Oncolytic vaccinia virus mutants and using same for cancer treatment

Patent metadata

Field	Value
Publication number	US-10842835-B2
Application number	US-201716304564-A
Country	US
Kind code	B2
Filing date	May 25, 2017
Priority date	May 25, 2016
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

Abstract

Methods utilizing vaccinia virus with mutations in E3L to infect and cause lysis of cancer cells with less than normal protein levels of RIP3 and/or DAI. Further, the disclosed vaccinia viruses with mutations in E3L cannot replicate well in cells with normal expression or upregulation of RIP3, DAI, and/or MLKL.

First claim

We claim:

1. A method of inducing lysis of cancer cells of a subject that have a deficiency in an ability to activate a programmed cell death pathway, comprising
screening cancer cells of the subject for expression of at least one of receptor-interacting protein kinase (RIP) 3, DNA-dependent activator of interferon regulatory factor (DAI), and mixed lineage kinase domain-like protein (MLKL);
selecting the subject for treatment if the screened cancer cells have between about 0% to about 50% of expressed protein levels, in comparison to non-cancerous cells of the same type, of at least one of RIP3, DAI, and MLKL; and
contacting cancer cells of the selected subject with a vaccinia virus (VACV) having an inactivating mutation in an E3L gene of said virus, thereby inducing lysis of the contacted cancer cells.

2. The method of claim 1 , wherein said cancer cells have between about 0% to about 50% of expressed protein levels, in comparison to non-cancerous cells of the same type, of both RIP3 and DAI.

3. The method of claim 1 , wherein said cancer cells have between about 0% to about 50% of expressed protein levels, in comparison to non-cancerous cells of the same type, of both RIP3 and MLKL.

4. The method of claim 1 , wherein the E3L gene of said virus is SEQ ID NO: 1.

5. The method of claim 1 , wherein the E3L gene is at least 90% identical with the sequence represented by SEQ ID NO: 1.

6. The method of claim 1 , wherein the VACV has a mutation in the E3L gene of said virus represented by deleting the entire E3L gene.

7. A method of inducing oncolysis in a subject having a tumor comprising cancer cells that have a deficiency in an ability to activate a programmed cell death pathway, comprising
screening cancer cells of a tumor of the subject for expression of at least one of receptor- interacting protein kinase (RIP) 3, DNA-dependent activator of interferon regulatory factor (DAI), and mixed lineage kinase domain-like protein (MLKL);
selecting the subject for treatment if the screened cancer cells of the tumor have between about 0% to about 50% of expressed protein levels, in comparison to non-cancerous cells of the same type, of at least one of RIP3, DAI, and MLKL; and
administering to the selected subject a therapeutic effective amount of a pharmaceutical composition comprising a vaccinia virus (VACV) having an inactivating mutation in an E3L gene of said virus, whereby administration results in lysis of cancer cells of the tumor.

8. The method of claim 7 , wherein said cancer cells have between about 0% to about 50% of normal cell expression levels of both RIP3 and DAI.

9. The method of claim 7 , wherein said cancer cells have between about 0% to about 50% of normal cell expression levels of both RIP3 and MLKL.

10. The method of claim 7 , wherein the administering further comprises injection into the tumor, whereby oncolysis is induced in the tumor and in at least one tumor that is not injected with the VACV.

11. The method of claim 7 , wherein the tumor is a melanoma tumor, a breast tumor, or a colon tumor.

12. The method of claim 7 , further comprising administering to the subject a therapeutic effective amount of at least one chemotherapeutic agent.

Assignees

• Univ Arizona State

Inventors

• Jacobs Bertram
• Koehler Heather
• Arndt William
• Kibler Karen
• Trainor Kelly
• Mitnik Chandra
• Langland Jeffrey

Classifications

• C12N2710/24121

  Viruses as such, e.g. new isolates, mutants or their genomic sequences · CPC title

• C12N2710/24132

  Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent · CPC title

• C12N7/00

  Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00) · CPC title

• C12N2710/24122

  New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes · CPC title

• A61K35/768 Primary

  Oncolytic viruses not provided for in groups A61K35/761 - A61K35/766 · CPC title