Genetically modified cells and uses thereof

Abstract

The present invention relates generally to a population of stem cells (e.g., iPSCs or HSCs) that comprise nucleic acids encoding a T cell receptor and a chimeric antigen receptor directed to multiple distinct antigenic determinants, for example two distinct tumour antigenic determinants. The present invention is also directed to a population of T cells that co-express a T cell receptor and a chimeric antigen receptor directed to multiple distinct antigenic determinants, such as two distinct tumour antigenic determinants. The cells of the present invention can be derived from chosen donors whose HLA type is compatible with significant sectors of the populations, and are useful in a wide variety of applications, in particular in the context of the therapeutic treatment of neoplastic conditions.

1 .- 74 . (canceled) 
     
     
         75 . A composition, comprising:
 (i) a nucleic acid encoding a first chimeric antigen receptor (CAR) which comprises an antigen recognition moiety operably linked to a T cell activation moiety through a hinge region and a transmembrane domain and directed to a first antigenic determinant; and   (ii) a nucleic acid encoding an antigen-binding receptor lacking a functional signaling intracellular domain which comprises an antigen recognition moiety, a hinge and a transmembrane region of a CAR, directed to a second antigenic determinant.   
     
     
         76 . The construct of  claim 75 , wherein the hinge region in the antigen-binding receptor has cysteine residues either removed or substituted to prevent the formation of dimers. 
     
     
         77 . The construct according to  claim 75 , wherein the hinge region in the antigen-binding receptor is selected from a CD8 hinge and a CD28 hinge. 
     
     
         78 . The construct according to  claim 75 , wherein the hinge region in the CAR comprises one or more cysteine residues to direct dimerization of the CAR. 
     
     
         79 . The construct according to  claim 75 , wherein the hinge region in the CAR is selected from a CD8 hinge and a CD28 hinge. 
     
     
         80 . The construct according to  claim 75 , wherein the first antigenic determinant is selected from TAG-72, CD19 and MAGE. 
     
     
         81 . The construct according to  claim 75 , wherein the second antigenic determinant is CD47. 
     
     
         82 . The construct of according to  claim 75 , wherein the first antigenic determinant is TAG-72 and the second antigenic determinant is CD47. 
     
     
         83 . The construct according to  claim 75 , wherein the nucleic acid encoding the CAR is operably linked to the nucleic acid encoding the antigen-binding receptor through a nucleotide sequence encoding a self-cleaving peptide. 
     
     
         84 . A cell or a population thereof, wherein
 (i) the cell is (a) stem cell or (b) a derivative cell obtained from differentiating the cell of (a); and   (ii) the cell comprises the construct as defined in  claim 75 .   
     
     
         85 . The cell according to  claim 84 , wherein the cell expresses at least one homozygous HLA haplotype. 
     
     
         86 . The cell according to  claim 84  for use in the treatment of a neoplastic condition, a microorganism infection, or an autoimmune condition.