. Also provided are pharmaceutical compositions, kits, and packages containing such devices. Additional embodiments relate to methods for making the devices, compositions, and kits/packages. Further embodiments relate to methods for using the devices, compositions, and/or kits in the diagnosis or therapy of diseases such as autoimmune diseases or cancers.

1 . An immune-cell trapping device, comprising
 a physiologically-compatible porous polymer scaffold, and   a plurality of purified antigens,   wherein the plurality of antigens attract and trap a plurality of immune cells specific to the plurality of antigens in the device.   
     
     
         2 . The device of  claim 1 , wherein the antigens are absorbed onto the polymer scaffold or are encapsulated by the polymer scaffold. 
     
     
         3 .- 5 . (canceled) 
     
     
         6 . The device of  claim 1 , wherein the device further comprises an immune cell recruiting agent. 
     
     
         7 . The device of  claim 6 , wherein the immune cell recruiting agent:
 comprises an agent selected from the group consisting of a T-cell recruiting agent, a dendritic cell recruiting agent, and a macrophage recruiting agent, or a combination thereof;   comprises an agent selected from the group consisting of natural killer (NK) cell recruiting agent, a CD3+ T-cell recruiting agent, a CD4+ T-cell recruiting agent, a CD8+ T cell recruiting agent, a CD8+ T cell recruiting agent, a regulatory T-cell (Treg) recruiting agent, or a combination thereof; or   is a growth factor, a cytokine, an interleukin, an adhesion signaling molecule, an integrin signaling molecule, an interferon, a lymphokine, or a chemokine, or a fragment thereof, or a combination thereof.   
     
     
         8 .- 10 . (canceled) 
     
     
         11 . The device of  claim 1 , wherein the device further comprises an agent which enhances infiltration of the immune cells into the device. 
     
     
         12 . The device of  claim 1 , wherein the plurality of antigens are cancer antigens, non-self antigens, or self antigens. 
     
     
         13 . The device of  claim 12 , wherein the cancer antigens are selected from the group consisting of MAGE-1, MAGE-2, MAGE-3, CEA, Tyrosinase, midkin, BAGE, CASP-8, β-catenin, β-catenin, γ-catenin, CA-125, CDK-1, CDK4, ESO-1, gp75, gp100, MART-1, MUC-1, MUM-1, p53, PAP, PSA, PSMA, ras, trp-1, HER-2, TRP-1, TRP-2, IL13Ralpha, IL13Ralpha2, AIM-2, AIM-3, NY-ESO-1, C9orf 112, SART1, SART2, SART3, BRAP, RTN4, GLEA2, TNKS2, KIAA0376, ING4, HSPH1, C13orf24, RBPSUH, C6orf153, NKTR, NSEP1, U2AF1L, CYNL2, TPR, SOX2, GOLGA, BMI1, COX-2, EGFRvIII, EZH2, LICAM, Livin, Livinβ, MRP-3, Nestin, OLIG2, ART1, ART4, B-cyclin, Gli1, Cav-1, cathepsin B, CD74, E-cadherin, EphA2/Eck, Fra-1/Fosl 1, GAGE-1, Ganglioside/GD2, GnT-V, β1,6-N, Ki67, Ku70/80, PROX1, PSCA, SOX10, SOX11, Survivin, UPAR, WT-1, Dipeptidyl peptidase IV (DPPIV), adenosine deaminase-binding protein (AD Abp), cyclophilin b, Colorectal associated antigen (CRC)-C017-1A/GA733, T-cell receptor/CD3-zeta chain, GAGE-family of tumor antigens, RAGE, LAGE-I, NAG, GnT-V, RCAS1, α-fetoprotein, pl20ctn, Pmel117, PRAME, brain glycogen phosphorylase, SSX-I, SSX-2 (HOM-MEL-40), SSX-I, SSX-4, SSX-5, SCP-I, CT-7, cdc27, adenomatous polyposis coli protein (APC), fodrin, HA, Connexin 37, Ig-idiotype, pl5, GM2, GD2 gangliosides, Smad family of tumor antigens, lmp-1, EBV-encoded nuclear antigen (EBNA)-I, UL16-binding protein-like transcript 1 (Multi), RAE-1 proteins, H60, MICA, MICB, and c-erbB-2, or an immunogenic peptide thereof, and combinations thereof. 
     
     
         14 . (canceled) 
     
     
         15 . The device of  claim 12 , wherein:
 (i) the non-self antigens are pathogenic antigens derived from a pathogen selected from the group consisting of a virus, a bacteria, a protozoan, a parasite, and a fungus;   (ii) the antigens are derived from a lysate of a cell to which an autoimmune response is directed; or   (iii) the antigen is a pancreatic beta cell antigen, a neuronal cell antigen, a bone or joint associated autoimmune disease associated antigen, or a gastrointestinal-disease associated antigen.   
     
     
         16 .- 20 . (canceled) 
     
     
         21 . The device of  claim 1 , wherein the device further comprises an RGD peptide, a CpG oligonucleotide or a granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine, or a fragment thereof or a combination thereof. 
     
     
         22 . (canceled) 
     
     
         23 . The device of  claim 1 , wherein:
 (i) the device preferentially attracts T-cells compared to other immune cells and wherein the device further comprises a chemokine selected from the group consisting of CCL1, CCL2 (MCP-1), CCL-3, CCL-4, CCL-5 (RANTES), CCL-17, CCL-22, CXCL12 and XCL1, or a fragment thereof, or a combination thereof;   (ii) the device preferentially attracts dendritic cells (DC) or macrophages compared to other immune cells and wherein the device further comprises a chemokine selected from the group consisting of CCL2, CCL3, CCL5, CCL7, CCL8, CCL13, CCL17, and CCL22 or a fragment thereof, or a combination thereof; or   (iii) the device preferentially attracts both T-cells and dendritic cells (DC) compared to other immune cells and wherein the device further comprises a chemokine selected from the group consisting of CCL17 and CCL22, or a fragment thereof, or a combination thereof.   
     
