Co-stimulatory domains for use in genetically-modified cells

Abstract

The present disclosure provides novel co-stimulatory domains useful in genetically-modified cells to promote cell proliferation and/or promote cytokine secretion after antigen recognition. For example, disclosed herein are genetically-modified cells comprising a chimeric antigen receptor or an inducible regulatory construct incorporating the co-stimulatory domains disclosed herein. Also disclosed herein are plasmids and viral vectors comprising a nucleic acid sequence encoding the co-stimulatory domains, and methods of administering compositions comprising the novel co-stimulatory domains to subjects in order to reduce the symptoms, progression, or occurrence of disease, such as cancer.

1 .- 62 . (canceled) 
     
     
         63 . A co-stimulatory domain comprising an amino acid sequence set forth in SEQ ID NO: 8. 
     
     
         64 . A chimeric antigen receptor (CAR) comprising an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain, wherein said intracellular domain comprises said co-stimulatory domain of  claim 63  and an intracellular signaling domain. 
     
     
         65 . The CAR of  claim 64 , wherein said intracellular signaling domain comprises a CD3 ζ intracellular signaling domain. 
     
     
         66 . The CAR of  claim 64 , wherein said transmembrane domain comprises a CD8 alpha transmembrane domain. 
     
     
         67 . The CAR of  claim 64 , wherein said extracellular ligand-binding domain comprises a single-chain variable fragment (scFv). 
     
     
         68 . The CAR of  claim 64 , wherein said extracellular ligand-binding domain has specificity for a tumor antigen. 
     
     
         69 . A genetically-modified eukaryotic cell comprising said co-stimulatory domain of  claim 63 . 
     
     
         70 . A genetically-modified eukaryotic cell comprising said CAR of  claim 64 . 
     
     
         71 . The genetically-modified eukaryotic cell of  claim 69 , wherein said genetically-modified eukaryotic cell is a genetically-modified human T cell. 
     
     
         72 . The genetically-modified eukaryotic cell of  claim 70 , wherein said genetically-modified eukaryotic cell is a genetically-modified human T cell. 
     
     
         73 . The genetically-modified eukaryotic cell of  claim 69 , wherein said genetically-modified eukaryotic cell is a genetically-modified human natural killer (NK) cell. 
     
     
         74 . The genetically-modified eukaryotic cell of  claim 70 , wherein said genetically-modified eukaryotic cell is a genetically-modified human NK cell. 
     
     
         75 . A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and said genetically-modified human T cell of  claim 71 . 
     
     
         76 . A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and said genetically-modified human T cell of  claim 72 . 
     
     
         77 . A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and said genetically-modified human NK cell of  claim 73 . 
     
     
         78 . A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and said genetically-modified human NK cell of  claim 74 .