Compositions and methods for glioblastoma treatment

Abstract

The present disclosure concerns an oncolytic virus for the treatment of cancer, such as in brain cancer, for example glioblastoma. The oncolytic virus may exhibit reduced levels of neurotoxicity. The oncolytic virus may be an isolated viral particle capable of producing a cDNA polynucleotide that includes a sequence according to SEQ ID NO: 1 when the virus is in a host cell. The oncolytic virus may be an isolated viral particle that includes an RNA polynucleotide that includes a sequence according to SEQ ID NO: 2. The oncolytic virus may be an isolated viral particle having a genome that includes open reading frames that encode: proteins having sequences comprising SEQ ID NOs: 3, 4, 5, 6 and 7; or variants thereof.

1 . A method for inducing an immunogenic response in a patient, the method comprising administering to the patient:
 A) an isolated viral particle having a genome comprising open reading frames that encode:
 a protein having a sequence that is at least 95% identical to SEQ ID NO: 3; 
 a protein having a sequence that is at least 95% identical to SEQ ID NO: 4; 
 a protein having a sequence that is at least 95% identical to SEQ ID NO: 5; 
 a protein having a sequence that is at least 95% identical to SEQ ID NO: 6; and 
 a protein having a sequence that is at least 95% identical to SEQ ID NO: 7, 
   wherein at least one of the encoded proteins contains at least one non-naturally occurring substitution modification relative to SEQ ID NO: 3, 4, 5, 6, or 7;   B) an isolated viral particle that produces a cDNA polynucleotide when the viral particle is in a host cell, the cDNA polynucleotide comprising:
 a sequence that is at least 95% identical to SEQ ID NO: 8; 
 a sequence that is at least 95% identical to SEQ ID NO: 9; 
 a sequence that is at least 95% identical to SEQ ID NO: 10; 
 a sequence that is at least 95% identical to SEQ ID NO: 11; and 
 a sequence that is at least 95% identical to SEQ ID NO: 12, 
   wherein at least one of the sequences contains at least one non-naturally occurring substitution modification relative to SEQ ID NO: 8, 9, 10, 11, or 12;   C) an isolated viral particle that produces a cDNA polynucleotide when the viral particle is in a host cell, wherein the cDNA polynucleotide comprises: a sequence that is at least 95% identical and is less than 99% identical to SEQ ID NO: 1 and contains at least one non-naturally occurring substitution modification relative to SEQ ID NO: 1; or   D) an isolated viral particle comprising an RNA polynucleotide comprising a sequence that is at least 95% identical and is less than 99% identical to SEQ ID NO:2 and contains at least one non-naturally occurring substitution modification relative to SEQ ID NO: 2.   
     
     
         2 . The method according to  claim 1 , wherein the method comprises administering to the patient the isolated viral particle having a genome comprising open reading frames that encode:
 a protein having a sequence that is at least 95% identical to SEQ ID NO: 3;   a protein having a sequence that is at least 95% identical to SEQ ID NO: 4;   a protein having a sequence that is at least 95% identical to SEQ ID NO: 5;   a protein having a sequence that is at least 95% identical to SEQ ID NO: 6; and   a protein having a sequence that is at least 95% identical to SEQ ID NO: 7,   wherein at least one of the encoded proteins contains at least one non-naturally occurring substitution modification relative to SEQ ID NO: 3, 4, 5, 6, or 7.   
     
     
         3 . The method according to  claim 2 , wherein the open reading frames encode:
 a protein having a sequence that is at least 99% identical to SEQ ID NO: 3;   a protein having a sequence that is at least 99% identical to SEQ ID NO: 4;   a protein having a sequence that is at least 99% identical to SEQ ID NO: 5;   a protein having a sequence that is at least 99% identical to SEQ ID NO: 6; and   a protein having a sequence that is at least 99% identical to SEQ ID NO: 7.   
     
     
         4 . The method according to  claim 1 , wherein the method comprises administering to the patient the isolated viral particle that produces a cDNA polynucleotide when the viral particle is in a host cell, the cDNA polynucleotide comprising:
 a sequence that is at least 95% identical to SEQ ID NO: 8;   a sequence that is at least 95% identical to SEQ ID NO: 9;   a sequence that is at least 95% identical to SEQ ID NO: 10;   a sequence that is at least 95% identical to SEQ ID NO: 11; and   a sequence that is at least 95% identical to SEQ ID NO: 12,   wherein at least one of the sequences contains at least one non-naturally occurring substitution modification relative to SEQ ID NO: 8, 9, 10, 11, or 12.   
     
     
         5 . The method according to  claim 4 , wherein the cDNA polynucleotide further comprises at least one promoter sequence. 
     
     
         6 . The method according to  claim 1 , wherein the method comprises administering to the patient the isolated viral particle that produces a cDNA polynucleotide when the viral particle is in a host cell, wherein the cDNA polynucleotide comprises: a sequence that is at least 95% identical and is less than 99% identical to SEQ ID NO: 1 and contains at least one non-naturally occurring substitution modification relative to SEQ ID NO: 1. 
     
