METHODS OF TREATING IMMUNOTHERAPY-RELATED TOXICITY USING A GM-CSF ANTAGONIST

1 . A method for reducing relapse rate or preventing occurrence of tumor relapse in a subject treated with immunotherapy, the method comprising administering to the subject a recombinant anti-hGM-CSF antibody.

2 . The method of claim 1 , wherein said immunotherapy comprises adoptive cell transfer, administration of monoclonal antibodies, administration of cytokines, administration of a cancer vaccine, T cell engaging therapies, or any combination thereof.

3 . The method of claim 2 , wherein the adoptive cell transfer comprises administering chimeric antigen receptor-expressing T-cells (CAR T-cells), T-cell receptor (TCR) modified T-cells, tumor-infiltrating lymphocytes (TIL), chimeric antigen receptor (CAR)-modified natural killer cells, or dendritic cells, or any combination thereof.

4 . The method of claim 1 , wherein the anti-hGM-CSF antibody binds a human GM-CSF.

5 . The method of claim 1 , wherein the anti-hGM-CSF antibody binds a primate GM-CSF.

6 . The method of claim 5 , wherein the primate is selected from a monkey, a baboon, a macaque, a chimpanzee, a gorilla, a lemur, a lorise, a tarsier, a galago, a potto, a sifaka, an indri, an aye-ayes or an ape.

7 . The method of claim 1 , wherein the anti-hGM-CSF antibody binds a mammalian GM-CSF.

8 . The method of claim 1 , wherein the anti-hGM-CSF antibody is a monoclonal antibody.

9 . The method of claim 1 , wherein the anti-hGM-CSF antibody is an antibody fragment that is a Fab, a Fab′, a F(ab′)2, a scFv, or a dAB.

10 . The method of claim 1 , wherein the anti-hGM-CSF antibody is a human GM-CSF neutralizing antibody.

11 . The method of claim 1 , wherein the anti-hGM-CSF antibody is a recombinant or chimeric antibody.

12 . The method of claim 1 , wherein the anti-hGM-CSF antibody is an engineered human antibody.

13 . The method of claim 1 , wherein the anti-hGM-CSF antibody binds to the same epitope as chimeric 19/2.

14 . The method of claim 1 , wherein the anti-hGM-CSF antibody comprises the VH region CDR3 and VL region CDR3 of chimeric 19/2.

15 . The method of claim 1 wherein the anti-hGM-CSF antibody comprises the VH region and VL region CDR1, CDR2, and CDR3 of chimeric 19/2.

16 . The method of claim 1 , wherein the anti-hGM-CSF antibody comprises a VH region that comprises a CDR3 binding specificity determinant RQRFPY (SEQ ID NO: 12) or RDRFPY (SEQ ID NO: 13), a J segment, and a V-segment, wherein the J-segment comprises at least 95% identity to human JH4 (YFDYWGQGTLVTVSS) (SEQ ID NO: 14) and the V-segment comprises at least 90% identity to a human germ line VH1 1-02 or VH1 1-03 sequence.

17 . The method of claim 16 , wherein the J segment comprises YFDYWGQGTLVTVSS (SEQ ID NO: 14).

18 . The method of claim 16 , wherein the CDR3 comprises RQRFPYYFDY (SEQ ID NO: 15) or RDRFPYYFDY (SEQ ID NO: 16).

19 . The method of claim 16 , wherein the VH region CDR1 is a human germline VH1 CDR1; the VH region CDR2 is a human germline VH1 CDR2; or both the CDR1 and CDR2 are from a human germline VH1 sequence.

20 . The method of claim 16 , wherein the anti-hGM-CSF antibody comprises a VH CDR1, a VH CDR2, or both a VH CDR1 and a VH CDR2 as shown in a VH region set forth in FIG. 1 .

21 . The method of claim 16 , wherein the V-segment sequence has a VH V segment sequence shown in FIG. 1 .

22 . The method of claim 16 , wherein the VH has the sequence of VH #1, VH #2, VH #3, VH #4, or VH #5 set forth in FIG. 1 .

23 . The method of claim 1 , wherein the anti-hGM-CSF antibody comprises a VL-region that comprises a CDR3 comprising the amino acid sequence FNK or FNR.

24 . The method of claim 23 , wherein the anti-hGM-CSF antibody comprises a human germline JK4 region.

25 . The method of claim 23 , wherein the VL region CDR3 comprises QQFN(K/R)SPLT (SEQ ID NO: 17).

26 . The method of claim 25 , wherein the anti-hGM-CSF antibody comprises a VL region that comprises a CDR3 comprising QQFNKSPLT (SEQ ID NO: 18).

27 . The method of claim 25 , wherein the anti-hGM-CSF antibody comprises a VL region that comprises a CDR3 comprising QQFNRSPLT (SEQ ID NO: 28).

28 . The method of claim 23 , where the VL region comprises a CDR1, a CDR2, or both a CDR1 and CDR2 of a VL region shown in FIG. 1 .

29 . The method of claim 23 , wherein the VL region comprises a V segment that has at least 95% identity to the VKIII A27 V-segment sequence as shown in FIG. 1 .