     
         24 .- 28 . (canceled) 
     
     
         29 . The device of  claim 1 , further comprising a plurality of adhesion receptors for T-cells selected from the group consisting of LFA-1, MAdCAM-1, VCAM-1, CD28 and CTLA-4 or a fragment thereof or a combination thereof. 
     
     
         30 . (canceled) 
     
     
         31 . The device of  claim 1 , wherein the device comprises about 10 μg to about 2.0 mg of the antigens, or about 0.1 μg to about 400 μg of the antigens per gram of dry weight of the scaffold. 
     
     
         32 . (canceled) 
     
     
         33 . The device of  claim 1 , wherein the device has a porosity of between about 40% to about 90%. 
     
     
         34 . The device of  claim 1 , wherein the porous polymer scaffold comprises pores having a diameter of about 10 μM to about 500 μM. 
     
     
         35 . The device of  claim 1 , wherein the porous polymer scaffold comprises a compound selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), poly(lactide-co-glycolide) (PLGA), alginate or a derivative thereof, gelatin, collagen, fibrin, hyaluronic acid (HA), agarose, a polysaccharide, a polyamino acid, a polypeptide, a polyester, a polyanhydride, a polyphosphazine, a polyvinyl alcohol (PVA), a polyalkylene oxides (PAO), a polyallyl amines)(PAM), a polyacrylate, a modified styrene polymer, a pluronic polyol, a polyoxamer, a polyuronic acid, and a polyvinylpyrrolidone or a co-polymer thereof, or a graft polymer thereof. 
     
     
         36 . A pharmaceutical composition comprising the device of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         37 .- 38 . (canceled) 
     
     
         39 . A method of treating a disease in a subject in need thereof, comprising
 administering the device of  claim 1  to a subject, wherein the plurality of antigens are specific for the disease;   collecting a plurality of immune cells trapped in the device, wherein the plurality of immune cells are specific to the plurality of antigens; and   administering the plurality of immune cells into the subject, thereby treating the disease in the subject.   
     
     
         40 .- 51 . (canceled) 
     
     
         52 . A method for obtaining immune cells specific for an antigen, comprising
 administering the device of  claim 1  to a subject; and   harvesting immune cells trapped in the device, thereby obtaining immune cells specific for the antigen.   
     
     
         53 .- 57 . (canceled) 
     
     
         58 . A method for determining whether a subject has an autoimmune disease, comprising
 administering the device of  claim 1  into a subject, wherein the plurality of antigens are specific for the autoimmune disease;   collecting immune cells trapped in the device, wherein the immune cells are specific to the autoimmune disease; and   determining the number of immune cells specific to the autoimmune disease trapped in the device, thereby determining whether a subject has an autoimmune disease.   
     
     
         59 .- 63 . (canceled) 
     
     
         64 . A method for making the device of  claim 1 , comprising
 incubating plurality of purified antigens with a physiologically compatible polymer to generate a polymer-antigen mixture;   freezing, lyophilizing and mixing the polymer-antigen mixture with a porogen;   compression molding the mixture to produce a disc;   subjecting the disk to a high-pressure CO 2  environment and rapidly reducing the pressure to expand and fuse the polymer into an interconnected scaffold structure; and   leaching the porogen from the scaffold structure by immersing the structure in water to generate a porous article, thereby making the device.   
     
     
         65 .- 66 . (canceled) 
     
     
         67 . The device of  claim 1 , wherein the plurality of antigens attract and trap a plurality of B cells specific to the plurality of antigens in the device; and
 wherein the plurality of antigens engage a specific B cell receptor on the plurality of B cells causing the plurality of B cells to remain in the device.   
     
     
         68 . The device of  claim 1 , wherein the plurality of antigens attract and trap a plurality of T cells specific to the plurality of antigens in the device; and
 wherein the plurality of antigens engage a specific T cell receptor on the plurality of T cells causing the plurality of T cells to remain in the device.   
     
     
         69 . The device of  claim 1 , wherein the device further comprises a B cell recruitment agent and/or a B cell specific adhesion molecule. 
     
     
         70 . The device of  claim 1 , wherein the device further comprises one or more interleukins and/or cytokines. 
     
     
         71 . A pharmaceutical composition comprising:
 (i) a T cell trapping device;   (ii) a B cell trapping device; and   (iii) a pharmaceutically acceptable carrier.   
     
     
         72 . The composition of  claim 71 , wherein
 (i) the T cell trapping device, comprises
 a physiologically-compatible porous polymer scaffold, and 
 a plurality of antigens, 
 wherein the plurality of antigens attract and trap a plurality of T cells specific to the plurality of antigens in the device, and 
 wherein the plurality of antigens engage a specific T-cell receptor on the plurality of T-cells causing the plurality of T-cells to remain in the device; and/or 
   (ii) the B cell trapping device, comprises
 a physiologically-compatible porous polymer scaffold, and 
 a plurality of antigens, 
 wherein the plurality of antigens attract and trap a plurality of B cells specific to the plurality of antigens in the device; and 
 wherein the plurality of antigens engage a specific B cell receptor on the plurality of B cells causing the plurality of B cells to remain in the device.