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A technology for oncolytic viruses and viruses, applied in the direction of viruses, virus antigen components, viruses/bacteriophages, etc.
Pending Publication Date: 2021-04-02
REPLIMUNE
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[0013] The above discussion indicates that there is still considerable room for improvement of oncolytic agents and cancer therapy utilizing oncolytic agents
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Embodiment 1
[0270] Example 1. Clinical isolates with improved antitumor effects
[0271] The virus species used to illustrate the invention is HSV, particularly HSV1. Cold sores were collected from more than 20 healthy volunteers. Samples from each swab were used to infect BHK cells. HSV1-containing samples were identified by the presence of cytopathic effect (CPE) 24-72 hours after infection and by immunohistochemistry, and virus stocks of major clinical isolates were generated from positive samples.
[0272] The primary clinical isolates of HSV1 were tested for their ability to kill a panel of human tumor-derived cell lines, and the strain with the greatest ability to rapidly kill large numbers of such cells at low doses was selected. The tumor cell lines used for this comparison were HT29 (colorectal cancer), MDA-MB-231 (breast cancer), SK-MEL-28 (melanoma), Fadu (squamous cell carcinoma), MCF7 (breast cancer), A549 (lung cancer), MIAPACA-2 (pancreatic cancer), CAPAN-1 (pancreatic c...
Embodiment 2
[0275] Example 2. Modification of clinical isolates
[0276] In this example, by using a plasmid (HSV1 nucleotides 145300 to 145582 is the sequence to be deleted; HSV1 strain 17 The clinical isolates selected in Example 1 were modified by homologous recombination (see Genbank file NC_001806.2 for sequence) by deleting ICP47 from the viral genome. Viral plaques expressing GFP were selected, then GFP was removed by homologous recombination with empty flanking regions, and plaques not expressing GFP were selected. This produces an ICP47-deficient virus in which US11 is expressed as an IE protein since it is now under the control of the ICP47 promoter. Then by using a plasmid (HSV1 nucleotides 124953 to 125727 is the sequence to be deleted; HSV1 strain 17 sequence is referring to Genbank file NC_001806 .2) Perform homologous recombination to delete ICP34.5. Viral plaques expressing GFP were again selected and then passed through with the same flanking regions (but in between ar...
Embodiment 3
[0281] Example 3. Expression of two immunostimulatory molecules from viruses expressing fusogenic proteins
[0282] Viruses similar to those expressing GALV-R- and mGM-CSF above were constructed, but additionally expressing a CD40L form. Here, instead of using a plasmid containing an ICP34.5 flanking region and an expression cassette containing GM-CSF and GALV-R driven by CMV and RSV promoters, a plasmid containing an ICP34.5 flanking region and containing an expression cassette driven by CMV, RSV and Plasmids for the expression cassettes of GM-CSF, GALV, and CD40L driven by the SV40 promoter were used for recombination with viruses containing GFP inserted into ICP34.5, and again plaques that did not express GFP were selected.
[0283] In more detail, a plasmid (HSV1 nucleotides 145300 to 145582 is the sequence to be deleted; HSV1 strain 17 sequence see Homologous recombination of Genbank file NC_001806.2) deleted ICP47 from the viral genome. Viral plaques expressing GFP wer...
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Abstract
An oncolytic virus is 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 patientswith 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 / orcancer 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 panelof 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.
Description
technical field [0001] The present invention relates to an oncolytic immunotherapeutic agent and the use of the oncolytic immunotherapeutic agent in treating cancer. Background technique [0002] Viruses have the unique ability to enter cells with high efficiency. After entering the cell, the viral genes are expressed and the virus replicates. This usually results in the death of the infected cell and the release of the cell's antigenic components, as the cell ruptures as it dies. As a result, virus-mediated cell death tends to result in an immune response to these cellular components, including those derived from the host cell and those encoded by or incorporated into the virus itself. The immune response is also enhanced due to host recognition of so-called damage-associated molecular patterns (DAMPs) that aid in the activation of the immune response. [0003] Viruses also interact with various regulators of the innate immune response as part of the host's response to r...
Claims
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