30 . The method of claim 23 , wherein the VL region has the sequence of VK #1, VK #2, VK #3, or VK #4 set forth in FIG. 1 .

31 . The method of claim 1 , wherein the anti-hGM-CSF antibody has a VH region CDR3 binding specificity determinant RQRFPY (SEQ ID NO: 12) or RDRFPY (SEQ ID NO: 13) and a VL region that has a CDR3 comprising QQFNKSPLT (SEQ ID NO: 18) or QQFNRSPLT (SEQ ID NO: 28).

32 . The method of claim 1 , wherein the anti-hGM-CSF antibody has a VH region sequence set forth in FIG. 1 and a VL region sequence set forth in FIG. 1 .

33 . The method of claim 32 , wherein the VH region or the VL region, or both the VH and VL region amino acid sequences comprise a methionine at the N-terminus.

34 . The method of claim 33 , wherein the VH region or the VL region, or both the VH and VL region amino acid sequences comprise a methionine at the N-terminus.

35 . The method of claim 1 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #1 set forth in FIG. 1 and the VL region having the sequence of VK #3 set forth in FIG. 1 .

36 . The method of claim 1 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #2 set forth in FIG. 1 and the VL region having the sequence of VK #3 set forth in FIG. 1 .

37 . The method of claim 1 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #3 set forth in FIG. 1 and the VL region having the sequence of. VK #1 set forth in FIG. 1 .

38 . The method of claim 1 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #4 set forth in FIG. 1 and the VL region having the sequence of. VK #4 set forth in FIG. 1 .

39 . The method of claim 1 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #4 set forth in FIG. 1 and the VL region having the sequence of. VK #2 set forth in FIG. 1 .

40 . The method of claim 1 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #5 set forth in FIG. 1 and the VL region having the sequence of. VK #1 set forth in FIG. 1 .

41 . The method of claim 1 , wherein the anti-hGM-CSF antibody comprises a VH region having the sequence of VH #5 set forth in FIG. 1 and a VL region having sequence VK #2 set forth in FIG. 1 .

42 . The method of claim 1 , wherein the anti-hGM-CSF antibody has a VH region CDR3 binding specificity determinant RQRFPY (SEQ ID NO: 12) and a VL region that has a CDR3 comprising QQFNKSPLT (SEQ ID NO: 18).

43 . The method of claim 3 , wherein the CAR-T cells are CD19 CAR-T cells.

44 . The method of claim 1 , wherein the reducing relapse rate or preventing occurrence of tumor relapse in the subject occurs in an absence of an incidence of immunotherapy-related toxicity.

45 . The method of claim 1 , wherein the reducing relapse rate or preventing occurrence of tumor relapse in the subject occurs in a presence of an incidence of immunotherapy-related toxicity.

46 . The method of claim 45 , wherein the immunotherapy-related toxicity is CAR-T related toxicity.

47 . The method of claim 46 , wherein the CAR-T related toxicity is cytokine release syndrome, neurotoxicity or neuro-inflammation.

48 . The method of claim 1 , wherein the tumor relapse occurrence is reduced by from 50% to 100% in the first one-quarter of a year after administering the recombinant anti-hGM-CSF antibody compared to tumor relapse occurrence in a subject treated with immunotherapy and not administered a recombinant anti-hGM-CSF antibody.

49 . The method of claim 1 , wherein the tumor relapse occurrence is reduced by from 50% to 95% in the first half-year after administering the recombinant anti-hGM-CSF antibody.

50 . The method of claim 1 , wherein the tumor relapse occurrence is reduced by from 50% to 90% in the first year after administering the recombinant anti-hGM-CSF antibody.

51 . The method of claim 1 , wherein the tumor relapse occurrence is prevented long-term.

52 . The method of claim 1 , wherein the tumor relapse occurrence is prevented by 12-36 months.

53 . The method of claim 1 , wherein the tumor relapse occurrence is prevented completely (100%).

54 . The method of claim 1 , wherein the subject has acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML).

55 . The method of claim 1 , wherein the subject has a refractory cancer or a relapsed cancer.

56 . The method of claim 55 , wherein the refractory cancer or the relapsed cancer is non-Hodgkin lymphoma (NHL).

57 . The method of claim 56 , wherein the refractory cancer or the relapsed cancer is aggressive B cell non-Hodgkin lymphoma or chemo-refractory B cell lymphoma.

58 . The method of claim 55 , wherein the refractory cancer or the relapsed cancer is hormone-refractory prostate cancer, a pediatric cancer, a neuroblastoma, an adrenal cancer, a breast cancer, a colon cancer, a rectal cancer, a colorectal cancer, a T-cell lymphoma, a head and neck cancer, a brain cancer, a spinal cord cancer, a tumor of bone or soft tissue, bone cancer, esophageal cancer, gall bladder cancer, kidney cancer, lung cancer melanoma, ovarian cancer, pancreatic cancer, a skin cancer, salivary gland cancer, uterine smooth muscle cancer, testicular cancer, stomach cancer, gastrointestinal cancer, bladder cancer, adipose tissue neoplasm, an adenocarcinoma, a thymoma, angiosarcoma or a metastasis thereof.