CELL

1 - 3 . (canceled)

4 . A nucleic acid comprising a nucleotide sequence encoding a first chimeric antigen receptor (CAR) and a nucleotide sequence encoding a second CAR as separate molecules, each CAR comprising: an antigen-binding domain; a spacer; a trans-membrane domain; and an endodomain, wherein the antigen-binding domain of the first CAR binds to CD19 and the antigen-binding domain of the second CAR binds to CD22.

5 . A nucleic acid sequence according to claim 4 , which has the following structure:

AuB1-spacer1-TM1-endo1-coexpr-AaB2-spacer2-TM2-endo2

in which

AgB1 is a nucleic acid sequence encoding the antigen-binding domain of the first CAR; spacer1 is a nucleic acid sequence encoding the spacer of the first CAR;

CAR;

TM1 is a nucleic acid sequence encoding the transmembrane domain of the first CAR;

endol is a nucleic acid sequence encoding the endodomain of the first CAR;

coexpr is a nucleic acid sequence enabling co-expression of both CARs;

AgB2 is a nucleic acid sequence encoding the antigen-binding domain of the second CAR;

cpaccr 2 spacer2 is a nucleic acid sequence encoding the spacer of the second CAR;

TM2 is a nucleic acid sequence encoding the transmembrane domain of the second CAR; and

endo2 is a nucleic acid sequence encoding the endodomain of the second CAR;

which nucleic acid sequence, when expressed in a T cell, encodes a polypeptide which is cleaved at a cleavage site such that the first and second CARs are co-expressed as separate molecules at the T cell surface.

6 . A nucleic acid according to claim 5 , wherein coexpr encodes a sequence comprising a self-cleaving peptide.

7 . A nucleic acid according to claim 5 , wherein alternative codons are used in regions of sequence encoding the same or similar amino acid sequences, in order to avoid homologous recombination.

8 . A kit which comprises a first nucleic acid that comprises a nucleotide sequence encoding a first chimeric antigen receptor (CAR) and second nucleic acid that comprises a nucleotide sequence encoding a second CAR, each CAR comprising: an antigen-binding domain; a spacer; a trans-membrane domain; and an endodomain, wherein the antigen-binding domain of the first CAR binds to CD19 and the antigen-binding domain of the second CAR binds to CD22,

wherein the nucleic acid sequence of the first nucleic acid has the following structure:

AgB1-spacer1-TM1-endo1

in which

AgB1 is a nucleic acid sequence encoding the antigen-binding domain of the first CAR;

spacer1 is a nucleic acid sequence encoding the spacer of the first CAR;

TM1 is a nucleic acid sequence encoding the transmembrane domain of the first CAR;

and

endol is a nucleic acid sequence encoding the endodomain of the first CAR;

and

wherein the nucleic acid sequence of the second nucleic acid has the following structure:

AdB2-spacer2-TM2-endo2

in which

AgB2 is a nucleic acid sequence encoding the antigen-binding domain of the second CAR;

spacer2 is a nucleic acid sequence encoding the spacer of the second CAR;

TM2 is a nucleic acid sequence encoding the transmembrane domain of the second CAR; and

endo2 is a nucleic acid sequence encoding the endodomain of the second CAR.

9 . A kit comprising:

a first vector which comprises a first nucleic acid comprising a nucleotide sequence encoding a first chimeric antigen receptor (CAR) and

a second vector which comprises a nucleic acid comprising a nucleotide sequence encoding a second CAR, each CAR comprising: an antigen-binding domain; a spacer; a trans-membrane domain; and an endodomain, wherein the antigen-binding domain of the first CAR binds to CD19 and the antigen-binding domain of the second CAR binds to CD22.

10 . A kit according to claim 9 , wherein the vectors are integrating viral vectors or transposons.

11 . A vector comprising a nucleic acid according to claim 4 .

12 . A vector according to claim 11 which is a retroviral vector or a lentiviral vector or a transposon.

