Modified Monocytes/Macrophage Expressing Chimeric Antigen Receptors and Uses Thereof

Abstract

The present invention includes methods and compositions for treating cancer, whether a solid tumor or a hematologic malignancy. By expressing a chimeric antigen receptor in a monocyte, macrophage or dendritic cell, the modified cell is recruited to the tumor microenvironment where it acts as a potent immune effector by infiltrating the tumor and killing the target cells. One aspect includes a modified cell and pharmaceutical compositions comprising the modified cell for adoptive cell therapy and treating a disease or condition associated with immunosuppression.

What is claimed is: 
     
         1 - 30 . (canceled) 
     
     
         31 . A modified cell comprising a chimeric antigen receptor (CAR), wherein the CAR comprises
 an anti-HER2 antigen binding domain, an anti-PSMA binding domain, or an anti-mesothelin antigen binding domain,   a transmembrane domain, and   an intracellular domain of a stimulatory and/or co-stimulatory molecule, and 
 wherein the modified cell is a dendritic cell. 
     
     
         32 . The modified cell of  claim 31 , wherein the CAR further comprises a hinge domain. 
     
     
         33 . The modified cell of  claim 32 , wherein the hinge domain comprises a CD8 hinge domain or an Ig hinge domain. 
     
     
         34 . The modified cell of  claim 31 , wherein the transmembrane domain comprises a CD8 transmembrane domain, a CD28 transmembrane domain, a Dectin-1 transmembrane, a CD64 transmembrane domain, a CD16 transmembrane domain, a TLR1 transmembrane domain, a TLR2 transmembrane domain, a TLR4 transmembrane domain, a TLR5 transmembrane domain, or a TLR6 transmembrane domain. 
     
     
         35 . The modified cell of  claim 31 , wherein the intracellular domain comprises dual signaling domains. 
     
     
         36 . The modified cell of  claim 31 , wherein the intracellular domain comprises a CD3 zeta intracellular domain, a CD3γ intracellular domain, a CD3δ intracellular domain, a CD3ε intracellular domain, a CD86 intracellular domain, an FcεRI common γ subunit intracellular domain, an FcRβ intracellular domain, a CD79a intracellular domain, a CD79b intracellular domain, an FCγRIIa intracellular domain, a DAP10 intracellular domain, a DAP12 intracellular domain, a Dectin-1 intracellular domain, a CD16 intracellular domain, a TLR1 intracellular domain, a TLR2 intracellular domain, a TLR4 intracellular domain, a TLR5 intracellular domain, a TLR6 intracellular domain, a TLR7 intracellular domain, a TLR8 intracellular domain, a TLR9 intracellular domain, a CD40 intracellular domain, a TCR intracellular domain, a CD27 intracellular domain, a CD28 intracellular domain, a 4-1BB intracellular domain, an OX40 intracellular domain, a CD30 intracellular domain, a CD40 intracellular domain, a PD-1 intracellular domain, an ICOS intracellular domain, an LFA-1 intracellular domain, a CD2 intracellular domain, a CD7 intracellular domain, a LIGHT intracellular domain, a NKG2C intracellular domain, a B7-H3 intracellular domain, a CD83 ligand intracellular domain, a CDS intracellular domain, an ICAM-1 intracellular domain, a GITR intracellular domain, a BAFFR intracellular domain, an HVEM intracellular domain, a SLAMF7 intracellular domain, an NKp80 intracellular domain, a CD127 intracellular domain, a CD160 intracellular domain, a CD19 intracellular domain, a CD4 intracellular domain, a CD8α intracellular domain, a CD8β intracellular domain, an IL2Rβ intracellular domain, an IL2Rγ intracellular domain, an IL7Rα intracellular domain, an ITGA4 intracellular domain, a VLA1 intracellular domain, a CD49a intracellular domain, an ITGA4 intracellular domain, an IA4 intracellular domain, a CD49D intracellular domain, an ITGA6 intracellular domain, a VLA-6 intracellular domain, a CD49f intracellular domain, an ITGAD intracellular domain, a CD11d intracellular domain, an ITGAE intracellular domain, a CD103 intracellular domain, an ITGAL intracellular domain, a CD11a intracellular domain, an LFA-1 intracellular domain, an ITGAM intracellular domain, a CD11b intracellular domain, an ITGAX intracellular domain, a CD11e intracellular domain, an ITGB1 intracellular domain, a CD29 intracellular domain, an ITGB2 intracellular domain, a CD18 intracellular domain, an LFA-1 intracellular domain, an ITGB7 intracellular domain, a TNFR2 intracellular domain, a TRANCE/RANKL intracellular domain, a DNAMI (CD226) intracellular domain, a SLAMF4 (CD244) intracellular domain, a CD84 intracellular domain, a CD96 intracellular domain, a CEACAM1 intracellular domain, a CRTAM intracellular domain, a Ly9 (CD229) intracellular domain, a CD160 (BY55) intracellular domain, a PSGL1 intracellular domain, a CD100 (SEMA4D) intracellular domain, a CD69 intracellular domain, a SLAMF6 intracellular domain, a SLAM (CD150) intracellular domain, a BLAME (SLAMF8) intracellular domain, an SELPLG (CD162) intracellular domain, an LTBR intracellular domain, an LAT intracellular domain, a GADS intracellular domain, an SLP-76 intracellular domain, a PAG/Cbp intracellular domain, an NKp44 intracellular domain, an NKp30 intracellular domain, an NKp46 intracellular domain, an NKG2D intracellular domain, or a combination of any 2 of the above, or a combination of any 3 of the above. 
     
     
         37 . The modified cell of  claim 31 , wherein the antigen binding domain is selected from a group consisting of monoclonal antibody, a polyclonal antibody, a synthetic antibody, human antibody, humanized antibody, single domain antibody, single chain variable fragment, and antigen-binding fragments thereof. 
     
     
         38 . The modified cell of  claim 31 , wherein the modified cell is a human cell. 
     
     
         39 . The modified cell of  claim 31 , further comprising one or more spacer domains linking the transmembrane domain to the antigen binding domain and/or the intracellular domain. 
     
     
         40 . The modified cell of  claim 31 , further comprising an agent, wherein the agent is selected from the group consisting of a nucleic acid, an antibiotic, an anti-inflammatory agent, an antibody or antibody fragments thereof, a growth factor, a cytokine, an enzyme, a protein, a peptide, a fusion protein, a synthetic molecule, an organic molecule, a carbohydrate or the like, a lipid, a hormone, a microsome, a derivative or a variation thereof, and any combination thereof. 
     
     
         41 . The modified cell of  claim 31 , further comprising one or more adenoviral components and/or one or more lentiviral components. 
     
     
         42 . The modified cell of  claim 42 , wherein the one or more adenoviral components comprises an Ad5F35 adenoviral component. 
     
     
         43 . A pharmaceutical composition comprising the modified cell of  claim 31  and a pharmaceutically acceptable carrier.