Multimeric IL-15-based molecules

1. An isolated soluble fusion protein complex comprising at least two soluble proteins, wherein

a first soluble protein comprises an interleukin-15 (IL-15) polypeptide domain and a second

soluble protein comprises a soluble IL-15 receptor alpha sushi-binding domain (IL-15RαSu) fused to

an immunoglobulin Fc domain,

wherein the second soluble protein is substantially identical to SEQ ID NO:14 or SEQ ID NO:16, and

wherein the IL-15 domain of the first soluble protein binds to the IL-15RαSu domain of the second soluble protein to form a soluble fusion protein complex.

2. The soluble fusion protein complex of claim 1 , wherein one of the first or second soluble protein further comprises a second binding domain that specifically binds to a disease antigen, immune checkpoint molecule, or immune signaling molecule.

3. The soluble fusion protein complex of claim 1 , wherein the IL-15 polypeptide is an IL-15 variant comprising an N72D mutation (IL-15N72D).

4. The soluble fusion protein complex of claim 1 , wherein the first soluble protein comprises the amino acid sequence set forth in one of SEQ ID NOs: 2, 6, 10, 18, 20, 24, 28, 32, or 38 and wherein the second soluble protein is substantially identical to SEQ ID NO:14 or SEQ ID NO:16.

5. A method for treating a neoplasia in a subject in need thereof comprising administering to the subject an effective amount of the soluble fusion protein complex of claim 1 .

6. The method of claim 5 , wherein the subject is suffering a neoplasia selected from the group consisting of a glioblastoma, prostate cancer, hematological cancer, B-cell neoplasms, multiple myeloma, B-cell lymphoma, B cell non-Hodgkin lymphoma, Hodgkin's lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, cutaneous T-cell lymphoma, T-cell lymphoma, a solid tumor, urothelial/bladder carcinoma, melanoma, lung cancer, renal cell carcinoma, breast cancer, gastric and esophageal cancer, prostate cancer, pancreatic cancer, colorectal cancer, ovarian cancer, non-small cell lung carcinoma, and squamous cell head and neck carcinoma.

7. The method of claim 5 , wherein the effective amount is between about 1 and 100 μg/kg said fusion protein complex.

8. The method of claim 5 , wherein the fusion protein complex is administered at least one time per week.

9. The method of claim 5 , wherein the fusion protein complex is administered systemically, locally, intravenously, subcutaneously or intratumorally.

10. The method of claim 5 , wherein said fusion protein complex increases immune cell proliferation.

11. The method of claim 5 , wherein the fusion protein complex stimulates immune cell responses against cells associated with the neoplasia.

12. An isolated soluble fusion protein complex comprising at least:

a first soluble protein having at least 85% sequence identity to SEQ ID NO:2; and

a second soluble protein comprising an interleukin-15 (IL-15) receptor alpha sushi-binding

domain (IL-15RαSu) fused to an immunoglobulin Fc domain,

wherein the first soluble protein is bound to the second soluble protein to form a soluble fusion protein complex.

13. The soluble fusion protein complex of claim 12 , wherein the first soluble protein lacks the signal peptide of amino acids 1-18 of SEQ ID NO:2.

14. The soluble fusion protein complex of claim 13 , wherein the second soluble protein has at least 85% sequence identity to SEQ ID NO:4, and wherein the second soluble protein lacks the signal peptide of amino acids 1-18 of SEQ ID NO:4.

15. An isolated soluble fusion protein complex comprising at least:

a first soluble protein comprising an interleukin-15 (IL-15) polypeptide domain; and

a second soluble protein having at least 85% sequence identity to SEQ ID NO:4,

wherein the first soluble protein is bound to the second soluble protein to form a soluble fusion protein complex.

16. The soluble fusion protein complex of claim 15 , wherein the second soluble protein lacks the signal peptide of amino acids 1-18 of SEQ ID NO:4.