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US 6,602,499 B1Granted
Combination viral-based and gene-based therapy of tumors
AssigneeThe General Hospital Corporation
InventorsE. Antonio Chiocca, Xandra O. Breakefield
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Abstract
The present invention relates to viral mutants and methods of using these viral mutants for selectively killing neoplastic cells. The viral mutants of the invention are capable of selectively killing neoplastic cells by a combination of viral mediated oncolysis and anti-cancer (“suicide”) gene therapy.
Claims30
A method of killing neoplastic cells in a tumor expressing endogenous ribonucleotide reductase, said method comprising:
- (a) administering directly to a tumor an HSV-1 vector, wherein said HSV-1 vector comprises:
- a mutation in a ribonucleotide reductase gene of said HSV-1 vector, wherein said ribonucleotide reductase gene is necessary for viral replication and wherein said mutation results in inactivation of said ribonucleotide reductase gene;
- and a transgene encoding cytochrome P450, wherein said transgene is inserted into said ribonucleotide reductase gene;
- and
- (b) administering a therapeutically effective amount of a chemotherapeutic agent to said tumor, wherein said chemotherapeutic agent is a chemotherapeutic agent activated by cytochrome P450, and wherein said HSV-1 vector is replicated and said cytochrome P450 is expressed, which activates said therapeutically effective amount of the chemotherapeutic agent.
2 more elements
The viral vector rRp450.
A method of killing neoplastic cells in the tumor expressing endogenous ribonucleotide reductase, said method comprising:
- (a) administering directly to a tumor an HSV-2 vector, wherein said HSV2 vector comprises:
- a mutation in a ribonucleotide reductase gene of said HSV-2 vector, wherein said ribonucleotide reductase gene is necessary for viral replication and wherein said mutation results in inactivation of said ribonucleotide reductase gene;
- and a transgene encoding cytochrome P450, wherein said transgene is inserted into said ribonucleotide reductase gene;
- and
- (b) administering a therapeutically effective amount of a chemotherapeutic agent to said tumor, wherein said chemotherapeutic agent is a chemotherapeutic agent activated by cytochrome P450, and wherein said HSV-2 vector is replicated and said cytochrome P450 is expressed, which activates said therapeutically effective amount of the chemotherapeutic agent.
2 more elements
A method of killing neoplastic cells in the tumor expressing endogenous thymidine kinase, said method comprising:
- (a) administering directly to a tumor an HSV-1 vector, wherein said HSV-1 vector comprises:
- a mutation in a thymidine kinase gene of said HSV-1 vector, wherein said thymidine kinase gene is necessary for viral replication and wherein said mutation results in inactivation of said thymidine kinase gene;
- and a transgene encoding cytochrome P450, wherein said transgene is inserted into said thymidine kinase gene;
- and
- (b) administering a therapeutically effective amount of a chemotherapeutic agent to said tumor, wherein said chemotherapeutic agent is a chemotherapeutic agent activated by cytochrome P450, and wherein said HSV-1 vector is replicated and said cytochrome P450 is expressed, which activates said therapeutically effective amount of the chemotherapeutic agent.
2 more elements
A method of killing neoplastic cells in a tumor expressing endogenous thymidine kinase, said method comprising:
- (a) administering directly to a tumor an HSV-2 vector, wherein said HSV-2 vector comprises:
- a mutation in a thymidine kinase gene of said HSV-2 vector, wherein said thymidine kinase gene is necessary for viral replication and wherein said mutation results in inactivation of said thymidine kinase gene;
- and a transgene encoding cytochrome P450, wherein said transgene is inserted into said thymidine kinase gene;
- and
- (b) administering a therapeutically effective amount of a chemotherapeutic agent to said tumor, wherein said chemotherapeutic agent is a chemotherapeutic agent activated by cytochrome P450, and wherein said HSV-2 vector is replicated and said cytochrome P450 is expressed, which activates said therapeutically effective amount of the chemotherapeutic agent.
2 more elements
A method of killing neoplastic cells in a tumor expressing endogenous ribonucleotide reductase, said method comprising:
- (a) administering directly to a tumor an HSV vector, wherein said HSV vector comprises:
- a mutation in a ribonucleotide reductase gene of said HSV vector, wherein said ribonucleotide reductase gene is necessary for viral replication and wherein said mutation results in inactivation of said ribonucleotide reductase gene;
- and a transgene encoding cytochrome P450, wherein said transgene is inserted into said ribonucleotide reductase gene;
- and
- (b) administering a therapeutically effective amount of a chemotherapeutic agent to said tumor, wherein said chemotherapeutic agent is a chemotherapeutic agent activated by cytochrome P450, and wherein said HSV vector is replicated and said cytochrome P450 is expressed, which activates said therapeutically effective amount of the chemotherapeutic agent.
2 more elements
A method of killing neoplastic cells in a tumor expressing endogenous thymidine kinase, said method comprising:
- (a) administering directly to a tumor an HSV vector, wherein said HSV vector comprises:
- a mutation in a thymidine kinase gene of said HSV vector, wherein said thymidine kinase gene is necessary for viral replication and wherein said mutation results in inactivation of said thymidine kinase gene;
- and a transgene encoding cytochrome P450, wherein said transgene is inserted into said thymidine kinase gene;
- and
- (b) administering a therapeutically effective amount of a chemotherapeutic agent to said tumor, wherein said chemotherapeutic agent is a chemotherapeutic agent activated by cytochrome P450, and wherein said HSV vector is replicated and said cytochrome P450 is expressed, which activates said therapeutically effective amount of the chemotherapeutic agent.
2 more elements
A method of killing neoplastic cells in a tumor expressing endogenous ribonucleotide reductase, said method comprising:
- (a) administering directly to a tumor an HSV vector, wherein said HSV vector comprises:
- a mutation in a ribonucleotide reductase gene of said HSV vector, wherein said ribonucleotide reductase gene is necessary for viral replication and wherein said mutation results in inactivation of said ribonucleotide reductase gene;
- and a transgene encoding carboxylesterase;
- and
- (b) administering a therapeutically effective amount of a chemotherapeutic agent to said tumor, wherein said chemotherapeutic agent is a chemotherapeutic agent activated by carboxylesterase, and wherein said HSV vector is replicated and said carboxylesterase is expressed, which activates said therapeutically effective amount of the chemotherapeutic agent.
2 more elements
Dependencies are inferred from the claim text.