Cells expressing recombinant growth factor receptors
The present invention discloses cell lines and recombinant growth factor receptors useful in adoptive cell therapy (ACT), wherein the recombinant growth factor receptor can act as a molecular switch enabling cells expressing the rGFR protein to be expanded in-vitro or in- vivo. Thus the invention provides a T or NK cell, comprising a recombinant growth factor receptor (rGFR) comprising: (i) an extracellular (EC) domain; (ii) a thrombopoietin receptor transmembrane (TM) domain; and (iii) a growth factor receptor intracellular (IC) domain.
1. A T or natural killer (NK) cell comprising a recombinant thrombopoietin receptor (TpoR) comprising:
(i) a thrombopoietin receptor extracellular (EC) domain,
(ii) a thrombopoietin receptor transmembrane (TM) domain, and
(iii) an intracellular (IC) domain;
wherein the IC domain is from a human growth hormone receptor or a human prolactin receptor.
2. The T or NK cell of claim 1 wherein binding of a ligand to the TpoR induces proliferation of the T or NK cell.
3. The T or NK cell of claim 2 wherein the ligand is human thrombopoietin or a thrombopoietin receptor agonist.
4. The T or NK cell of claim 3 wherein the thrombopoietin receptor agonist binds to the TM domain.
5. The T or NK cell of claim 3 wherein the thrombopoietin receptor agonist is selected from Eltrombopag or Romiplostim.
6. The T or NK cell of claim 1 having the TM sequence of SEQ ID NO:3 or a variant thereof having at least 95% sequence identity to SEQ ID NO:3 which binds a thrombopoietin receptor agonist.
7. The T or NK cell of claim 1 , wherein the IC domain comprises the sequence of SEQ ID NO:4 or a variant thereof having at least 95% sequence identity to SEQ ID NO:4.
8. The T or NK cell of claim 1 , wherein the TM domain comprises the sequence of SEQ ID NO:3 or a variant thereof having at least 95% sequence identity to SEQ ID NO:3, and
wherein the IC domain comprises the sequence of SEQ ID NO:4 or a variant thereof having at least 95% sequence identity to SEQ ID NO:4.
9. The T or NK cell of claim 1 which comprises the sequence of SEQ ID NO:8 or 9, or a variant thereof having at least 95% sequence identity to SEQ ID NO: 8 or 9 but retains the capacity to i) bind to human thrombopoietin or a human thrombopoietin receptor and ii) induce cell proliferation or survival.
10. The T cell or NK cell of claim 1 , wherein the EC domain does not have a growth factor binding function and the TM domain binds to Eltrombopag.
11. The T cell or NK cell of claim 1 , wherein the T cell is selected from a Tumour Infiltrating Lymphocyte (TIL), a T Regulatory Cell (Treg) or a primary T cell.
12. The T cell or NK cell of claim 1 , further comprising a recombinant T-cell receptor (TCR) and/or Chimeric Antigen Receptor (CAR).
13. A nucleic acid encoding a recombinant thrombopoietin receptor (TpoR) comprising:
(i) a thrombopoietin receptor extracellular (EC) domain,
(ii) a thrombopoietin receptor transmembrane (TM) domain, and
(iii) an intracellular (IC) domain;
wherein the IC domain is from a human growth hormone receptor or a human prolactin receptor.
14. A vector comprising the nucleic acid of claim 13 .
15. A method of making the T or NK cell of claim 1 comprising a step of introducing the nucleic acid of claim 13 , or the vector of claim 14 , into a T or NK cell.
16. A pharmaceutical composition comprising the T or NK cell of claim 1 , or the vector of claim 14 , together with a pharmaceutically acceptable carrier, diluent or excipient.
17. A method of in vivo cell expansion comprising:
administering the T or NK cell of claim 1 , or the vector of claim 14 , to a subject; and
administering thrombopoietin or a thrombopoietin receptor agonist to the subject.
18. A method of adoptive cell therapy comprising administering the T or NK cell of claim 1 , or the vector of claim 14 , to a subject in need thereof.
19. A method of treating cancer comprising a step of administering the T or NK cell of claim 1 to a subject in need thereof.
20. The method of claim 18 comprising administering an effective amount of Eltrombopag to the subject.
21. A method of in vitro or ex vivo expansion of the T or NK cell of claim 1 comprising contacting the T or NK cell of claim 1 with Eltrombopag.
22. A method of treating a cancer comprising administering a composition comprising the T or NK cell of claim 1 in combination with thrombopoietin or a thrombopoietin receptor agonist.