Methods of treating immunotherapy-related toxicity using a gm-csf antagonist

Abstract

Methods for reducing relapse rate or preventing occurrence of tumor relapse in a subject treated with immunotherapy, in an absence of an incidence of immunotherapy-related toxicity or in a presence of immunotherapy-related toxicity. Methods for reducing a level of a cytokine or chemokine other than GM-CSF in a subject having an incidence of immunotherapy-related toxicity, the methods comprising administering a recombinant GM-CSF antagonist to the subject. Methods for treating or preventing immunotherapy-related toxicity in a subject, the methods comprising administering to the subject chimeric antigen receptor-expressing T-cells (CAR-T cells), the CAR-T cells having a GM-CSF gene knockout (GM-CSF k/o CAR-T cells), and a recombinant hGM-CSF antagonist.

What is claimed is: 
     
         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.