Granted Patent
B2
US 12,685,767 · App. 17/250,205 · Granted Jul 21, 2026
Treatment using oncolytic virus
Assignee:
Replimune Limited
A61K39/245A61K38/177A61K38/193A61K39/3955A61K47/50A61P35/00C12N7/00A61K2039/5254A61K2039/5256A61K2039/545A61K2039/585C12N2710/16634C12N2710/16643C12N2710/16671
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Abstract
An oncolytic virus for use in a method of treating or preventing cutaneous squamous cell carcinoma (CSCC), renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), small cell lung cancer (SCLC), advanced recurrent head and neck cancer, squamous cell carcinoma of the head and neck (SCCHN), nasopharyngeal carcinoma (NPC), hepatocellular carcinoma (HCC), anal cancer, colorectal cancer (CRC), basal cell carcinoma (BCC), Merkel cell carcinoma, appendiceal carcinoma, sarcoma of the skin, recurrent melanoma after surgery, advanced or metastatic urothelial carcinoma, liver metastases, microsatellite instability high cancer (MSI-H), mixed advanced solid tumors, virally caused cancer, locoregionally advanced cancer, pediatric cancer, cancer in patients with no or minimal pre-existing anti-cancer immunity, cancer as first line therapy, cancer in previously treated patients, cancer in patients who have not received checkpoint blockade therapy, and/or cancer in patients who have received checkpoint blockade therapy, wherein the oncolytic virus: is, or is derived from, a clinical isolate which has been selected by comparing the abilities of a panel of three or more clinical isolates of the same viral species to kill tumor cells of two or more tumor cell lines in vitro and selecting a clinical isolate which is capable of killing cells of two or more tumor cell lines more rapidly and/or at a lower dose in vitro than one or more of the other clinical isolates in the panel; comprises (i) a fusogenic protein-encoding gene; and (ii) an immune stimulatory molecule or an immune stimulatory molecule-encoding gene; comprises (i) a GM-CSF-encoding gene; and (ii) an immune co-stimulatory pathway activating molecule or an immune co-stimulatory pathway activating molecule-encoding gene; and/or comprises a gene encoding a CTLA-4 inhibitor.
Claims (46)
1 . A method of treating melanoma in patients who have previously been treated by surgery and/or checkpoint blockade therapy,
wherein the method comprises administering by intra-tumoral injection into a solid tumor a therapeutically effective amount of an oncolytic herpes simplex virus (HSV) to a patient in need thereof, wherein
the oncolytic virus comprises (i) a fusogenic protein-encoding gene, wherein the fusogenic protein is the glycoprotein from gibbon ape leukemia virus (GALV) and has the R transmembrane peptide mutated or removed (GALV-R−); and (ii) an immune stimulatory molecule-encoding gene, wherein the immune stimulatory molecule is GM-CSF, and wherein the administration of the oncolytic virus elicits a systemic immune response to induce regression of the tumor injected by the oncolytic virus and a tumor not injected by the oncolytic virus, and to prevent tumor reoccurrence.
2 . The method according to claim 1 , wherein the oncolytic virus is a modified clinical isolate.
3 . The method according to claim 1 , wherein the virus comprises:
(a) more than one immune stimulatory molecule encoding genes; and/or
(b) more than one fusogenic protein-encoding genes.
4 . The method according to claim 1 , wherein:
the oncolytic virus comprises a further immune stimulatory molecule selected from IL-2, IL-12, IL-15, IL-18, IL-21, IL-24, a type I interferon, interferon gamma, a type III interferon, TNF alpha, an antagonist of TGF beta, an immune checkpoint antagonist or an agonist of an immune potentiating pathway such as an agonist of CD40, ICOS, GITR, 4-1-BB, OX40 or flt3.
5 . The method according to claim 4 , wherein the further immune stimulatory molecule is a CTLA-4 inhibitor comprising an anti-CTLA-4 antibody, or an antigen binding fragment thereof.
6 . The method according to claim 5 , wherein the fragment comprises a scFv.
7 . The method according to claim 5 , wherein the fragment is a scFv molecule linked to one or more IgG1 constant regions.
8 . The method according to claim 5 , wherein the antibody or fragment comprises a light chain variable region sequence linked to an IgG heavy chain.
9 . The method according to claim 5 , wherein the antibody or fragment comprises (a) the light chain variable region sequence shown in SEQ ID NO: 46 and the heavy chain variable region sequence shown in SEQ ID NO: 48; or (b) the light chain variable region sequence shown in SEQ ID NO: 56 and the heavy chain variable region sequence shown in SEQ ID NO: 57.
10 . The method according to claim 9 , wherein the antibody or fragment comprises (a) the amino acid sequence of SEQ ID NO: 54; or (b) the amino acid sequence of SEQ ID NO: 59.
11 . The method according to claim 5 , wherein the antibody or fragment is encoded by (a) the nucleotide sequence of SEQ ID NO: 55; or (b) the nucleotide sequence of SEQ ID NO: 60.
