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, wherein the agonist is expressed by the virus. 
     
     
         2 . A chimeric NDV, comprising a packaged genome which encodes an antagonist of an inhibitory receptor of an immune cell, wherein the antagonist is expressed by the virus. 
     
     
         3 . (canceled) 
     
     
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         5 . The chimeric NDV of  claim 1 , wherein
 (a) the co-stimulatory receptor is glucocorticoid-induced tumor necrosis factor receptor (GITR), OX40, CD27, 4-1IBB, inducible T-cell costimulator (ICOS), lymphotoxin alpha (LT alpha), lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT), CD226, cytotoxic and regulatory T cell molecule (CRTAM), death receptor 3 (DR3), lymphotoxin-beta receptor (LTBR), transmembrane activator and CAML interactor (TACI), B cell-activating factor receptor (BAFFR), or B cell maturation protein (BCMA);   (b) the agonist is an antibody that specifically binds to the co-stimulatory receptor;   (c) the agonist is a ligand that specifically binds to the co-stimulatory receptor;   (d) the agonist is an antibody specifically binds to GITR, OX40, CD27, 4-1BB, ICOS, LT alpha, LIGHT, CD226, CRTAM, DR3, LTBR, TACI, BAFFR, or BCMA.   
     
     
         6 . The chimeric NDV of  claim 2 , wherein
 (a) the inhibitory receptor is programmed cell death protein 1 (PD1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), B and T-lymphocyte attenuator (BTLA), killer cell immunoglobulin-like receptor (KIR), lymphocyte activation gene 3 (LAG3), CD160, adenosine A2a receptor (A2aR), T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), or T-cell membrane protein 3 (TIM3);   (b) the antagonist is an antibody that specifically binds to the inhibitory receptor;   (c) the antagonist is an antibody that specifically hinds to PD1, CTLA-4, BTLA, KIR, LAG3, CD160, A2aR, TIGIT, LAIRI, or TIM3;   (d) the antagonist is a soluble receptor of a ligand of the inhibitory receptor;   (e) the antagonist is an antibody that specifically binds to a ligand of the inhibitory receptor;   (f) the antagonist is an antibody that specifically binds to PDL1, PDL2, B7-H3, B7-H4, HVEM, or Gal9.   
     
     
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         19 . A pharmaceutical composition comprising the chimeric NDV of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         20 . A pharmaceutical composition comprising the chimeric NDV of  claim 2  or  17  and a pharmaceutically acceptable carrier. 
     
     
         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 or in an embryonated egg; 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 . A method for producing a pharmaceutical composition, the method comprising:
 a. propagating the chimeric NDV of  claim 2  in a cell line that is susceptible to a NDV infection or in an embryonated egg; 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.   
     
     
         23 . A cell line or an embryonated egg comprising the chimeric NDV of  claim 1 . 
     
     
         24 . A cell line or an embryonated egg comprising the chimeric NDV of  claim 2 . 
     
     
         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 . A method for treating cancer, comprising administering to a subject in need thereof a pharmaceutical composition comprising the chimeric NDV of  claim 2 . 
     
     
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         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . A method for treating cancer, comprising administering to a subject in need thereof a chimeric NDV and an agonist of a co-stimulatory receptor of an immune cell, wherein the chimeric NDV comprises a packaged genome encoding a cytokine which is expressed by the virus. 
     
     
         34 . A method for treating cancer, comprising administering to a subject in need thereof a chimeric NDV and an antagonist of an inhibitory receptor of an immune cell, wherein the chimeric NDV comprises a packaged genome encoding a cytokine which is expressed by the virus. 
     
     
         35 . The method of  claim 33 , wherein the cytokine is IL-2, IL-7, IL-9, IL-15, IL-17, IL-21, IL-22, IFN-gamma, GM-CSF, or TNF-alpha. 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
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         39 . The method of  claim 34 , wherein the cytokine is IL-2, IL-7, IL-9, IL-15, IL-17, IL-21, IL-22, IFN-gamma, GM-CSF, or TNF-alpha. 
     
     
         40 . The method of  claim 33 , wherein
 (a) the co-stimulatory receptor is GITR, OX40, CD27, 4-1BB, ICOS, LT alpha, LIGHT, CD226, CRTAM, DR3, LTBR, TACI, BAFFR, or BCMA;   (b) the agonist s an antibody that specifically hinds to the co-stimulatory receptor;   (c) the agonist is a ligand that specifically binds to the co-stimulatory receptor; or   (d) the agonist is an antibody specifically binds to GITR, OX40, CD27, 4-1BB, ICOS, LT alpha, LIGHT, CD226, CRTAM, DR3, LTBR, TACI, BAFFR, or BCMA.   
     
     
         41 . The method of  claim 34 , wherein
 (a) the inhibitory receptor is PD1, CTLA-4, BTLA, KIR, LAG3, CD160, A2aR, TIGIT, LAIRI, or TIM3;   (b) the antagonist is an antibody that specifically binds to the inhibitory receptor;   (c) the antagonist is an antibody that specifically binds to PD1, CTLA-4, BTLA, KIR, LAG3, CD160, A2aR, TIGIT, LAIRI, or TIM3;   (d) the antagonist is a soluble receptor of a ligand of the inhibitory receptor;   (e) the antagonist is an antibody that specifically binds to a ligand of the inhibitory receptor; or   (f) the antagonist is an antibody that specifically hinds to PDL1, PDL2, B7-H3, B7-H4, HVEM, or Gal9.   
     
     
         42 . (canceled) 
     
     
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         58 . The method of  claim 34 , wherein the inhibitory receptor is PD1. 
     
     
         59 . The method of  claim 34 , wherein the antagonist is an antibody that specifically hinds to PD1.