Methods of using interleukin-10 for treating diseases and disorders

Abstract

Methods of modulating immune responses in subjects having oncology- and immune-related diseases, disorders and conditions by the administration of an IL-10 agent, including pegylated IL-10.

1 - 123 . (canceled) 
     
     
         124 . A genetically modified T-cell transformed with a first nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises:
 a) at least one antigen-specific targeting region that specifically binds a cell surface antigen present on the target cell population,   b) a transmembrane domain, and   c) an intracellular signaling domain,   and a second nucleic acid sequence, wherein the second nucleic acid sequence comprises:   a) a nucleic acid encoding a signal peptide (SP); and   b) a nucleic acid encoding an IL-10 polypeptide   the nucleic acid encoding the signal peptide being in frame with the nucleic acid sequence encoding the IL-10 polypeptide;   wherein said first and second nucleic acid sequences are operably linked to at least one transcriptional and translational regulatory sequence capable of directing the transcription and translation of a nucleic acid sequence in the genetically modified T-cell, such that the genetically modified T-cell expresses the CAR and the IL-10 polypeptide encoded by said first and second nucleic acid sequences respectively.   
     
     
         125 . The genetically modified T-cell of  claim 124  wherein the first nucleic acid sequence and the second nucleic acid sequence are provided on a single vector. 
     
     
         126 . The genetically modified T-cell of  claim 125  wherein the vector is a plasmid. 
     
     
         127 . The genetically modified T-cell of  claim 125  wherein the vector is a viral vector. 
     
     
         128 . The genetically modified T-cell of  claim 125  wherein the first nucleic acid sequence and the second nucleic acid sequence are each operably linked to a transcriptional and translational regulatory sequence capable of directing the transcription and translation of the operably linked nucleic acid sequence in the genetically modified T-cell. 
     
     
         129 . The genetically modified T-cell of  claim 125  wherein the first nucleic acid sequence and the second nucleic acid sequence are operably linked to a single transcriptional and translational regulatory sequence capable of directing the transcription and translation of the first and second nucleic acid sequences in the genetically modified T-cell. 
     
     
         130 . The genetically modified T-cell of  claim 128  wherein the vector is a viral vector. 
     
     
         131 . The genetically modified T-cell of  claim 129  wherein the vector is a viral vector. 
     
     
         132 . The genetically modified T-cell of  claim 128  wherein the transcriptional and translational regulatory sequences each comprises a promoter wherein the promoter is a constituitive promoter. 
     
     
         133 . The genetically modified T-cell of  claim 128  wherein the transcriptional and translational regulatory sequences each comprises a promoter wherein the promoter is an inducible promoter. 
     
     
         134 . The genetically modified T-cell of  claim 129  wherein the transcriptional and translational regulatory sequence comprises a promoter wherein the promoter is a constituitive promoter. 
     
     
         135 . The genetically modified T-cell of  claim 129  wherein the transcriptional and translational regulatory sequence comprises a promoter wherein the promoter is an inducible promoter. 
     
     
         136 . The genetically modified T-cell of  claim 124  wherein the CAR comprises a first nucleic acid sequence and the second nucleic acid sequence are each provided on a separate vector. 
     
     
         137 . The genetically modified T-cell of  claim 136  wherein the vector is a plasmid. 
     
     
         138 . The genetically modified T-cell of  claim 136  wherein the vector is a viral vector. 
     
     
         139 . The genetically modified T-cell of  claim 136  wherein the first nucleic acid sequence and the second nucleic acid sequence are each operably linked to a transcriptional and translational regulatory sequence capable of directing the transcription and translation of the operably linked nucleic acid sequence in the genetically modified T-cell. 
     
     
         140 . The genetically modified T-cell of  claim 136  wherein the first nucleic acid sequence and the second nucleic acid sequence are operably linked to a single transcriptional and translational regulatory sequence capable of directing the transcription and translation of the first and second nucleic acid sequences in the genetically modified T-cell. 
     
     
         141 . The genetically modified T-cell of  claim 139  wherein the vector is a viral vector. 
     
     
         142 . The genetically modified T-cell of  claim 140  wherein the vector is a viral vector. 
     