13 . A method for making a cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR as separate molecules at the cell surface, each CAR comprising: an antigen-binding domain; a spacer; a trans-membrane domain; and an endodomain, wherein the antigen-binding domain of the first CAR binds to CD19 and the antigen-binding domain of the second CAR binds to CD22, the method comprising a step of introducing: a nucleic acid according to claim 4 into a cell, or introducting a vector comprising said nucleic acid into the cell.

14 . A method according to claim 13 , wherein the cell is from a sample isolated from a subject.

15 - 45 . (canceled)

46 . A nucleic acid according to claim 6 , wherein alternative codons are used in regions of sequence encoding the same or similar amino acid sequences, in order to avoid homologous recombination.

47 . The nucleic acid according to claim 4 , wherein the first CAR and the second CAR each comprises a CD3 zeta endodomain.

48 . The nucleic acid according to claim 5 , wherein the first CAR and the second CAR each comprises a CD3 zeta endodomain.

49 . The nucleic acid according to claim 4 , wherein the first CAR and the second CAR each comprises a compound endodomain comprised of (a) a CD3 zeta domain and (b) a co-stimulatory domain or a TNF receptor family endodomain.

50 . The nucleic acid according to claim 49 , wherein each compound endodomain comprises a 41 BB endodomain, an OX40 endodomain, or a CD28 endodomain.

51 . The nucleic acid according to claim 5 , wherein the first CAR and the second CAR each comprises a compound endodomain comprised of (a) a CD3 zeta domain and (b) a co-stimulatory domain or a TNF receptor family endodomain.

52 . The nucleic acid according to claim 51 , wherein each compound endodomain comprises a 41 BB endodomain, an OX40 endodomain, or a CD28 endodomain.

53 . A method for making a cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR as separate molecules at the cell surface, each CAR comprising: an antigen-binding domain; a spacer; a trans-membrane domain; and an endodomain, wherein the antigen-binding domain of the first CAR binds to CD19 and the antigen-binding domain of the second CAR binds to CD22, the method comprising a step of introducing a nucleic acid according to claim 5 into a cell, or introducing a vector comprising said nucleic acid into the cell.

54 . A method for making a cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR as separate molecules at the cell surface, the method comprising introducing first and second nucleic acids into the cell:

wherein the first nucleic acid comprises a nucleotide sequence with the following structure:

AgB1-spacerl-TM1-endo1

in which AgB1 is a nucleic acid sequence encoding the antigen-binding domain of the first CAR; spacer1 is a nucleic acid sequence encoding the spacer of the first CAR; TM1 is a nucleic acid sequence encoding the transmembrane domain of the first CAR; and endol is a nucleic acid sequence encoding the endodomain of the first CAR; and

wherein the second nucleic acid sequence comprises a nucleotide sequence with the following structure:

Ag B2-spacer2-TM2-endo2

in which AgB2 is a nucleic acid sequence encoding the antigen-binding domain of the second CAR; spacer2 is a nucleic acid sequence encoding the spacer of the second CAR; TM2 is a nucleic acid sequence encoding the transmembrane domain of the second CAR; and endo2 is a nucleic acid sequence encoding the endodomain of the second CAR,

wherein the antigen-binding domain of the first CAR binds to CD19 and the antigen-binding domain of the second CAR binds to CD22.

55 . A method for making a cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR as separate molecules at the cell surface, the method comprising introducing first and second vectors into the cell:

wherein the first vector comprises a nucleic acid comprising a nucleotide sequence encoding the first CAR and the second vector comprises a nucleic acid comprising a nucleotide sequence encoding the second CAR, each CAR comprising: an antigen-binding domain; a spacer; a trans-membrane domain; and an endodomain,

wherein the antigen-binding domain of the first CAR binds to CD19 and the antigen-binding domain of the second CAR binds to CD22.

56 . A method according to claim 55 , wherein the vectors are integrating viral vectors or transposons.