USE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA COACTIVATOR 1-ALPHA (PGC1ALPHA) AGONISTS TO IMPROVE EX VIVO EXPANSION OF TUMOR INFILTRATING LYMPHOCYTES (TILS)

• US 20190307796A1
• Filed: 06/05/2017
• Published: 10/10/2019
• Est. Priority Date: 06/03/2016
• Status: Active Grant

• Current Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Delgoffe, Greg M.
• Granted Patent: US 12,048,717 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/876 Skin, melanoma
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2239/57 Skin; melanoma
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 2800/78 Enzyme modulators, e.g. Enzyme agonists
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/429 condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 38/1774 Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/46449 Melanoma antigens
• CPC Class Codes: A61K 45/05 Immunological preparations stimulating the reticulo-endothelial system, e.g. against cancer
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2827 : against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C12N 2501/39 : Steroid hormones
• CPC Class Codes: C12N 2501/999 : Small molecules not provided for elsewhere
• CPC Class Codes: C12N 5/0636 : T lymphocytes

Abstract

The present disclosure provides methods for expanding tumor-infiltrating lymphocytes (TILs), such as tumor-infiltrating T cells, utilizing an agonist of PGC1α in vivo, ex vivo, or both. Exhausted T cells present in the TIL population fail to effectively proliferate, produce cytokines, or kill target cells. The present disclosure provides methods to correct these defects through the use of pharmacologic agents to reprogram the metabolism of the exhausted intratumoral T cells. Exemplary agonists of PGC1α include proliferator-activated receptor (PPAR)-gamma agonists (e.g., a thiazolidinedione (TZD), aleglitazar, farglitazar, muraglitazar, or tesaglitazar), AMPK activators (e.g., 5-aminoimidazole-4-carboxamide ribonucleotide, AICAR), and sirtuin activators (e.g., resveratrol, SRT1720, SRT2104, SRT2183, SRT1460). Also provided are kits can compositions that can be used with such methods.

Claims

1. A method of treating exhausted tumor infiltrating lymphocytes (TILs) from a tumor, comprising:

contacting TILs from a tumor with an effective amount of one or more agents that increase peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α

) activity in the TILs, thereby treating the exhausted TILs.

2. The method of claim 1, wherein contacting TILs from a tumor with the effective amount of one or more agents that increase PGC1α

activity in the TILs comprises;

incubating the TILs from a tumor ex vivo with the effective amount of the one or more agents that increase PGC1α

activity in the TILs;

administering the effective amount of the one or more agents that increase PGC1α

activity in the TILs to a subject with the tumor;

or

combinations thereof.

3. The method of claim 1, wherein the method is at least partially performed ex vivo, and comprises:

contacting TILs from the tumor ex vivo with the effective amount of one or more agents that increase PGC1α

activity in the TILs; and

incubating the TILs ex vivo under conditions that permit expansion of the TILs.

4. The method of claim 1, wherein the method is at least partially performed in vivo, and comprises:

administering the effective amount of the one or more agents that increase PGC1α

activity in the TILs to a subject with the tumor;

obtaining the TILs from the tumor; and

incubating the TILs ex vivo under conditions that permit expansion of the TILs.

5. The method of claim 4, further comprising:

contacting TILs from the tumor ex vivo with the effective amount of one or more agents that increase PGC1α

activity in the TILs;

administering the treated TILs to the subject; and

optionally subsequently administering an effective amount of the one or more agents that increase PGC1α

activity to the subject with the tumor.

6. The method of claim 1, wherein the exhausted TILs from the tumor:

have sustained expression of PD-1;

have sustained expression of LAG-3;

have sustained expression of Tim-3;

have reduced mitochondrial mass;

have reduced expression of PGC1α

;

or combinations thereof.

7. The method of claim 1, wherein the TILs are further contacted ex vivo with interleukin 2 (IL-2), anti-CD3, anti-CD28, or combinations thereof.

8. The method of claim 1, wherein the TILs are further contacted ex vivo with anti-CD3, anti-CD28, and IL-2.

9. The method of claim 7, wherein the anti-CD3 and the anti-CD28 are attached to a bead.

10. The method of claim 1, wherein the from a tumor TILs comprise exhausted tumor infiltrating T-cells.

11. Isolated TILs treated using the method of claim 1.

12. A method of treating a tumor in a subject, comprising:

administering an effective amount of the isolated TILs of claim 11 to the subject, thereby treating the tumor.

13. The method of claim 12, further comprising administering an effective amount of IL-2 to the subject before, after, or both before and after, administering the isolated TILs.

14. The method of claim 12, further comprising administering an effective amount of one or more agents that increase PGC1α

activity to the subject before, after, or both before and after, administering the isolated TILs.

15. The method of claim 12, further comprising administering an effective amount of nonmyeloablative chemotherapy or radiotherapy to the subject to deplete native lymphocytes prior to administering an effective amount of the isolated TILs.

16. The method of claim 12, wherein treating the tumor comprises reducing the volume or weight of the tumor, reducing the number of metastases, reducing the size or weight of a metastasis, increasing the survival time of the subject, or combinations thereof.

17. The method of claim 1, wherein the tumor is a colorectal cancer, melanoma, cervical cancer, lung cancer, ovarian cancer, bladder cancer, breast cancer, or head and neck cancer.

20. The method of claim 1, wherein the one or more agents that increase PGC1α

activity comprise a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, AMPK activator, sirtuin activator, or combinations thereof.

21. The method of claim 20, wherein the PPAR-gamma agonist is a thiazolidinedione (TZD), aleglitazar, farglitazar, muraglitazar, or tesaglitazar.

22. The method of claim 21, wherein

the TZD is pioglitazone, rosiglitazone, rivoglitazone, or troglitazone;

the AMPK activator comprises 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR); and

/or

the sirtuin activator comprises resveratrol, SRT1720, SRT2104, SRT2183, SRT1460, or combinations thereof.

18. A composition comprising:

one or more agents that increase PGC1α

activity; and

one or more of anti-CD3, anti-CD28, and IL-2.

19. A kit comprising:

one or more agents that increase PGC1α

activity; and

one or more of anti-CD3, anti-CD28, and IL-2,

optionally wherein reagents of the kit are present in separate containers.