     
         143 . The genetically modified T-cell of  claim 139  wherein the transcriptional and translational regulatory sequences each comprises a promoter wherein the promoter is a constituitive promoter. 
     
     
         144 . The genetically modified T-cell of  claim 140  wherein the transcriptional and translational regulatory sequences each comprises a promoter wherein the promoter is an inducible promoter. 
     
     
         145 . The genetically modified T-cell of  claim 124  wherein a nucleic acid encoding an IL-10 polypeptide encodes a mature human IL-10 polypeptide. 
     
     
         146 . The genetically modified T-cell of  claim 124  wherein the cell surface antigen present on the target cell population is selected from the group consisting of CD19, CD20, CD22, ROR1, mesothelin, CD33/IL3Ra, c-Met, PSMA, glycolipid F77, EGFRvIII, GD-2, NY-ESO-1 TCR, MAGE A3 TCR, or any combination thereof. 
     
     
         147 . The genetically modified T-cell of  claim 146  wherein the intracellular signaling domain selected from the group consisting of the zeta chain of the T-cell receptor complex, the human CD3 zeta chain, CD3 δ polypeptide, CD3 Δ polypeptide, CD3 ε polypeptide, syk family tyrosine kinases, src family tyrosine kinases, CD2, CD5 and CD28. 
     
     
         148 . The genetically modified T-cell of  claim 147 , wherein the CAR further comprises a co-stimulatory domain. 
     
     
         149 . The genetically modified T-cell of  claim 146 , wherein the co-stimulatory domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), Dap10, CD27, CD2, CD5, ICAM-1, LFA-1 (CD11a/CD18), Lck, TNFR-I, TNFR-II, Fas, CD30, and CD40 domains. 
     
     
         150 . A method of treating a mammalian subject having a cancer-related disease, disorder or condition, comprising administering to the subject a therapeutically effective amount of a genetically modified T-cell transformed with a first nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises:
 a) at least one antigen-specific targeting region that specifically binds a cell surface antigen present on the target cell population,   b) a transmembrane domain, and   c) an intracellular signaling domain,   and a second nucleic acid sequence, wherein the second nucleic acid sequence comprises:   a) a nucleic acid encoding a signal peptide (SP); and   b) a nucleic acid encoding an IL-10 polypeptide   the nucleic acid encoding the signal peptide being in frame with the nucleic acid sequence encoding the IL-10 polypeptide;   wherein said first and second nucleic acid sequences are operably linked to at least one transcriptional and translational regulatory sequence capable of directing the transcription and translation of a nucleic acid sequence in the genetically modified T-cell, such that the genetically modified T-cell expresses the CAR and the IL-10 polypeptide encoded by said first and second nucleic acid sequences respectively.   
     
     
         151 . The method of  claim 150  wherein the T-cells are obtained from the subject, genetically modified ex vivo and reintroduced into the subject. 
     
     
         152 . The method of  claim 150  wherein the wherein the cell surface antigen present on the target cell population is selected from the group consisting of CD19, CD20, CD22, ROR1, mesothelin, CD33/IL3Ra, c-Met, PSMA, glycolipid F77, EGFRvIII, GD-2, NY-ESO-1 TCR, MAGE A3 TCR, or any combination thereof. 
     
     
         153 . The method of  claim 150  wherein the wherein the wherein the intracellular signaling domain selected from the group consisting of the zeta chain of the T-cell receptor complex, the human CD3 zeta chain, CD3 δ polypeptide, CD3 Δ polypeptide, CD3 ε polypeptide, syk family tyrosine kinases, src family tyrosine kinases, CD2, CD5 and CD28. 
     
     
         154 . The method of  claim 150  wherein the wherein the CAR further comprises a co-stimulatory domain. 
     
     
         155 . The genetically modified T-cell of  claim 149 , wherein the co-stimulatory domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), Dap10, CD27, CD2, CD5, ICAM-1, LFA-1 (CD11a/CD18), Lck, TNFR-I, TNFR-II, Fas, CD30, and CD40 domains. 
     
     
         156 . The method of  claim 150  wherein a nucleic acid encoding an IL-10 polypeptide encodes a mature human IL-10 polypeptide.