Oncolytic herpes simplex viruses (HSVs) represent a novel frontier against tumors resistant to standard therapies, like glioblastoma (GBM). The oncolytic HSVs that entered clinical trials so far showed encouraging results; however, they are marred by the fact that they are highly attenuated. We engineered HSVs that maintain unimpaired lytic efficacy and specifically target cells that express tumor-specific receptors, thus limiting the cytotoxicity only to cancer cells, and leaving unharmed the neighboring tissues. We report on the safety and efficacy in a high-grade glioma (HGG) model of R-LM113, an HSV recombinant retargeted to human epidermal growth factor receptor 2 (HER2), frequently expressed in GBMs. We demonstrated that R-LM113 is safe in vivo as it does not cause encephalitis when intracranially injected in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, extremely sensitive to wild-type HSV. The efficacy of R-LM113 was assessed in a platelet-derived growth factor (PDGF)-induced infiltrative glioma model engineered to express HER2 and transplanted intracranially in adult NOD/SCID mice. Mice injected with HER2-engineered glioma cells infected with R-LM113 showed a doubled survival time compared with mice injected with uninfected cells. A doubling in survival time from the beginning of treatment was obtained also when R-LM113 was administered into already established tumors. These data demonstrate the efficacy of R-LM113 in thwarting tumor growth.

The healthy cervicovaginal microbiota is dominated by various Lactobacillus species, which support a condition of eubiosis. Among their many functions, vaginal lactobacilli contribute to the maintenance of an acidic pH, produce antimicrobial compounds, and modulate the host immune response to protect against vaginal bacterial and fungal infections. Increasing evidence suggests that these beneficial bacteria may also confer protection against sexually transmitted infections (STIs) caused by viruses such as human papillomavirus (HPV), human immunodeficiency virus (HIV) and herpes simplex virus (HSV). Viral STIs pose a substantial public health burden globally, causing a range of infectious diseases with potentially severe consequences. Understanding the molecular mechanisms by which lactobacilli exert their protective effects against viral STIs is paramount for the development of novel preventive and therapeutic strategies. This review aims to provide more recent insights into the intricate interactions between lactobacilli and viral STIs, exploring their impact on the vaginal microenvironment, host immune response, viral infectivity and pathogenesis, and highlighting their potential implications for public health interventions and clinical management strategies.

Previously, we engineered oncolytic herpes simplex viruses (o-HSVs) retargeted to the HER2 (epidermal growth factor receptor 2) tumor cell specific receptor by the insertion of a single chain antibody (scFv) to HER2 in gD, gH, or gB. Here, the insertion of scFvs to three additional cancer targets—EGFR (epidermal growth factor receptor), EGFRvIII, and PSMA (prostate specific membrane antigen)—in gD Δ6–38 enabled the generation of specifically retargeted o-HSVs. Viable recombinants resulted from the insertion of an scFv in place of aa 6–38, but not in place of aa 61–218. Hence, only the gD N-terminus accepted all tested scFv inserts. Additionally, the insertion of mIL12 in the US1-US2 intergenic region of the HER2- or EGFRvIII-retargeted o-HSVs, and the further insertion of Gaussia Luciferase, gave rise to viable recombinants capable of secreting the cytokine and the reporter. Lastly, we engineered two known mutations in gB; they increased the ability of an HER2-retargeted recombinant to spread among murine cells. Altogether, current data show that the o-HSV carrying the aa 6–38 deletion in gD serves as a platform for the specific retargeting of o-HSV tropism to a number of human cancer targets, and the retargeted o-HSVs serve as simultaneous vectors for two molecules.

Oncolytic viruses are smart therapeutics against cancer due to their potential to replicate and produce the needed therapeutic dose in the tumor, and to their ability to self-exhaust upon tumor clearance. Oncolytic virotherapy strategies based on the herpes simplex virus are reaching their thirties, and a wide variety of approaches has been envisioned and tested in many different models, and on a range of tumor targets. This huge effort has culminated in the primacy of an oncolytic HSV (oHSV) being the first oncolytic virus to be approved by the FDA and EMA for clinical use, for the treatment of advanced melanoma. The path has just been opened; many more cancer types with poor prognosis await effective and innovative therapies, and oHSVs could provide a promising solution, especially as combination therapies and immunovirotherapies. In this review, we analyze the most recent advances in this field, and try to envision the future ahead of oHSVs.

Glioblastoma is a lethal primary brain tumor lacking effective therapy. The secluded onset site, combined with the infiltrative properties of this tumor, require novel targeted therapies. In this scenario, the use of oncolytic viruses retargeted to glioblastoma cells and able to spread across the tumor cells represent an intriguing treatment strategy. Here, we tested the specificity, safety and efficacy of R-613, the first oncolytic HSV fully retargeted to EGFRvIII, a variant of the epidermal growth factor receptor carrying a mutation typically found in glioblastoma. An early treatment with R-613 on orthotopically transplanted EGFRvIII-expressing human glioblastoma significantly increased the median survival time of mice. In this setting, the growth of human glioblastoma xenotransplants was monitored by a secreted luciferase reporter and showed that R-613 is able to substantially delay the development of the tumor masses. When administered as late treatment to a well-established glioblastomas, R-613 appeared to be less effective. Notably the uninfected tumor cells derived from the explanted tumor masses were still susceptible to R-613 infection ex vivo, thus suggesting that multiple treatments could enhance R-613 therapeutic efficacy, making R-613 a promising oncolytic HSV candidate for glioblastoma treatment.

Oncolytic viruses (OVs) are the frontier therapy for refractory cancers, especially in integration with immunomodulation strategies. In cancer immunovirotherapy, the many available “omics” and systems biology technologies generate at a fast pace a challenging huge amount of data, where apparently clashing information mirrors the complexity of individual clinical situations and OV used. In this review, we present and discuss how currently big data analysis, on one hand and, on the other, simulation, modeling, and computational technologies, provide invaluable support to interpret and integrate “omic” information and drive novel synthetic biology and personalized OV engineering approaches for effective immunovirotherapy. Altogether, these tools, possibly aided in the future by artificial intelligence as well, will allow for the blending of the information into OV recombinants able to achieve tumor clearance in a patient-tailored way. Various endeavors to the envisioned “synthesis” of turning OVs into personalized theranostic agents are presented.