Granted Patent B2

US 12,455,279 · App. 17/424,499 · Granted Oct 28, 2025

Inventor: Mia Levite (Savyon, IL)

G01N33/5047A61K40/11A61K40/42A61K2239/53

Abstract

Claims (87)

1. A method of person-specific adoptive neuroimmunotherapy in a subject in need thereof, the method comprising:

(I) a diagnostic stage, comprising:

(a) providing a T cells sample from the subject;

(b) contacting ex vivo the T cells with one or more combinations of molecules selected from the group consisting of glutamate+neuropeptide Y; dopamine+neuropeptide Y; glutamate+dopamine; dopamine+GnRH-II; glutamate+GnRH-II; neuropeptide Y+GnRH-II: dopamine+glutamate+GnRH-I; dopamine+glutamate+GnRH-II; glutamate+calcitonin gene-related peptide (CGRP); GnRH-II+CGRP; and neuropeptide Y+CGRP;

(c) measuring the expression level and/or the functional level of the Programmed Cell Death 1 (PD-1) protein and/or the PD-1 gene in the T cells;

(d) testing and measuring in the T cells at least one T cell function selected from the group consisting of:

(i) the ability to proliferate when cultured alone;

(ii) the ability to kill disease-causing cells;

(iii) the ability to kill an infectious organism;

(iv) the expression level of CD3 zeta-chain;

(v) migration ability;

(vi) adhesion ability;

(vii) homing ability;

(viii) penetration ability;

(ix) secretion of therapeutic proteins ability; and

(x) expression levels and functional levels of proteins

and/or genes involved and needed in T cell functions (i)-(ix);

(e) selecting at least one combination of molecules of (b) that induced in the contacted T cells a decreased expression and/or function of the PD-1 protein and/or the PD-1 gene compared to non-contacted cells of the same T cells sample, and optionally further induced in the contacted T cells one or more of: increased proliferation ability when cultured alone: increased killing of disease causing cells: increased ability to kill an infectious organism: increased expression of CD3 zeta-chain; increased migration ability; increased adhesion ability; increased homing ability; increased penetration ability; increased secretion ability of at least one therapeutic protein; or increased expression or function of at least one protein or gene involved in T cell functions (i)-(ix); and

(II) a therapeutic stage comprising:

(a) providing a therapeutically effective amount of autologous T cells whose origin is the same as the sample T cells;

(b) contacting the T cells with at least one combination of molecules selected in diagnostic stage (I)(e); and

(c) administering the contacted second T cells of (b) to the subject;

thereby performing person-specific adoptive neuroimmunotherapy in said subject.

2. The method of claim 1 , wherein said subject suffers from a disease, condition, injury or wound that may benefit from improved immunotherapeutic potential of its T cells, said disease, condition, injury or wound being selected from the group consisting of a cancer, an infectious disease, a genetic immunodeficiency, an acquired immunodeficiency, a degenerative disease, an autoimmune disease, a metabolic disease, a genetic disease, a neurological or neuropsychiatric disease, and post-organ transplant accompanied by immune incompetence.

3. The method of claim 2 , wherein the disease, condition, injury or wound is associated with suboptimal T cell number, activity or both.

4. The method of claim 1 , wherein:

the T cells are selected from the group consisting of effector T cells, helper T cells, cytotoxic T cells, regulator T cells, suppressor T cells, natural killer T cell, inflammatory T cells, memory T cells, gamma delta T cells, tissue/organ-infiltrating T cells, tumor-infiltrating T cells, mucosal associated T cells, repairing T cells, pro-regenerative T cells, activated T cells, and inactivated T cells; or any combination thereof.

5. The method of claim 1 , wherein:

the administration in the therapeutic stage (II)(c) comprises administering an amount of between 2×10 6 and 10 9 of the contacted T cells; or

said administering comprises repeated administration of the contacted second T cells; or

said administering comprises administration of the contacted second T cells indefinitely; or

any combination thereof.

6. The method of claim 1 , wherein the administered contacted second T cells perform at least one of the following functions in the subject:

(a) kill disease-causing cells;

(b) kill an infectious organism;

(c) cure said disease or condition;

(d) improve the subject's condition;

(e) repair a tissue or organ;

(f) replace damaged cells, or tissue;

(g) compensate for a loss or deficiency;

(h) prevent said disease or condition; and

(i) regenerate a tissue or organ.

7. The method of claim 1 , wherein the selecting step (e) further requires that the selected combination of molecules induces a synergistic effect in decreasing the expression level of PD-1 gene or the function of the PD-1 protein in the first T cells.

8. The method of claim 1 , wherein the T cells provided from the subject are exhausted T cells.

9. The method of claim 1 , wherein the steps of the diagnostic stage are performed one or more times, at different time points and conditions.

