Method of modulating the number and the distribution of tumor-infiltrating leukocytes in tumors

1. A method for modulating number and/or spatial distribution of NK cells that infiltrate a tumor in the treatment of a subject suffering from the tumor, wherein the method comprises administering to the subject a molecule that inhibits signaling between SDF-1 and CXCR4 and/or CXCR7 thereby modulating number and/or the spatial distribution of NK cells that infiltrate the tumor; and at least one checkpoint inhibitor, wherein said molecule comprises an L-nucleic acid and is selected from the group consisting of an SDF-1 binding nucleic acid molecule of type B, an SDF-1 binding nucleic acid molecule of type C, an SDF-1 binding nucleic acid molecule of type A and an SDF-1 binding nucleic acid molecule of type D, wherein

the SDF-1 binding nucleic acid molecule of type B comprises in 5′→3′ direction a first terminal stretch of nucleotides, a central stretch of nucleotides and a second terminal stretch of nucleotides; or a second terminal stretch of nucleotides, a central stretch of nucleotides and a first terminal stretch of nucleotides, and wherein the central stretch of nucleotides comprises the nucleotide sequence of

(SEQ ID NO: 52)

5′ GUGUGAUCUAGAUGUADWGGCUGWUCCUAGUYAGG 3′;

the SDF-binding nucleic acid molecule of type C comprises in 5′→3′ direction a first terminal stretch of nucleotides, a central stretch of nucleotides and a second terminal stretch of nucleotides; or a second terminal stretch of nucleotides, a central stretch of nucleotides and a first terminal stretch of nucleotides, and wherein the central stretch of nucleotides comprises the nucleotide sequence of GGUYAGGGCUHRX A AGUCGG (SEQ ID NO:108), wherein X A is either absent or is A;

the SDF-binding nucleic acid molecule of type A comprises in 5′→3′ direction a first terminal stretch of nucleotides, a central stretch of nucleotides and a second terminal stretch of nucleotides; or a second terminal stretch of nucleotides, a central stretch of nucleotides and a first terminal stretch of nucleotides, and wherein the central stretch of nucleotides comprises the nucleotide sequence of 5′ AAAGYRACAHGUMAAX A UGAAAGGUARC 3′ (SEQ ID NO:74), wherein X A is either absent or is A; or

the SDF-1 binding nucleic acid molecule of type D comprises the nucleotide sequence according to any one of SEQ ID NO:142 to SEQ ID NO:144.

2. The method of claim 1 , wherein the method comprises inducing an NK cell mediated immune response against the tumor.

3. The method of claim 1 , wherein the molecule:

a) increases the number of NK cells in a tumor, and/or

b) leads to a more homogeneous spatial distribution of NK cells in a tumor as compared to not using the method of claim 1 , and/or

c) leads to a spatial distribution of NK cells to more compartments in a tumor as compared to not using the method of claim 1 .

4. The method of claim 2 , wherein the NK cell mediated immune response against the tumor is enhanced, and/or an antibody-dependent cellular cytotoxicity is enhanced.

5. The method of claim 1 , wherein the tumor is selected from the group consisting of a solid tumor, a lymphoma, a myeloma and precursor thereof.

6. The method of claim 1 , wherein the central stretch of nucleotides of a type B nucleic acid molecule comprises the following nucleotide sequence:

(SEQ ID NO: 53)

5′ GUGUGAUCUAGAUGUADUGGCUGAUCCUAGUCAGG 3′.

7. The method of claim 1 , wherein the SDF-1 binding nucleic acid molecule of type B comprises the nucleotide sequence according to any one of SEQ ID NO:5 to SEQ ID NO:20 or SEQ ID NO:22 to SEQ ID NO:28.

8. The method of claim 7 , wherein the SDF-1 binding nucleic acid molecule of type B comprises the nucleotide sequence according to any one of SEQ ID NO:22 or SEQ ID NO:28.

9. The method of claim 1 , wherein the central stretch of nucleotides of a type C SDF-1 binding nucleic acid molecule comprises the nucleotide sequence of 5′ GGUYAGGHRAAGUCGG 3′ (SEQ ID NO:109), 5′ GGUYAGGGCUHRAGUCGG 3′ (SEQ ID NO:110) or 5′ GGUUAGGGCUHGAAGUCGG 3′ (SEQ ID NO:111).

10. The method of claim 1 , wherein the type C SDF-1 binding nucleic acid molecule comprises the nucleotide sequence according to any one of SEQ ID NO:95 to SEQ ID NO:107, SEQ ID NO:112 to SEQ ID NO:137, SEQ ID NO:223 or SEQ ID NO:224.

11. The method of claim 1 , wherein the central stretch of nucleotides of a type A SDF-1 binding nucleic acid molecule comprises the nucleotide sequence of

(SEQ ID NO: 75)

5′AAAGYRACAHGUMAAUGAAAGGUARC 3′,

or

(SEQ ID NO: 76)

5′ AAAGYRACAHGUMAAAUGAAAGGUARC 3′,

or

(SEQ ID NO: 77)

5′ AAAGYAACAHGUCAAUGAAAGGUARC 3′.

12. The method of claim 1 , wherein the SDF-1 binding nucleic acid molecule of type A comprises the nucleotide sequence according to any one of SEQ ID NO:60 to SEQ ID NO:73, SEQ ID NO:78 to SEQ ID NO:82, SEQ ID NO:84 to SEQ ID NO:87, SEQ ID NO:89 to SEQ ID NO:94, SEQ ID NO:145 or SEQ ID NO:146.

13. The method of claim 1 , wherein the molecule comprises a modification, whereby the modification allows modifying characteristics of the nucleic acid molecule in terms of residence time in an animal or a human body.

14. The method of claim 13 , wherein the modification is selected from the group consisting of an HES moiety, a PEG moiety, biodegradable modifications thereof and combinations thereof.

15. The method of claim 1 , wherein

the checkpoint inhibitor is selected from the group consisting of a PD-1 signaling inhibitor, a CTLA-4 antagonist, a TIM-3 antagonist and an LAG3 antagonist.

16. The method of claim 15 , wherein the PD-1 signaling inhibitor is a PD-1 inhibitor or a PDL-1 inhibitor.

17. The method of claim 16 , wherein if the PD-1 inhibitor is administered, the PD-1 inhibitor is an anti-PD-1 antibody, and wherein if the PDL-1 inhibitor is administered, the PDL-1 inhibitor is an anti-PDL-1 antibody.