Newcastle Disease Viruses and Uses Thereof

Abstract

Described herein are chimeric Newcastle disease viruses engineered to express an agonist of a co-stimulatory signal of an immune cell and compositions comprising such viruses. Also described herein are chimeric Newcastle disease viruses engineered to express an antagonist of an inhibitory signal of an immune cell and compositions comprising such viruses. The chimeric Newcastle disease viruses and compositions are useful in the treatment of cancer. In addition, described herein are methods for treating cancer comprising administering Newcastle disease viruses in combination with an agonist of a co-stimulatory signal of an immune and/or an antagonist of an inhibitory signal of an immune cell.

1 . A chimeric Newcastle disease virus (NDV), comprising a packaged genome which encodes an agonist of a co-stimulatory receptor of an immune cell or an antagonist of an inhibitory receptor of an immune cell, wherein the agonist or antagonist is expressed by the virus. 
     
     
         2 . (canceled) 
     
     
         3 . The chimeric NDV of  claim 1 , wherein the packaged genome encodes a mutated F protein and the mutated F protein is expressed by the virus. 
     
     
         4 . The chimeric NDV of  claim 1 , wherein the immune cell is a T lymphocyte or natural killer (NK) cell. 
     
     
         5 . The chimeric NDV of  claim 1 , wherein the co-stimulatory receptor is glucocorticoid-induced tumor necrosis factor receptor (GITR), OX40, CD27, CD28, 4-1BB or CD40. 
     
     
         6 . The chimeric NDV of  claim 1 , wherein the inhibitory receptor is cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD1), B and T-lymphocyte attenuator (BTLA), killer cell immunoglobulin-like receptor (KIR), lymphocyte activation gene 3 (LAG3), or T-cell membrane protein 3 (TIM3). 
     
     
         7 . The chimeric NDV of  claim 1 , wherein the agonist is an antibody or a ligand that specifically binds to the co-stimulatory receptor. 
     
     
         8 . (canceled) 
     
     
         9 . The chimeric NDV of  claim 7 , wherein the antibody specifically binds to GITR, OX40, CD27, CD28, 4-1BB or CD40, or the ligand is GITRL, CD40L, CD137L, OX40L or CD70. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The chimeric NDV of  claim 1 , wherein the antagonist is an antibody that specifically binds to the inhibitory receptor, a soluble receptor of a ligand of the inhibitory receptor, or an antibody that specifically binds to a ligand of the inhibitory receptor. 
     
     
         13 . The chimeric NDV of  claim 1 , wherein the antagonist is an antibody that specifically binds to CTLA-4, PD-1, BTLA, KIR, LAG3, or TIM3. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The chimeric NDV of  claim 12 , wherein the antagonist is an antibody that specifically binds to PDL1, PDL2, B7-H3, B7-H4, HVEM, or Gal9. 
     
     
         17 . The chimeric NDV of  claim 12 , wherein the soluble receptor is the extracellular domain of PD1, BTLA, KIR, LAG3 or TIM3. 
     
     
         18 . (canceled) 
     
     
         19 . A pharmaceutical composition comprising the chimeric NDV of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         20 . (canceled) 
     
     
         21 . A method for producing a pharmaceutical composition, the method comprising:
 a. propagating the chimeric NDV of  claim 1  in a cell line that is susceptible to a NDV infection; and   b. collecting the progeny virus,   
       wherein the virus is grown to sufficient quantities and under sufficient conditions that the virus is free from contamination, such that the progeny virus is suitable for formulation into a pharmaceutical composition. 
     
     
         22 . (canceled) 
     
     
         23 . A cell line or an embryonated egg comprising the chimeric NDV of  claim 1 . 
     
     
         24 . (canceled) 
     
     
         25 . A method for treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition comprising the chimeric NDV of  claim 1 . 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 25  further comprising administering to the subject a second agonist of a co-stimulatory receptor of an immune cell or a second antagonist of an inhibitory receptor of an immune cell. 
     
     
         28 . (canceled) 
     
     
         29 . A method for treating cancer, comprising administering to a subject in need thereof an NDV and an agonist of a co-stimulatory receptor of an immune cell or an antagonist of an inhibitory receptor of an immune cell. 
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 29 , wherein the NDV is a chimeric NDV and wherein the chimeric NDV comprises a packaged genome encoding a cytokine which is expressed by the virus. 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 31 , wherein the cytokine is IL-2, IL-7, IL-15 or IL-21. 
     
     
         36 . The method of  claim 29 , wherein the co-stimulatory receptor is GITR, OX40, CD27, CD28, 4-1BB or CD40, or the inhibitory receptor is CTLA-4, PD1, BTLA, KIR, LAG3, or TIM3. 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 29 , wherein the agonist is an antibody or a ligand that specifically binds to the co-stimulatory receptor. 
     
     
         39 . (canceled) 
     
     
         40 . The method of  claim 29 , wherein the agonist is an antibody specifically binds to GITR, OX40, CD27, CD28, 4-1BB or CD40. 
     
     
         41 . (canceled) 
     
     
         42 . The method of  claim 38 , wherein the ligand is CD137L, OX40L, CD40L, GITRL, or CD70. 
     
     
         43 . The method of  claim 29 , wherein the antagonist is an antibody that specifically binds to the inhibitory receptor, a soluble receptor of a ligand of the inhibitory receptor, or an antibody that specifically binds to a ligand of the inhibitory receptor. 
     
     
         44 . The method of  claim 29 , wherein the antagonist is an antibody that specifically binds to CTLA-4, PD1, BTLA, KIR, LAG3, or TIM3. 
     
     
         45 . (canceled) 
     
     
         46 . (canceled) 
     
     
         47 . The method of  claim 29 , wherein the antagonist is an antibody that specifically binds to PDL1, PDL2, B7-H3, B7-H4, HVEM, or Gal9. 
     
     
         48 . The method of  claim 43 , wherein the soluble receptor is the extracellular domain of PD1, BTLA, KIR, LAG3 or TIM3. 
     
     
         49 . (canceled) 
     
     
         50 . The method of  claim 29 , wherein the cancer is melanoma, colorectal cancer, breast cancer, ovarian cancer, renal cell cancer, malignant melanoma, malignant glioma, renal cell carcinoma, pancreatic adenocarcinoma, malignant mesothelioma, lung adenocarcinoma, lung small cell carcinoma, lung squamous cell carcinoma, anaplastic thyroid cancer or head and neck squamous cell carcinoma. 
     
     
         51 . (canceled)