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 infection in an individual in need thereof, comprising administering to the individual a composition suitable for use in human therapy comprising a therapeutically effective amount of an isolated modified primary human T cell, which is derived from a primary human T cell isolated from a human donor, that: (i) is modified to functionally impair or to reduce expression of the endogenous T cell receptor (TCR), and (ii) is further modified to express at least one functional exogenous non-TCR that comprises a chimeric receptor comprising a pathogen-associated receptor ligand binding domain attached to a signaling domain, wherein said modified primary human T cell is suitable for use in human therapy, and further wherein the isolated primary human T cell modified as in (i) and (ii) elicits no or a reduced GVHD response in a histoincompatible human recipient as compared to the GVHD response elicited by a primary human T cell isolated from the same human donor that is only modified as in (ii).
2. The method of claim 1 , wherein the T cell can be used to treat infectious disease caused by a virus, bacterium, protozoan, or parasite.
3. The method of claim 2 , wherein the infectious disease to be treated is caused by a virus.
4. The method of claim 3 , wherein the virus is 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.
5. The method of claim 1 , wherein the T cell is derived from an allogeneic T cell or primary human PBMCs isolated from a human subject.
6. The method of claim 1 , wherein the T cell expresses CD4 or CD8.
7. The method of claim 1 , wherein the reduced GVHD response is evidenced by the isolated primary human T cell modified as in (i) and (ii) eliciting reduced expression of gamma interferon as compared to a primary human T cell isolated from the same human donor that is only modified as in (ii).
8. The method of claim 1 , wherein the reduced GVHD response is evidenced by the isolated primary human T cell modified as in (i) and (ii) not eliciting an increase in expression of gamma interferon as compared to a primary human T cell isolated from the same human donor that is only modified as in (ii).
9. The method of claim 1 , wherein the isolated primary human T cell modified as in (i) and (ii) does not elicit a GVHD response in a human recipient.
10. The method of claim 1 , wherein the individual is undergoing or has undergone a transplant surgery.
11. The method of claim 1 , wherein the composition is administered to the individual prior to a transplant surgery.
12. The method of claim 2 , wherein the infectious disease to be treated is caused by a bacterium.
13. The method of claim 12 , wherein the bacterium is a Staphylococcus sp., an Enterococcus sp., Bacillus anthracis , a Lactobacillus sp., a Listeria sp., Corynebacterium diphtherias , a Nocardia sp., a Streptococcus sp., a Pseudomonas sp., a Gardnerella sp., a Streptomyces sp., Thermoactinomyces vulgaris , a Treponema sp., a Campylobacter sp., Pseudomonas aeruginosa , a Legionella sp., Neisseria gonorrhoeae, Neisseria meningitidis, Flavobacterium meningosepticum, Flavobacterium odoratum , a Brucella sp., Bordetella pertussis, Bordetella bronchiseptica, Escherichia coli , a Klebsiella sp., an Enterobacter sp., Serratia marcescens, Serratia liquefaciens , an Edwardsiella sp., Proteus mirabilis, Proteus vulgaris , a Streptobacillus sp., Rickettsia rickettsii, Chlamydia psittaci, Chlamydia trachomatis, Mycobacterium (M.) tuberculosis, M. intracellulare, M. fortuitum, M. leprae, M. avium, M. bovis, M. africanum, M. kansasii, M. lepraemurium , a Chlamydia sp., or a Rickettsia sp.
14. The method of claim 2 , wherein the infectious disease to be treated is caused by a protozoan.
15. The method of claim 14 , wherein the protozoan is a Trypanosoma sp.