10. A method of person-specific adoptive neuroimmunotherapy of cancer in a subject in need thereof, the method comprising:

(I) a diagnostic stage, comprising:

(a) providing a T cells sample from the subject;

(b) contacting ex vivo the T cells with one or more of combination of molecules selected from the group consisting of glutamate+neuropeptide Y; dopamine+neuropeptide Y; glutamate+dopamine; dopamine+GnRH-II; glutamate+GnRH-II; neuropeptide Y+GnRH-II; dopamine+glutamate+GnRH-I; dopamine+glutamate+GnRH-II; glutamate+calcitonin gene-related peptide (CGRP); GnRH-II+CGRP; and neuropeptide Y+CGRP;

(c) measuring the expression level and/or the functional level of the Programmed Cell Death 1 (PD-1) protein and/or the PD-1 gene in the T cells;

(d) testing and measuring in the T cells at least one T cell function selected from the group consisting of:

(i) the ability to proliferate when cultured alone;

(ii) the ability to proliferate when cocultured with cancerous cells associated with the cancer;

(iii) the ability to kill cancerous cells associated with the cancer;

(iv) the expression level of CD3 zeta-chain;

(v) migration ability;

(vi) adhesion ability;

(vii) homing ability;

(viii) penetration ability;

(ix) secretion of therapeutic proteins ability; and

(x) expression levels and functional levels of proteins and/or genes involved and needed in T cell functions (i)-(ix);

(e) selecting at least one combination of molecules of (b) that induced in the contacted T cells a decreased expression and/or function of the PD-1 protein and/or the PD-1 gene compared to non-contacted cells of the same T cells sample, and optionally further induced in the contacted T cells one or more of; and optionally further induced in the contacted T cells one or more of: increased proliferation ability when cultured alone or cocultured with the cancerous cells; increased killing of cancerous cells; increased expression of CD3 zeta-chain; increased migration ability; increased adhesion ability; increased homing ability; increased penetration ability; increased secretion ability of at least one therapeutic protein; or increased expression or function of at least one protein or gene involved in T cell functions (i)-(ix); and

(II) a therapeutic stage comprising:

(a) providing a therapeutically effective amount of autologous T cells whose origin is the same as the sample T cells;

(b) contacting the T cells with at least one combination of molecules selected in diagnostic stage (I)(e); and

(c) administering the contacted second T cells of (II)(b) to the subject;

thereby performing person-specific adoptive neuroimmunotherapy of cancer in the subject.

11. The method of claim 10 , wherein the T cells provided from the subject are exhausted T cells.

12. The method of claim 10 , wherein the steps of the diagnostic stage are performed one or more times, at different time points and conditions.

13. A method of selecting a subject suitable for person-specific adoptive neuroimmunotherapy, the method comprising,

(a) providing a T cells sample from the subject;

(b) contacting ex vivo the T cells with one or more combinations of molecules selected from the group consisting of glutamate+neuropeptide Y; dopamine+neuropeptide Y; glutamate+dopamine; dopamine+GnRH-II; glutamate+GnRH-II; neuropeptide Y+GnRH-II; dopamine+glutamate+GnRH-I; dopamine+glutamate+GnRH-II; glutamate+calcitonin gene-related peptide (CGRP); GnRH-II+CGRP; and neuropeptide Y+CGRP

(c) measuring the expression level and/or the functional level of the programmed cell death 1 (PD-1) protein and/or the PD-1 gene in the T cells;

(d) testing and measuring in the T cells at least one T cell function selected from the group consisting of:

i. the ability to proliferate when cultured alone;

ii. the ability to proliferate when cocultured with cancerous cells, in response to the cancerous cells;

iii. the ability to kill cancerous cells when cocultured with cancerous cells, in response to the cancerous cells

(iv) the ability to kill disease-causing cells;

(v) the ability to kill an infectious organism;

(vi) the expression level of CD3 zeta-chain;

vii. migration ability;

viii. adhesion ability;

ix. homing ability;

ix. penetration ability;

xi. secretion of therapeutic proteins ability; and

xii expression levels and functional levels of proteins and genes involved and needed in T cell functions xi;

(e) determining that the subject is suitable for person-specific adoptive neuroimmunotherapy when one or more combinations of (b) induced in the subject's contacted T cells a decrease in expression and/or function of PD-1 protein and/or PD-1 gene compared to non-contacted cells of the same T cells sample, and optionally further induced in the contacted T cells one or more of increased proliferation ability when cultured alone or cocultured with cancerous cells, in response to the cancerous cells; increased killing ability of cancerous cells when cocultured with the cancerous cells, in response to the cancerous cells; increased killing of disease causing cells; increased ability to kill an infectious organism; increased adhesion ability; increased homing ability; increased secretion ability of at least one therapeutic protein; or increased expression or function of at least one protein or gene involved in T cell functions i-xi.

Continuity (2)

References Cited (24)