# US 11,896,634 B2 · Oncolytic virotherapy with helper-dependent adenoviral-based vectors expressing immunomodulatory molecules > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,896,634 B2 - Document ID: US11896634B2 - Status: Granted - Kind: B2 - Application number: 16/607,066 - Filed: 2018-04-20 - Published: 2020-10-15 - Granted: 2024-02-13 - Earliest claimed: 2017-04-21 - Assignees: Baylor College of Medicine - Applicants: Baylor College of Medicine - Inventors: Masataka Suzuki; Amanda Rosewell Shaw; Caroline Elaine Porter; Norihiro Watanabe; Malcolm K. Brenner - Web page: https://patentgrep.com/patent/US11896634B2 ## CPC - A61K 35/761: Adenovirus - A61K 38/1774: {Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)} - A61K 38/208: {IL-12} - A61K 38/43: Enzymes; Proenzymes; Derivatives thereof - A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines} - A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells - A61K 40/31: Chimeric antigen receptors [CAR] - A61K 40/4205: {Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ ErbB4} - A61P 35/00: Antineoplastic agents - C07K 16/2827: {against B7 molecules, e.g. CD80, CD86} - C12N 15/861: Adenoviral vectors - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - A61K 2239/13: Antibody-based - A61K 2239/31: characterized by the route of administration - C07K 14/5434: {IL-12} - C07K 14/7051: {T-cell receptor (TcR)-CD3 complex} - C07K 14/70521: {CD28, CD152} - C07K 16/2818: {against CD28 or CD152} - C07K 16/32: against translation products of oncogenes - C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered - C07K 2317/565: Complementarity determining region [CDR] - C07K 2317/622: Single chain antibody (scFv) - C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation - C07K 2319/03: containing a transmembrane segment - C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies - C12N 15/86: Viral vectors - C12N 2710/10332: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent - C12N 2710/10343: viral genome or elements thereof as genetic vector - 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) - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) ## Abstract The present disclosure concerns combination therapy for cancer that utilizes (i) an oncolytic virus; (ii) a virus comprising nucleic acid encoding an immunomodulatory factor; and (iii) at least one cell comprising a chimeric antigen receptor (CAR) specific for a cancer cell antigen. In particular embodiments, the virus comprises nucleic acid encoding an immunomodulatory factor comprises nucleic acid encoding IL-12 and/or antagonist anti-PD-L1 antibody. ## Claims ### Claim 1 A method of treating a cancer, comprising administering to a subject: (i) an oncolytic virus; (ii) a helper dependent adenovirus (HDAd) comprising a nucleic acid encoding IL-12 and an antagonist anti-PD-L1 antibody; and (iii) at least one cell comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain capable of specific binding to HER2; wherein the cancer comprises cells expressing HER2. ### Claim 2 (depends on 1) The method according to claim 1, wherein the oncolytic virus is an oncolytic adenovirus (OncAd). ### Claim 3 (depends on 1) The method according to claim 1, wherein the oncolytic virus is derived from adenovirus 5 (Ad5). ### Claim 4 (depends on 1) The method according to claim 1, wherein the oncolytic virus encodes an E1A protein which displays reduced binding to Rb protein as compared to E1A protein encoded by Ad5. ### Claim 5 (depends on 1) The method according to claim 1, wherein the oncolytic virus encodes an E1A protein lacking the amino acid sequence LTCHEACF (SEQ ID NO:52). ### Claim 6 (depends on 1) The method according to claim 1, wherein the oncolytic virus encodes an E1A protein comprising, or consisting of, the amino acid sequence SEQ ID NO:34. ### Claim 7 (depends on 1) The method according to claim 1, wherein the at least one cell comprising a CAR is a T cell. ### Claim 8 (depends on 1) The method according to claim 