T cell modification and use thereof
This invention relates to modified T cells that inducibly express a bioactive molecule, such as IL-7, and constitutively expresses an antigen receptor, such as a T cell receptor or chimeric antigen receptor that binds to a tumour antigen. The modified T cells may comprise a nucleic acid construct that comprises a first nucleotide sequence encoding the bioactive molecule, a second nucleotide sequence encoding the antigen receptor; an inducible promoter operably linked to the first nucleotide sequence and a constitutive promoter operably linked to the second nucleotide. Nucleic acid constructs and vectors are provided, as well as T cells comprising such constructs and vectors and therapeutic methods and uses thereof.
1. A method of treating cancer using immunotherapy, comprising administering to a patient having cancer a population of modified T cells comprising a nucleic acid construct, wherein the cancer expresses one or more tumor antigens selected from NY-ESO1, PRAME, alpha-fetoprotein (AFP), MAGE A4, MAGE A1, MAGE A10 and MAGE B2; and wherein the nucleic acid construct comprises:
(i) a first nucleotide sequence encoding IL 7,
(ii) a second nucleotide sequence encoding an antigen receptor, wherein the antigen receptor is a chimeric antigen receptor (CAR) that binds to said one or more tumor antigens, or a T cell receptor (TCR) that binds to an MHC-displayed peptide fragment of said one or more tumor antigens;
(iii) an inducible promoter operably linked to the first nucleotide sequence; and
(iv) a constitutive promoter operably linked to the second nucleotide sequence wherein the administration of said modified T cells results in the treatment of the patient's cancer.
2. The method according to claim 1 wherein expression from the inducible promoter is induced by activation of the modified T cells.
3. The method according to claim 1 wherein the inducible promoter comprises a nuclear factor of activated T cells (NFAT) transcriptional response element (TRE).
4. The method according to claim 3 wherein the NFAT TRE has the nucleic acid sequence of SEQ ID NO: 14 or a variant thereof.
5. The method according to claim 3 wherein the inducible promoter comprises three or more copies of the NFAT TRE.
6. The method according to claim 1 wherein the nucleic acid construct comprises the sequence of SEQ ID NO: 1.
7. The method according to claim 1 wherein the constitutive promoter is the Human elongation factor-1 alpha promoter.
8. The method according to claim 1 wherein the IL-7 is human IL-7.
9. The method according to claim 1 wherein the TCR comprises the amino acid sequence of any one of SEQ ID NOs: 5, 6 or 11.
10. The method according to claim 1 wherein the tumour antigen is NY-ESO-1 and the method is for treatment of cancer expressing NY-ESO-1.
11. The method according to claim 1 wherein the nucleic acid construct is provided in a vector.
12. The method according to claim 11 wherein the vector is a lentiviral vector.
13. The method according to claim 1 wherein the cancer is characterized by the presence of one or more cancer cells which bind to said antigen receptor.
14. The method according to claim 1 wherein the modified T cells are autologous to the patient.
15. The method according to claim 1 wherein the modified T cells are allogeneic to the patient.
16. The method according to claim 1 wherein the tumor antigen is MAGE-A10 and the method is for treatment of cancer expressing MAGE-A10.
17. The method according to claim 1 wherein the tumour antigen is NY-ESO-1 or MAGE-A10.
18. The method according to claim 17 wherein the method is for treatment of cancer expressing NY-ESO-1 or MAGE-A10.