T cells with increased immunosuppression resistance
This invention relates to the treatment of cancer in an individual by administration of a population of modified T cells that express a recombinant cAMP phosphodiesterase (PDE) or a fragment thereof and an antigen receptor which binds specifically to cancer cells in the individual. Populations of modified T cells and methods of producing populations of modified T cells are provided, along with pharmaceutical compositions and methods of treatment.
1. A population of modified T cells which express an antigen receptor which binds specifically to cancer cells and a cAMP phosphodiesterase (PDE) or fragment thereof,
wherein said cells comprise a heterologous nucleic acid encoding the cAMP phosphodiesterase (PDE).
2. The population of claim 1 wherein the nucleic acid encoding the cAMP PDE or fragment is comprised in an expression vector.
3. The population of claim 1 wherein the cAMP phosphodiesterase (PDE) is cAMP phosphodiesterase 7A (PDE7A) or cAMP phosphodiesterase 4C (PDE4C).
4. The population of claim 1 wherein the antigen receptor is a T cell receptor (TCR).
5. The population of claim 4 wherein the antigen receptor is a heterologous TCR.
6. The population of claim 5 wherein said cells comprise a heterologous nucleic acid encoding the TCR.
7. The population of claim 6 wherein the heterologous nucleic acid encoding the TCR is comprised in an expression vector.
8. The population of claim 4 wherein the TCR binds specifically to an MHC displaying a peptide fragment of a tumour antigen expressed by the cancer cells.
9. The population of claim 8 wherein the tumour antigen is NY-ESO-1, MAGE-A4 or MAGE-A10.
10. The population of claim 1 wherein the antigen receptor is a chimeric antigen receptor (CAR).
11. The population of claim 10 wherein the CAR binds specifically to a tumour antigen expressed by the cancer cells.
12. The population of claim 1 wherein the cancer cells are melanoma cells.
13. The population of claim 1 wherein the population of modified T cells comprises CD4 + T cells; CD8 + T cells; or CD4 + T cells and CD8 + T cells.
14. The population of claim 1 wherein the modified T cells are produced by a method comprising modifying a population of T cells obtained from a donor individual to express a cAMP phosphodiesterase (PDE) or a fragment thereof.
15. The population of claim 14 wherein the T cells express an antigen receptor which binds specifically to cancer cells from the donor individual.
16. The population of claim 14 wherein the method further comprises modifying the population of T cells to express an antigen receptor which binds specifically to cancer cells.
17. A pharmaceutical composition comprising the population of claim 1 and a pharmaceutically acceptable excipient.