1, wherein the CAR comprises an antigen binding domain comprising: a VL domain comprising: LC-CDR1: SEQ ID NO:10; LC-CDR2: SEQ ID NO:11; LC-CDR3: SEQ ID NO:12; and a VH domain comprising: HC-CDR1: SEQ ID NO:13; HC-CDR2: SEQ ID NO:14; HC-CDR3: SEQ ID NO:15; or a VL domain comprising: LC-CDR1: SEQ ID NO:18; LC-CDR2: SEQ ID NO:19; LC-CDR3: SEQ ID NO:20; and a VH domain comprising: HC-CDR1: SEQ ID NO:21; HC-CDR2: SEQ ID NO:22; HC-CDR3: SEQ ID NO:23; or a VL domain comprising: LC-CDR1: SEQ ID NO:26; LC-CDR2: SEQ ID NO:27; LC-CDR3: SEQ ID NO:28; and a VH domain comprising: HC-CDR1: SEQ ID NO:29; HC-CDR2: SEQ ID NO:30; HC-CDR3: SEQ ID NO:31; or a VL domain comprising: LC-CDR1: SEQ ID NO:57; LC-CDR2: SEQ ID NO:58; LC-CDR3: SEQ ID NO:59; and a VH domain comprising: HC-CDR1: SEQ ID NO:60; HC-CDR2: SEQ ID NO:61; HC-CDR3: SEQ ID NO:62. ### Claim 9 (depends on 1) The method according to claim 1, wherein the CAR comprises an antigen binding domain comprising: a VL comprising, or consisting of, an amino acid sequence having at least 75% sequence identity to SEQ ID NO:16 and a VH comprising, or consisting of, an amino acid sequence having at least 75% sequence identity to SEQ ID NO:17, and further wherein the VL comprises LC-CDR1: SEQ ID NO:10; LC-CDR2: SEQ ID NO:11; and LC-CDR3: SEQ ID NO:12; and the VH comprises HC-CDR1: SEQ ID NO:13; HC-CDR2: SEQ ID NO:14; and HC-CDR3: SEQ ID NO:15; or a VL comprising, or consisting of, an amino acid sequence having at least 75% sequence identity to SEQ ID NO:24 and a VH comprising, or consisting of, an amino acid sequence having at least 75% sequence identity to SEQ ID NO:25, and further wherein the VL comprises LC-CDR1: SEQ ID NO:18; LC-CDR2: SEQ ID NO:19; and LC-CDR3: SEQ ID NO:20; and the VH comprises HC-CDR1: SEQ ID NO:21; HC-CDR2: SEQ ID NO:22; and HC-CDR3: SEQ ID NO:23; or a VL comprising, or consisting of, an amino acid sequence having at least 75% sequence identity to SEQ ID NO:32 and a VH comprising, or consisting of, an amino acid sequence having at least 75% sequence identity to SEQ ID NO:33, and further wherein the VL comprises LC-CDR1: SEQ ID NO:26; LC-CDR2: SEQ ID NO:27; and LC-CDR3: SEQ ID NO:28; and the VH comprises HC-CDR1: SEQ ID NO:29; HC-CDR2: SEQ ID NO:30; and HC-CDR3: SEQ ID NO:31; or a VL comprising, or consisting of, an amino acid sequence having at least 75% sequence identity to SEQ ID NO:63 and a VH comprising, or consisting of, an amino acid sequence having at least 75% sequence identity to SEQ ID NO:64, and further wherein the VL comprises LC-CDR: SEQ ID NO:57; LC-CDR2: SEQ ID NO:58; and LC-CDR3: SEQ ID NO:59; and the VH comprises HC-CDR1: SEQ ID NO:60; HC-CDR2: SEQ ID NO:61; and HC-CDR3: SEQ ID NO:62. ### Claim 10 (depends on 1) The method according to claim 1, wherein the helper dependent adenovirus comprises a nucleic acid encoding an enzyme capable of catalysing conversion of a non-toxic factor to a cytotoxic form. ### Claim 11 (depends on 10) The method according to claim 10, wherein the enzyme is selected from: thymidine kinase, cytosine deaminase, nitroreductase, cytochrome P450, carboxypeptidase G2, purine nucleoside phosphorylase, horseradish peroxidase and carboxylesterase. ### Claim 12 (depends on 1) The method according to claim 1, wherein the method of treating a cancer comprises: (a) isolating at least one cell from a subject; (b) modifying the at least one cell to express or comprise a CAR specific for a cancer cell antigen, or a nucleic acid encoding a CAR specific for a cancer cell antigen, wherein the CAR comprises an antigen binding domain capable of specific binding to HER2; (c) optionally expanding the modified at least one cell, and; (d) administering the modified at least one cell to a subject. ### Claim 13 (depends on 1) The method according to claim 1, wherein the cancer is selected from head and neck cancer, nasopharyngeal carcinoma (NPC), cervical carcinoma (CC), oropharyngeal carcinoma (OPC), gastric carcinoma (GC), hepatocellular carcinoma (HCC) and lung cancer.