# US 9,862,932 B2 · Oncolytic virus therapy for resistant tumors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,862,932 B2 - Document ID: US9862932B2 - Status: Granted - Kind: B2 - Application number: 14/416,754 - Filed: 2013-03-15 - Published: 2015-07-16 - Granted: 2018-01-09 - Earliest claimed: 2012-07-24 - Assignees: The General Hospital Corporation - Applicants: The General Hospital Corporation - Inventors: Khalid Shah; Kaoru Tamura; Hiroaki Wakimoto - Web page: https://patentgrep.com/patent/US9862932B2 ## CPC - C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00) - A61K 35/763: Herpes virus - A61K 38/19: Cytokines; Lymphokines; Interferons - A61P 35/00: Antineoplastic agents - C07K 14/525: Tumour necrosis factor [TNF] - C12N 2710/16632: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent - C12N 2710/16642: virus or viral particle as vehicle, e.g. encapsulating small organic molecule - C12N 2710/16671: Demonstrated in vivo effect - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## Abstract Disclosed herein is a recombinant oncolytic virus comprising a nucleic acid sequence encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). One such oncolytic virus is oHSV. One form of TRAIL contained within the oncolytic virus is a secreted form of TRAIL. Examples of various forms of oHSV and secreted TRAIL are disclosed therein. Also disclosed are host cells and therapeutic formulations comprising the recombinant oncolytic virus. Also disclosed are methods of treating cancer in a subject by administering a therapeutic formulation comprising the recombinant oncolytic virus to the subject. ## Claims ### Claim 1 A recombinant oncolytic herpes simplex virus (oHSV) comprising a nucleic acid sequence encoding, in expressible form, a polypeptide comprising the extracellular domain of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) fused to an isoleucine zipper and the extracellular domain of hFlt3 ligand, wherein the oHSV is selected from the group consisting of G47Δ, HSV-R3616, 1716, R3616, and R4009, and wherein the recombinant oncolytic herpes simplex virus induces apoptosis in tumor cells that are resistant to apoptosis induction by TRAIL and by oncolytic herpes simplex virus. ### Claim 2 (depends on 1) The recombinant oHSV of claim 1, wherein the polypeptide encoded by said nucleic acid sequence is secreted by a cell infected by the recombinant oHSV. ### Claim 3 (depends on 2) The recombinant oHSV of claim 2, wherein the expression of said polypeptide is regulated by the HSV immediate early 4/5 promoter. ### Claim 4 (depends on 3) The recombinant oHSV of claim 3, wherein the virus contains an additional exogenous nucleic acid in expressible form. ### Claim 5 (depends on 1) The recombinant oHSV of claim 1 wherein the virus contains no additional exogenous nucleic acids. ### Claim 6 A pharmaceutical composition comprising a recombinant oncolytic herpes simplex virus (oHSV) comprising a nucleic acid sequence encoding, in expressible form, a polypeptide comprising the extracellular domain of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) fused to an isoleucine zipper and the extracellular domain of hFlt3 ligand, and a pharmaceutically acceptable carrier, wherein the oHSV is selected from the group consisting of G47Δ, HSV-R3616, 1716, R3616, and R4009, and wherein the recombinant oncolytic herpes simplex virus induces apoptosis in tumor cells that are resistant to apoptosis induction by TRAIL and by oncolytic herpes simplex virus. ### Claim 7 (depends on 6) The pharmaceutical composition of claim 6, wherein the polypeptide encoded by said nucleic acid sequence is secreted by a cell infected by the recombinant oHSV. ### Claim 8 (depends on 7) The pharmaceutical composition of claim 7, wherein the expression of said polypeptide is regulated by the HSV immediate early 4/5 promoter. ### Claim 9 (depends on 6) The pharmaceutical composition of claim 6 wherein the virus contains no additional exogenous nucleic acids. ### Claim 10 (depends on 6) The pharmaceutical composition of claim 6 which is formulated for delivery to the brain.