TGFBeta signal convertor
The present disclosure provides improved compositions for adoptive T cell therapies for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith.
1. A lentiviral vector comprising a polynucleotide encoding a fusion polypeptide comprising:
(a) a TGFβR2 polypeptide comprising:
(i) an extracellular TGFβI-binding domain of TGFβR2;
(ii) an IL-12Rβ2 transmembrane domain; and
(iii) an IL-12Rβ2 intracellular signaling domain;
(b) a viral self-cleaving 2A peptide; and
(c) a TGFβR1 polypeptide comprising:
(i) an extracellular TGFβ1-binding domain of TGFβR1;
(ii) an IL-12Rβ1 transmembrane domain; and
(iii) an IL-12Rβ1 intracellular signaling domain.
2. The lentiviral vector of claim 1 , wherein the viral self-cleaving 2A polypeptide is selected from the group consisting of: a foot-and-mouth disease virus (FMDV) (F2A) peptide, an equine rhinitis A virus (ERAV)(E2A) peptide, a Thosea asigna virus (TaV) (T2A) peptide, a porcine teschovirus-1 (PTV-1)(P2A) peptide, a Theilovirus 2A peptide, and an encephalomyocarditis virus 2A peptide.
3. The lentiviral vector of claim 1 , wherein the fusion polypeptide further comprises (i) an engineered antigen receptor and (ii) a second polypeptide cleavage signal or viral self-cleaving 2A polypeptide.
4. The lentiviral vector of claim 1 , wherein the viral self-cleaving 2A polypeptide is a porcine teschovirus-1 (PTV-1) (P2A) peptide.
5. A cell comprising the lentiviral vector of claim 1 .
6. The cell of claim 5 , wherein the cell is:
(a) a hematopoietic cell;
(b) a T cell;
(c) a CD3 + , CD4 + , and/or CD8 + cell;
(d) an immune effector cell;
(e) a cytotoxic T lymphocyte (CTL), a tumor infiltrating lymphocyte (TIL), or a helper T cell; or
(f) a natural killer (NK) cell or natural killer T (NKT) cell.
7. A composition comprising the cell of claim 6 .
8. The cell of claim 5 , wherein the cell is a hematopoietic cell.
9. The cell of claim 5 , wherein the cell is a T cell.
10. The cell of claim 5 , wherein the cell is a CD3 + , CD4 + , and/or CD8 + cell.
11. The cell of claim 5 , wherein the cell is an immune effector cell.
12. The cell of claim 5 , wherein the cell is a cytotoxic T lymphocyte (CTL).
13. The cell of claim 5 , wherein the cell is a tumor infiltrating lymphocyte (TIL).
14. The cell of claim 5 , wherein the cell is a helper T cell.
15. A lentiviral vector comprising a polynucleotide encoding a fusion polypeptide comprising:
(a) a TGFβR2 polypeptide comprising:
(i) an extracellular TGFβI-binding domain of TGFβR2;
(ii) an IL-12Rβ2 transmembrane domain; and
(iii) an IL-12Rβ2 intracellular signaling domain;
(b) a viral self-cleaving 2A peptide; and
(c) a TGFβR1 polypeptide comprising:
(i) an extracellular TGFβ1-binding domain of TGFβR1;
(ii) an IL-12Rβ1 transmembrane domain; and
(iii) an IL-12Rβ1 intracellular signaling domain.
16. The lentiviral vector of claim 15 , wherein the viral self-cleaving 2A polypeptide is selected from the group consisting of: a foot-and-mouth disease virus (FMDV) (F2A) peptide, an equine rhinitis A virus (ERAV) (E2A) peptide, a Thosea asigna virus (TaV) (T2A) peptide, a porcine teschovirus-1 (PTV-1) (P2A) peptide, a Theilovirus 2A peptide, and an encephalomyocarditis virus 2A peptide.
17. The lentiviral vector of claim 15 , wherein the fusion polypeptide further comprises (i) an engineered antigen receptor and (ii) a second polypeptide cleavage signal or viral self-cleaving 2A polypeptide.
18. A cell comprising the lentiviral vector of claim 15 .
19. The cell of claim 18 , wherein the cell is:
(a) a hematopoietic cell;
(b) a T cell;
(c) a CD3 + , CD4 + , and/or CD8 + cell;
(d) an immune effector cell;
(e) a cytotoxic T lymphocyte (CTL), a tumor infiltrating lymphocyte (TIL), or a helper T cell; or
(f) a natural killer (NK) cell or natural killer T (NKT) cell.
20. A composition comprising the cell of claim 18 .