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1. WO2020110127 - METHODS OF ACTIVATING DYSFUNCTIONAL IMMUNE CELLS AND TREATMENT OF CANCER

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[ EN ]

WHAT IS CLAIMED IS:

1. A method of activating dysfunctional

CD8+/Lag3+/PD1+/Tim3+/CD103+/CD39+/CD137+/Klrgl T cells, the method comprising, contacting dysfunctional CD8+/Lag3+/PD1+/Tim3+/CD103+/CD39+/CD137+/Klrgl T cells with an agent capable of down-regulating a target gene selected from the group consisting of AKAP5, DGKH, PAG1, GALM, FUT8, WARS, CBLB, PIK3AP1, APOBEC3G, SLAMF7, SIRPG, GALNT1 or an expression product thereof, thereby activating the dysfunctional immune cells.

2. A method of determining responsiveness of a subject having a tumor to an immune checkpoint inhibition, the method comprising determining in a tumor of a subject a level of dysfunctional CD8+/Lag3+/PD1+/Tim3+/CD103+/CD39+/CD137+/Klrgl T cells, wherein a level of said dysfunctional cells above a predetermined threshold is indicative of a response to an immune checkpoint inhibition.

3. A method of treating a subject having a tumor, the method comprising:

(a) determining responsiveness of a subject to immune checkpoint inhibition according to claim 2; and

(i) wherein when said level of said dysfunctional cells is above said predetermined threshold, treating or selecting treatment for the subject with immune checkpoint inhibition; or

(ii) wherein when said level of said dysfunctional cells is below said predetermined threshold, subjecting said dysfunctional cells to ex vivo expansion and subsequently treating or selecting treatment for the subject with said immune checkpoint inhibition.

4. A method of treating a subject having a tumor, the method comprising administering to the subject an immune checkpoint inhibitor and an agent capable of down regulating a target gene selected from the group consisting of AKAP5, DGKH, PAG1, GALM, FUT8, WARS, CBLB, PIK3AP1, APOBEC3G, SLAMF7, SIRPG, GALNT1 or an expression product thereof, thereby treating the subject having the tumor.

5. A method of treating a subject having a tumor, the method comprising administering to the subject an agent capable of down-regulating a target gene selected from the group consisting of AKAP5, DGKH, PAG1, GALM, FUT8, WARS, CBLB, PIK3AP1, APOBEC3G, SLAMF7, SIRPG, GALNT1 or an expression product thereof, thereby treating the subject having the tumor.

6. An agent capable of inhibiting a target gene or expression product thereof selected from the group consisting of AKAP5, DGKH, PAG1, GALM, FUT8, WARS, CBLB, PIK3AP1, APOBEC3G, SLAMF7, SIRPG, GALNT1 for use in treating a subject having a tumor.

7. An immune checkpoint inhibitor and an agent capable of inhibiting a target gene or expression product thereof selected from the group consisting of AKAP5, DGKH, PAG1, GALM, FUT8, WARS, CBLB, PIK3AP1, APOBEC3G, SLAMF7, SIRPG, GALNT1 for use in treating a subject having a tumor.

8. The method of claim 4, wherein said administering said immune checkpoint inhibitor is following said administering said agent.

9. The method of claim 1, wherein said activating is performed ex-vivo.

10. The method of claim 1, wherein said activating is performed in-vivo.

11. The method or inhibitor and agent of any one of claims 1-10, wherein said dysfunctional cells are in a proliferative cell state and/or are not in growth arrest.

12. The method or inhibitor and agent of any one of claims 2-11, wherein said tumor is a solid tumor.

13. The method or inhibitor and agent of claim 12, wherein said solid tumor is a melanoma.

14. The method or inhibitor and agent of any one of claims 1-3 and 9-13, wherein said dysfunctional T cells are tumor infiltrating cells.

15. The method or inhibitor and agent of any one of claims 2-4 and 7-14, wherein said immune checkpoint is selected from the group consisting of cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) or its ligands, lymphocyte activation gene-3 (LAG3), B7 homolog 3 (B7-H3), B7 homolog 4 (B7-H4), indoleamine (2,3)-dioxygenase (IDO), adenosine A2a receptor, neuritin, B- and T-lymphocyte attenuator (BTLA), killer immunoglobulin-like receptors (KIR), T cell immunoglobulin and mucin domain-containing

protein 3 (TIM-3), inducible T cell costimulator (ICOS), CD27, CD28, CD40, CD244 (2B4), CD 160, GARP, 0X40, CD137 (4-1BB), CD25, VISTA, BTLA, TNFR25, CD57, CCR2, CCRS, CCR6, CD39, CD73, CD4, CD18, CD49b, CDld, CDS, CD21, TIMI, CD19, CD20, CD23, CD24, CD38, CD93, IgM, B220 (CD45R), CD317, CDl lb, Ly6G, ICAM-1, FAP, PDGFR, Podoplanin, and TIGIT.

16. The method of any one of claims 2-3 and 11-15, wherein said determining said level of dysfunctional cells is performed by fluorescence activated cell sorting (FACS).

17. The method of any one of claims 2-3 and 11-15, wherein said determining said level of dysfunctional cells is performed by single cell transcriptome analysis.