Suzuki Takuma, Uchida Hiroaki, Shibata Tomoko, Sasaki Yasuhiko, Ikeda Hitomi, Hamada-Uematsu Mika, Hamasaki Ryota, Okuda Kosaku, Yanagi Shigeru, Tahara Hideaki
Project Division of Cancer Biomolecular Therapy, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
Mol Ther Oncolytics. 2021 Aug 19;22:265-276. doi: 10.1016/j.omto.2021.08.002. eCollection 2021 Sep 24.
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 relative to RR-oHSV. Here, we investigated the 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.
迄今为止，大多数溶瘤病毒疗法所使用的病毒缺乏在正常细胞而非癌细胞中复制所必需的基因。在肿瘤内注射此类病毒已对注射部位附近的病灶产生了具有临床意义的抗肿瘤效果，但对远处的内脏转移灶却没有效果。为克服这一局限性，我们研发了一种受体靶向性溶瘤单纯疱疹病毒，它采用单链抗体靶向肿瘤相关抗原（RR-oHSV）及其具有额外突变从而能够形成多核巨细胞的修饰版本（RRsyn-oHSV）。我们之前表明，相对于RR-oHSV，RRsyn-oHSV表现出保留的抗原特异性以及约20倍更高的杀瘤效力。在此，我们利用免疫缺陷小鼠体内的人癌异种移植模型研究了RRsyn-oHSV的抗肿瘤效果。仅在肿瘤内单次注射极低剂量的RRsyn-oHSV，所有接受治疗的肿瘤就完全消退了。此外，静脉注射RRsyn-oHSV即使对大肿瘤也产生了强大的抗肿瘤效果。我们发现，RRsyn-oHSV的这些强大抗肿瘤效果可能与形成不含非癌细胞的持久肿瘤细胞多核巨细胞有关，这些多核巨细胞似乎会触发自身死亡。这些结果有力地表明，患有远处转移的癌症患者可以用我们的RRsyn-oHSV进行有效治疗。
