Potent anti-tumor effects of receptor-retargeted syncytial oncolytic herpes simplex virus
| Autor: | Ryota Hamasaki, Shigeru Yanagi, Yasuhiko Sasaki, Hiroaki Uchida, Hitomi Ikeda, Tomoko Shibata, Takuma Suzuki, Kosaku Okuda, Mika Hamada-Uematsu, Hideaki Tahara |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Genetic enhancement medicine.disease_cause Antigen medicine cancer Pharmacology (medical) oncolytic virotherapy targeting RC254-282 Syncytium biology fusogenic HSV Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cancer herpes simplex virus medicine.disease gene therapy systemic delivery Oncolytic virus cell death Herpes simplex virus Oncology intravenous Cancer cell Cancer research biology.protein Molecular Medicine Original Article Antibody |
| Zdroj: | Molecular Therapy: Oncolytics, Vol 22, Iss, Pp 265-276 (2021) Molecular Therapy Oncolytics |
| ISSN: | 2372-7705 |
| Popis: | Most oncolytic virotherapy has thus far employed viruses deficient in genes essential for replication in normal cells but not in cancer cells. Intra-tumoral injection of such viruses has resulted in clinically significant anti-tumor effects on the lesions in the vicinity of the injection sites but not on distant visceral metastases. To overcome this limitation, we have developed a receptor-retargeted oncolytic herpes simplex virus employing a single-chain antibody for targeting tumor-associated antigens (RR-oHSV) and its modified version with additional mutations conferring syncytium formation (RRsyn-oHSV). We previously showed that RRsyn-oHSV exhibits preserved antigen specificity and an ∼20-fold higher tumoricidal potency in vitro relative to RR-oHSV. Here, we investigated the in vivo anti-tumor effects of RRsyn-oHSV using human cancer xenografts in immunodeficient mice. With only a single intra-tumoral injection of RRsyn-oHSV at very low doses, all treated tumors regressed completely. Furthermore, intra-venous administration of RRsyn-oHSV resulted in robust anti-tumor effects even against large tumors. We found that these potent anti-tumor effects of RRsyn-oHSV may be associated with the formation of long-lasting tumor cell syncytia not containing non-cancerous cells that appear to trigger death of the syncytia. These results strongly suggest that cancer patients with distant metastases could be effectively treated with our RRsyn-oHSV. Graphical abstract Exceptionally strong anti-tumor potency was achieved by intra-tumoral or intra-venous administration of receptor-retargeted syncytial oncolytic herpes simplex virus (RRsyn-oHSV). The robustness of RRsyn-oHSV was associated with the formation of long-lasting tumor cell syncytia not containing non-cancerous cells that otherwise trigger death of the syncytia before their sufficient expansion. |
| Databáze: | OpenAIRE |
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