Compositions, methods, and computer systems related to making and administering modified t cells

Abstract

Embodiments described herein relate to methods, devices, and computer systems thereof for the derivation of T CAR libraries (Universal Subject or Individual Subject) for personalized treatment of disease in a subject. In certain embodiments, differential screening of normal and diseased tissue expression data is utilized to determine disease-specific antigens and thereby generate T CAR cells reactive to such antigens to form a disease-specific library. In certain embodiments, determination of the most effective T CAR clones from the disease-specific library is based on the subject's own disease-specific antigens. In certain embodiments, a subject is treated with a therapeutically effective amount of T CAR clones.

What is claimed is: 
     
         1 .- 85 . (canceled) 
     
     
         86 . A composition, comprising:
 one or more T cells bearing one or more multi-specific Chimeric Antigen Receptors including at least two antigen binding sites, wherein the multi-specific Chimeric Antigen Receptors have decreased avidity for binding to at least two target antigens present on normal cells compared to the avidity for binding to the same target antigens also present on cancer cells.   
     
     
         87 . The composition of  claim 86 , wherein the avidity of each multi-specific Chimeric Antigen Receptor is optimized to increase the specificity of the Chimeric Antigen Receptor for cancer cells by selecting the affinity of each of the at least two antigen binding sites for their respective target antigens based on at least one of the cell surface antigen density or expression levels of at least two target antigens on cancer cells, the Kd of each target antigen binding site, the density of the one or more multi-specific Chimeric Antigen Receptors on a T cell, the spatial arrangement of the target antigen binding sites of the one or more multi-specific Chimeric Antigen Receptors, or the length of a Chimeric Antigen Receptor single chain Fv linker. 
     
     
         88 . The composition of  claim 87 , wherein the cell surface antigen density or expression level of a target antigen on cancer cells is higher compared with the antigen density or expression level of the same target antigen on normal cells. 
     
     
         89 . The composition of  claim 86 , wherein the one or more T cells bearing multi-specific Chimeric Antigen Receptors recognize multiple epitopes of the same target antigen. 
     
     
         90 . The composition of  claim 86 , wherein the one or more T cells bearing multi-specific Chimeric Antigen Receptors have been generated from one or more stem cells. 
     
     
         91 . The composition of  claim 90 , wherein the one or more stem cells are one or more hematopoietic stem cells. 
     
     
         92 . The composition of  claim 86 , wherein the one or more T cells bearing multi-specific Chimeric Antigen Receptors target at least one antigen that is mutated on the subject's cancer cells. 
     
     
         93 . The composition of  claim 86 , wherein at least one of the target antigens includes at least one mutation in genetic sequence or difference in post-translational modification when expressed on cancer cells compared to when expressed on normal cells. 
     
     
         94 . The composition of  claim 86 , wherein the one or more T cells bearing multi-specific Chimeric Antigen Receptors recognize multiple epitopes of the same target antigen. 
     
     
         95 . The composition of  claim 86 , wherein the one or more multi-specific Chimeric Antigen Receptors include one or more transmembrane domains. 
     
     
         96 . The composition of  claim 86 , wherein the one or more multi-specific Chimeric Antigen Receptors include one or more extracellular domains. 
     
     
         97 . The composition of  claim 86 , wherein the one or more multi-specific Chimeric Antigen Receptors include one or more intracellular signaling domains. 
     
     
         98 . The composition of  claim 86 , wherein the antigen binding of the Chimeric Antigen Receptor is independent of HLA type. 
     
     
         99 . The composition of  claim 86 , wherein the one or more T cells bearing multi-specific Chimeric Antigen Receptors have been selected based on a stage of disease. 
     
     
         100 . The composition of  claim 86 , wherein the one or more T cells bearing multi-specific Chimeric Antigen Receptors further include at least one apoptotic or suicide gene. 
     
     
         101 . The composition of  claim 100 , wherein the apoptotic or suicide gene includes at least one conditionally inducible suicide gene. 
     
     
         102 . The composition of  claim 101 , wherein the at least one conditionally inducible suicide gene includes at least one of thymidylate kinase, inducible caspase 9, CD20, thymidine kinase, or modified FAS. 
     
     
         103 . The composition of  claim 86 , wherein the one or more T cells bearing multi-specific Chimeric Antigen Receptors is CD8+. 
     
     
         104 . The composition of  claim 86 , wherein the one or more T cells bearing multi-specific Chimeric Antigen Receptors is CD4+. 
     
     
         105 . The composition of  claim 86 , wherein at least one of the antigens includes at least one tumor-associated antigen. 
     
     
         106 . The composition of  claim 86 , wherein the at least one antigen includes at least one of EBNA-3, E6, E7, carcinoembryonic antigen, her-2/neu, Muc-1, MART-1, gp100, tyrosinase, p53, beta-catenin, CDK4, ras, alphafetoprotein, O antigens, H antigens, K antigens, or viral proteins. 
     
     
         107 . The composition of  claim 86 , further including at least one magnetic particle or magnetic nanoparticle. 
     
     
         108 . The composition of  claim 86 , wherein at least one of the multi-specific Chimeric Antigen Receptors is integrated into a host T cell at an endogenous T cell receptor locus. 
     
     
         109 . The composition of  claim 86 , wherein the one or more T cells bearing multi-specific Chimeric Antigen Receptors have been selected for the subject from a library of T cells bearing multi-specific Chimeric Antigen Receptors. 
     
     
         110 . A composition, comprising:
 one or more nucleic acid transcripts encoding one or more multi-specific Chimeric Antigen Receptors for at least two antigen binding sites, wherein when expressed on the surface of a cell, the multi-specific Chimeric Antigen Receptors have decreased avidity for binding to the at least two target antigens present on normal cells compared to the avidity for binding to the same target antigens also present on cancer cells.   
     
     
         111 . The composition of  claim 110 , further including encoding at least one site-specific insertion sequence. 
     
     
         112 . The composition of  claim 111 , wherein the at least one site-specific insertion sequence includes at least one endogenous T cell receptor locus of a host cell.