Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory Transgenes
Oncolytic virotherapy is a promising new tool for cancer treatment, but direct lytic destruction of tumor cells is not sufficient and must be accompanied by strong immune activation to elicit anti-tumor immunity. We report here the creation of a novel replication-competent recombinant oncolytic herp...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/8/11/484 |
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| author | Dmitry V. Chouljenko Jun Ding I-Fang Lee Yanal M. Murad Xuexian Bu Guoyu Liu Zahid Delwar Yi Sun Sheng Yu Ismael Samudio Ronghua Zhao William Wei-Guo Jia |
| author_facet | Dmitry V. Chouljenko Jun Ding I-Fang Lee Yanal M. Murad Xuexian Bu Guoyu Liu Zahid Delwar Yi Sun Sheng Yu Ismael Samudio Ronghua Zhao William Wei-Guo Jia |
| author_sort | Dmitry V. Chouljenko |
| collection | DOAJ |
| description | Oncolytic virotherapy is a promising new tool for cancer treatment, but direct lytic destruction of tumor cells is not sufficient and must be accompanied by strong immune activation to elicit anti-tumor immunity. We report here the creation of a novel replication-competent recombinant oncolytic herpes simplex virus type 1 (VG161) that carries genes coding for IL-12, IL-15, and IL-15 receptor alpha subunit, along with a peptide fusion protein capable of disrupting PD-1/PD-L1 interactions. The VG161 virus replicates efficiently and exhibits robust cytotoxicity in multiple tumor cell lines. Moreover, the encoded cytokines and the PD-L1 blocking peptide work cooperatively to boost immune cell function. In vivo testing in syngeneic CT26 and A20 tumor models reveals superior efficacy when compared to a backbone virus that does not express exogenous genes. Intratumoral injection of VG161 induces abscopal responses in non-injected distal tumors and grants resistance to tumor re-challenge. The robust anti-tumor effect of VG161 is associated with T cell and NK cell tumor infiltration, expression of Th1 associated genes in the injection site, and increased frequency of splenic tumor-specific T cells. VG161 also displayed a superb safety profile in GLP acute and repeated injection toxicity studies performed using cynomolgus monkeys. Overall, we demonstrate that VG161 can induce robust oncolysis and stimulate a robust anti-tumor immune response without sacrificing safety. |
| first_indexed | 2024-03-10T15:00:03Z |
| format | Article |
| id | doaj.art-a6d8ed029b5444409dd42fce8acb87b6 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T15:00:03Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-a6d8ed029b5444409dd42fce8acb87b62023-11-20T20:14:38ZengMDPI AGBiomedicines2227-90592020-11-0181148410.3390/biomedicines8110484Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory TransgenesDmitry V. Chouljenko0Jun Ding1I-Fang Lee2Yanal M. Murad3Xuexian Bu4Guoyu Liu5Zahid Delwar6Yi Sun7Sheng Yu8Ismael Samudio9Ronghua Zhao10William Wei-Guo Jia11Virogin Biotech Canada Ltd., 408-3800 Wesbrook Mall, Vancouver, BC V6S 2L9, CanadaVirogin Biotech Canada Ltd., 408-3800 Wesbrook Mall, Vancouver, BC V6S 2L9, CanadaVirogin Biotech Canada Ltd., 408-3800 Wesbrook Mall, Vancouver, BC V6S 2L9, CanadaVirogin Biotech Canada Ltd., 408-3800 Wesbrook Mall, Vancouver, BC V6S 2L9, CanadaVirogin Biotech Canada Ltd., 408-3800 Wesbrook Mall, Vancouver, BC V6S 2L9, CanadaVirogin Biotech Canada Ltd., 408-3800 Wesbrook Mall, Vancouver, BC V6S 2L9, CanadaVirogin Biotech Canada Ltd., 408-3800 Wesbrook Mall, Vancouver, BC V6S 2L9, CanadaVirogin Biotech Canada Ltd., 408-3800 Wesbrook Mall, Vancouver, BC V6S 2L9, CanadaVirogin Biotech Canada Ltd., 408-3800 Wesbrook Mall, Vancouver, BC V6S 2L9, CanadaVirogin Biotech Canada Ltd., 408-3800 Wesbrook Mall, Vancouver, BC V6S 2L9, CanadaVirogin Biotech Canada Ltd., 408-3800 Wesbrook Mall, Vancouver, BC V6S 2L9, CanadaVirogin Biotech Canada Ltd., 408-3800 Wesbrook Mall, Vancouver, BC V6S 2L9, CanadaOncolytic virotherapy is a promising new tool for cancer treatment, but direct lytic destruction of tumor cells is not sufficient and must be accompanied by strong immune activation to elicit anti-tumor immunity. We report here the creation of a novel replication-competent recombinant oncolytic herpes simplex virus type 1 (VG161) that carries genes coding for IL-12, IL-15, and IL-15 receptor alpha subunit, along with a peptide fusion protein capable of disrupting PD-1/PD-L1 interactions. The VG161 virus replicates efficiently and exhibits robust cytotoxicity in multiple tumor cell lines. Moreover, the encoded cytokines and the PD-L1 blocking peptide work cooperatively to boost immune cell function. In vivo testing in syngeneic CT26 and A20 tumor models reveals superior efficacy when compared to a backbone virus that does not express exogenous genes. Intratumoral injection of VG161 induces abscopal responses in non-injected distal tumors and grants resistance to tumor re-challenge. The robust anti-tumor effect of VG161 is associated with T cell and NK cell tumor infiltration, expression of Th1 associated genes in the injection site, and increased frequency of splenic tumor-specific T cells. VG161 also displayed a superb safety profile in GLP acute and repeated injection toxicity studies performed using cynomolgus monkeys. Overall, we demonstrate that VG161 can induce robust oncolysis and stimulate a robust anti-tumor immune response without sacrificing safety.https://www.mdpi.com/2227-9059/8/11/484immunotherapyoncolytic virusherpes simplex viruscancer vaccineantitumor immunitycombinatorial therapy |
| spellingShingle | Dmitry V. Chouljenko Jun Ding I-Fang Lee Yanal M. Murad Xuexian Bu Guoyu Liu Zahid Delwar Yi Sun Sheng Yu Ismael Samudio Ronghua Zhao William Wei-Guo Jia Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory Transgenes Biomedicines immunotherapy oncolytic virus herpes simplex virus cancer vaccine antitumor immunity combinatorial therapy |
| title | Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory Transgenes |
| title_full | Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory Transgenes |
| title_fullStr | Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory Transgenes |
| title_full_unstemmed | Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory Transgenes |
| title_short | Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory Transgenes |
| title_sort | induction of durable antitumor response by a novel oncolytic herpesvirus expressing multiple immunomodulatory transgenes |
| topic | immunotherapy oncolytic virus herpes simplex virus cancer vaccine antitumor immunity combinatorial therapy |
| url | https://www.mdpi.com/2227-9059/8/11/484 |
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