12 . The method according to claim 1 wherein the oncolytic virus is a HSV1.
13 . The method according to claim 12 , wherein the HSV1 is:
strain RH018A having the accession number ECACC 16121904;
strain RH004A having the accession number ECACC 16121902;
strain RH031A having the accession number ECACC 16121907;
strain RH040B having the accession number ECACC 16121908;
strain RH1015A having the accession number ECACC 16121903;
strain RH021A having the accession number ECACC 16121905;
strain RH023A having the accession number ECACC 16121906; or
strain RH047A having the accession number ECACC 16121909.
14 . The method according to claim 13 wherein the oncolytic virus is strain RH018A having the accession number ECACC 16121904.
15 . The method according to claim 1 , wherein the virus:
(a) does not express functional ICP34.5;
(b) does not express functional ICP47; and/or
(c) expresses the US11 gene as an immediate early gene.
16 . The method according to claim 15 , wherein: (a) the fusogenic protein-encoding gene and/or the immune stimulatory molecule-encoding gene are/is inserted into the ICP34.5 encoding locus, either by insertion, or partial or complete deletion, each under separate regulatory control, optionally in a back to back orientation in relation to each other; and/or
(b) the sequence of the gene encoding the fusogenic protein, and/or the sequence of the gene encoding the immune stimulatory molecule is codon optimized so as to increase expression levels in target cells.
17 . The method according to claim 1 , wherein the oncolytic virus expresses three heterologous genes, wherein each of the three heterologous genes is driven by a different promoter selected from the CMV promoter, the RSV promoter, the SV40 promoter and a retroviral LTR promoter.
18 . The method according to claim 17 , wherein the oncolytic virus expresses four heterologous genes driven by each of the CMV promoter, the RSV promoter, the SV40 promoter and a retroviral LTR promoter, respectively.
19 . The method according to claim 17 , wherein the retroviral LTR promoter is from MMLV.
20 . The method according to claim 1 , wherein the oncolytic virus expresses three heterologous genes, wherein each of the three heterologous genes is terminated by a different poly adenylation sequence selected from the BGH, SV40, HGH and RBG poly adenylation sequences.
21 . The method according to claim 20 , wherein the oncolytic virus expresses four heterologous genes terminated by each of the BGH, SV40, HGH and RBG poly adenylation sequences, respectively.
22 . The method according to claim 1 , which comprises administering a therapeutically effective amount of the virus in combination with a tyrosine kinase inhibitor.
23 . The method according to claim 22 , wherein the tyrosine kinase inhibitor is a MEK inhibitor or a BRAF inhibitor.
24 . The method according to claim 1 , which further comprises administering a therapeutically effective amount of a further anti-cancer agent to a patient in need thereof.
25 . The method according to claim 24 , wherein the further anti-cancer agent is selected from an antagonist of an immune co-inhibitory pathway, an agonist of an immune co-stimulatory pathway, radiation and/or chemotherapy, an agent that targets a specific genetic mutation which occurs in tumors, an agent intended to induce an immune response to one or more tumor antigen(s) or neoantigen(s), a cellular product derived from T cells or NK cells, an agent intended to stimulate the STING, cGAS, TLR or other innate immune response and/or inflammatory pathway, a second virus optionally an oncolytic virus, an inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway, a tyrosine kinase inhibitor and combinations thereof.
26 . The method according to claim 25 , wherein the antagonist of an immune co-inhibitory pathway is a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, a VISTA inhibitor, a CSF1R inhibitor, an IDO inhibitor, a CEACAM1 inhibitor, a KIR inhibitor, a SLAM F7 inhibitor or a CD47 inhibitor, and/or the agonist of an immune co-stimulatory pathway is a GITR agonist, a 4-1-BB agonist, an OX40 agonist, a CD40 agonist or an ICOS agonist, and/or the tyrosine kinase inhibitor is a MEK inhibitor or a BRAF inhibitor.
27 . The method according to claim 24 , wherein the further anti-cancer agent comprises an antibody.
28 . The method according to claim 24 , wherein the virus and the further anti-cancer agent(s) are administered separately.
29 . The method according to claim 24 , wherein the virus and the further anti-cancer agent(s) are administered concurrently.
Assignments (2)
SECURITY INTEREST
Recorded Jan 30, 2026
From: REPLIMUNE GROUP, INC.; REPLIMUNE, INC.; REPLIMUNE LIMITED
To: HERCULES CAPITAL, INC.
Reel/Frame 073644/0641 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 2, 2021
From: COFFIN, ROBERT STUART
To: REPLIMUNE LIMITED
Reel/Frame 055118/0354 →
Continuity (5)
Provisional Application
62687931
· Jun 21, 2018
Provisional Application
62687920
· Jun 21, 2018
Provisional Application
62687881
· Jun 21, 2018
Provisional Application
62687910
· Jun 21, 2018
Related Publication
20210252135A1
· Aug 19, 2021
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