T cell receptor-deficient T cell compositions
The invention is directed to modified T cells, methods of making and using isolated, modified T cells, and methods of using these isolated, modified T cells to address diseases and disorders. In one embodiment, this invention broadly relates to TCR-deficient T cells, isolated populations thereof, and compositions comprising the same. In another embodiment of the invention, these TCR-deficient T cells are designed to express a functional non-TCR receptor. The invention also pertains to methods of making said TCR-deficient T cells, and methods of reducing or ameliorating, or preventing or treating, diseases and disorders using said TCR-deficient T cells, populations thereof, or compositions comprising the same.
1. A method of treating an infectious condition in an individual in need thereof, comprising administering to the individual a composition comprising a therapeutically effective amount of isolated modified primary human T cells which are derived from a primary human T cell isolated from a human donor, which primary human T cells are:
(i) modified to functionally impair or to reduce expression of the endogenous T cell receptor (TCR), and
(ii) modified by the introduction of a nucleic acid construct comprising a nucleic acid which encodes for and results in the expression at least one exogenous non-TCR that comprises a pathogen-associated receptor ligand binding domain and further comprises a nucleic acid encoding a signaling domain, wherein said pathogen-associated receptor ligand binding domain and said signaling domain together mediate T cell signaling upon the binding of the ligand binding domain to a ligand expressed by a pathogen-infected target cell.
2. The method of claim 1 , wherein a histoincompatible human recipient is treated and said administration elicits no or a reduced GVHD response in said histoincompatible human recipient as compared to the GVHD response elicited by primary human T cells isolated from the same human donor that are only modified by the introduction of said nucleic acid which encodes for and results in the expression at least one exogenous non-TCR that comprises a pathogen-associated receptor ligand binding domain.
3. The method of claim 1 , wherein the treated infectious condition is caused by a virus, bacterium, protozoan, or parasite.
4. The method of claim 3 , wherein the treated infectious condition is caused by a virus.
5. The method of claim 4 , wherein the virus is an adenovirus, cytomegalovirus, human immunodeficiency virus type 1, human immunodeficiency virus type 2, hepatitis type A, hepatitis type B, hepatitis type C, hantavirus, papilloma virus, influenza, varicella, herpes simplex type 1, herpes simplex type 2, rinderpest, rhinovirus, echovirus, rotavirus, respiratory syncytial virus, echinovirus, arbovirus, coxsackie virus, mumps virus, measles virus, rubella virus, or polio virus.
6. The method of claim 1 , wherein said isolated modified primary human T cells are derived from an allogeneic T cell or primary human PBMCs isolated from a human subject.
7. The method of claim 2 , wherein said isolated modified primary human T cells are derived from an allogeneic T cell or primary human PBMCs isolated from a human subject.
8. The method of claim 1 , wherein said isolated modified primary human T cells express CD4 or CD8.
9. The method of claim 2 , wherein said isolated modified primary human T cells express CD4 or CD8.
10. The method of claim 1 , wherein the isolated modified primary human T cells are derived from primary human T cells comprised in human peripheral blood mononuclear cells or cytotoxic T cells.
11. The method of claim 2 , wherein the isolated modified primary human T cells are derived from primary human T cells comprised in human peripheral blood mononuclear cells or cytotoxic T cells.
12. The method of claim 1 , wherein the signaling domain is obtained from CD3 ζ.
13. The method of claim 2 , wherein said reduced GVHD response is evidenced by the isolated primary human T cells eliciting reduced expression of gamma interferon as compared to primary human T cells isolated from the same human donor that are only modified by the introduction of said nucleic acid which encodes for and results in the expression at least one exogenous non-TCR that comprises a pathogen-associated receptor ligand binding domain.
14. The method of claim 1 , wherein said reduced GVHD response is evidenced by said isolated primary human T cells not eliciting an increase in the expression of gamma interferon as compared to primary human T cells isolated from the same human donor that are only modified by the introduction of said nucleic acid which encodes for and results in the expression at least one exogenous non-TCR that comprises a pathogen-associated receptor ligand binding domain.
15. The method of claim 2 , wherein isolated primary human T cells do not elicit a GVHD response in a human recipient.
16. The method of claim 1 , wherein the individual is undergoing or has undergone a transplant surgery.
17. The method of claim 2 , wherein the individual is undergoing or has undergone a transplant surgery.
18. The method of claim 1 , wherein the composition is administered to the individual prior to a transplant surgery.
19. The method of claim 2 , wherein the composition is administered to the individual prior to a transplant surgery.