Vannini Andrea, Leoni Valerio, Sanapo Mara, Gianni Tatiana, Giordani Giorgia, Gatta Valentina, Barboni Catia, Zaghini Anna, Campadelli-Fiume Gabriella
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40126 Bologna, Italy.
Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy.
Cancers (Basel). 2021 Jan 12;13(2):266. doi: 10.3390/cancers13020266.
Our laboratory has pursued the generation of cancer-specific oncolytic herpes simplex viruses (oHSVs) which ensure high efficacy while maintaining a high safety profile. Their blueprint included retargeting to a Tumor-Associated Antigen, e.g., HER2, coupled to detargeting from natural receptors to avoid off-target and off-tumor infections and preservation of the full complement of unmodified viral genes. These oHSVs are "fully virulent in their target cancer cells". The 3 generation retargeted oHSVs carry two distinct retargeting moieties, which enable infection of a producer cell line and of the target cancer cells, respectively. They can be propagated in an ad hoc Vero cell derivative at about tenfold higher yields than 1 generation recombinants, and more effectively replicate in human cancer cell lines. The R-335 and R-337 prototypes were armed with murine IL-12. Intratumorally-administered R-337 conferred almost complete protection from LLC-1-HER2 primary tumors, unleashed the tumor microenvironment immunosuppression, synergized with the checkpoint blockade and conferred long-term vaccination against distant challenge tumors. In summary, the problem intrinsic to the propagation of retargeted oHSVs-which strictly require cells positive for targeted receptors-was solved in 3 generation viruses. They are effective as immunotherapeutic agents against primary tumors and as antigen-agnostic vaccines.
我们实验室致力于研发癌症特异性溶瘤单纯疱疹病毒（oHSV），这种病毒在确保高效性的同时能保持高度安全性。其设计蓝图包括重新靶向肿瘤相关抗原，如HER2，同时从天然受体上脱靶，以避免脱靶和肿瘤外感染，并保留完整的未修饰病毒基因。这些oHSV“在其靶癌细胞中具有完全毒性”。第三代重新靶向的oHSV携带两个不同的重新靶向部分，分别能够感染生产细胞系和靶癌细胞。它们可以在一种特制的Vero细胞衍生物中增殖，产量比第一代重组体高约十倍，并且能在人类癌细胞系中更有效地复制。R - 335和R - 337原型携带小鼠IL - 12。瘤内注射R - 337几乎能完全保护小鼠免受LLC - 1 - HER2原发性肿瘤的侵害，解除肿瘤微环境免疫抑制，与检查点阻断协同作用，并对远处挑战性肿瘤提供长期免疫。总之，第三代病毒解决了重新靶向oHSV增殖过程中固有的问题，即严格需要靶向受体呈阳性的细胞。它们作为针对原发性肿瘤的免疫治疗剂和与抗原无关的疫苗都很有效。