     
         7 . The method according to  claim 1 , wherein the method comprises administering to the patient the isolated viral particle comprising an RNA polynucleotide comprising a sequence that is at least 95% identical and is less than 99% identical to SEQ ID NO:2 and contains at least one non-naturally occurring substitution modification relative to SEQ ID NO: 2. 
     
     
         8 . The method according to  claim 1 , wherein the isolated viral particle is administered to the patient intrathecally, intravenously or via intracranial injection. 
     
     
         9 . The method according to  claim 1 , wherein the isolated viral particle is administered to the patient inside the blood/brain barrier by intracranial injection. 
     
     
         10 . A method for inducing an immunogenic response in a patient, the method comprising administering to the patient:
 A) an isolated viral particle having a genome comprising open reading frames that encode:
 a protein having a sequence that is at least 95% identical to SEQ ID NO: 3; 
 a protein having a sequence that is at least 95% identical to SEQ ID NO: 4; 
 a protein having a sequence that is at least 95% identical to SEQ ID NO: 5; 
 a protein having a sequence that is at least 95% identical to SEQ ID NO: 6; 
 a protein having a sequence that is at least 95% identical to SEQ ID NO: 7, and 
   at least one heterologous protein;   B) an isolated viral particle that produces a cDNA polynucleotide when the viral particle is in a host cell, the cDNA polynucleotide comprising:
 a sequence that is at least 95% identical to SEQ ID NO: 8; 
 a sequence that is at least 95% identical to SEQ ID NO: 9; 
 a sequence that is at least 95% identical to SEQ ID NO: 10; 
 a sequence that is at least 95% identical to SEQ ID NO: 11; 
 a sequence that is at least 95% identical to SEQ ID NO: 12; and 
 a sequence that encodes at least one heterologous protein; 
   C) an isolated viral particle that produces a cDNA polynucleotide when the viral particle is in a host cell, wherein the cDNA polynucleotide comprises: (i) a sequence that is at least 95% identical to SEQ ID NO: 1 and (ii) a sequence that encodes at least one heterologous protein; or   D) an isolated viral particle comprising an RNA polynucleotide comprising: (i) a sequence that is at least 95% identical to SEQ ID NO:2 and (ii) a sequence that encodes at least one heterologous protein.   
     
     
         11 . The method according to  claim 10 , wherein the method comprises administering to the patient the isolated viral particle having a genome comprising open reading frames that encode:
 a protein having a sequence that is at least 95% identical to SEQ ID NO: 3;   a protein having a sequence that is at least 95% identical to SEQ ID NO: 4;   a protein having a sequence that is at least 95% identical to SEQ ID NO: 5;   a protein having a sequence that is at least 95% identical to SEQ ID NO: 6;   a protein having a sequence that is at least 95% identical to SEQ ID NO: 7, and   at least one heterologous protein.   
     
     
         12 . The method according to  claim 11 , wherein the heterologous protein is an immunogenic protein. 
     
     
         13 . The method according to  claim 11 , wherein the open reading frames encode:
 a protein having a sequence that is at least 99% identical to SEQ ID NO: 3;   a protein having a sequence that is at least 99% identical to SEQ ID NO: 4;   a protein having a sequence that is at least 99% identical to SEQ ID NO: 5;   a protein having a sequence that is at least 99% identical to SEQ ID NO: 6;   a protein having a sequence that is at least 99% identical to SEQ ID NO: 7, and   at least one heterologous protein.   
     
     
         14 . The method according to  claim 10 , wherein the method comprises administering to the patient the isolated viral particle that produces a cDNA polynucleotide when the viral particle is in a host cell, the cDNA polynucleotide comprising:
 a sequence that is at least 95% identical to SEQ ID NO: 8;   a sequence that is at least 95% identical to SEQ ID NO: 9;   a sequence that is at least 95% identical to SEQ ID NO: 10;   a sequence that is at least 95% identical to SEQ ID NO: 11;   a sequence that is at least 95% identical to SEQ ID NO: 12, and   a sequence that encodes at least one heterologous protein.   
     
     
         15 . The method according to  claim 14 , wherein the cDNA polynucleotide further comprises at least one promoter sequence. 
     
     
         16 . The method according to  claim 14 , wherein the heterologous protein is an immunogenic protein. 
     
     
         17 . The method according to  claim 10 , wherein the method comprises administering to the patient the isolated viral particle that produces a cDNA polynucleotide when the viral particle is in a host cell, wherein the cDNA polynucleotide comprises: (i) a sequence that is at least 95% identical to SEQ ID NO: 1 and (ii) a sequence that encodes at least one heterologous protein. 
     
     
         18 . The method according to  claim 17 , wherein the heterologous protein is an immunogenic protein. 
     
     
         19 . The method according to  claim 11 , wherein the method comprises administering to the patient the isolated viral particle comprising an RNA polynucleotide comprising: (i) a sequence that is at least 95% identical to SEQ ID NO: 2 and (ii) a sequence that encodes at least one heterologous protein. 
     
     
         20 . The method according to  claim 19 , wherein the heterologous protein is an immunogenic protein.