Efficacy of Systemically Administered Retargeted Oncolytic Herpes Simplex Viruses—Clearance and Biodistribution in Naïve and HSV-Preimmune Mice

We investigated the anticancer efficacy, blood clearance, and tissue biodistribution of systemically administered retargeted oncolytic herpes simplex viruses (ReHVs) in HSV-naive and HSV-preimmunized (HSV-IMM) mice. Efficacy was tested against lung tumors formed upon intravenous administration of cancer cells, a model of metastatic disease, and against subcutaneous distant tumors. In naive mice, HER2- and hPSMA-retargeted viruses, both armed with mIL-12, were highly effective, even when administered to mice with well-developed tumors. Efficacy was higher for combination regimens with immune checkpoint inhibitors. A significant amount of infectious virus persisted in the blood for at least 1 h. Viral genomes, or fragments thereof, persisted in the blood and tissues for days. Remarkably, the only sites of viral replication were the lungs of tumor-positive mice and the subcutaneous tumors. No replication was detected in other tissues, strengthening the evidence of the high cancer specificity of ReHVs, a property that renders ReHVs suitable for systemic administration. In HSV-IMM mice, ReHVs administered at late times failed to exert anticancer efficacy, and the circulating virus was rapidly inactivated. Serum stability and in vivo whole blood stability assays highlighted neutralizing antibodies as the main factor in virus inactivation. Efforts to deplete mice of the neutralizing antibodies are ongoing

Sintesi di analoghi del paclitaxel vincolati conformazionalmente

Il paclitaxel (= Taxol) è un diterpenoide usato per il trattamento del carcinoma ovarico. Il composto ha grande potenziale terapeutico per il trattamento di altre patologie neoplastiche, e sono stati anche proposti impieghi non oncologici (ristenosi, patologie renali). Il paclitaxel è costituito da un nucleo diterpenico rigido cui sono legati residui acilici essenziali per l’attività biologica. Quantunque il farmacoforo non sia ancora stato caratterizzato in dettaglio, numerosi studi hanno mostrato che la presenza di un residuo fenilisoserinico in 13 è essenziale per il legame alla tubulina, il bersaglio molecolare dei tassoidi antitumorali. La catena amminoacidica del paclitaxel adotta conformazioni diverse a seconda della polarità del mezzo, e non è chiaro quale sia la conformazione “attiva” riconosciuta dalla tubulina1. Per affrontare questo problema è stata programmata la sintesi di analoghi del paclitaxel e del docetaxel vincolati conformazionalmente per introduzione di uno spaziatore fra la posizione 2’ e quella ortho dell’anello fenilico in 3’. L’introduzione di un gruppo metilico in 2’ aumenta la citotossicità del paclitaxel2, razionalizzando quindi l’uso di spaziatori. La sintesi degli analoghi vincolati conformazionalmente (Schema 1) parte da arilchetoni ciclici, e sfrutta l’amminoidrossilazione asimmetrica di Sharpless3 per l’introduzione regio-, stereo- e (parzialmente) enantioselettiva della funzionalità -ammino ossidrilica. 1. Vander Velde, D.G., Georg, G. I., Grunewald, G.L., Gunn, C. W., Mischer, L. A. J. Am. Chem. Soc. 1993, 115, 11650-11651. 2. Kant, J.; Schwartz, W. S.; Fairchild, C.; Gao, Q.; Huang, S.; Long, B. H.; Kadow, J. F.; Langley, D. R.; Farina, V., Vyas, D. Tetrahedron Lett., 1996, 37, 6495-6498. 3. Li, G.; Angert, H. H., Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1996, 35, 2813-2817

La Qualit\ue0 della Vita nei servizi per persone con disabilit\ue0: sfide e prospettive

Il contributo, muovendosi all'interno del costrutto teorico della Qualit\ue0 della Vita, presenta una proposta progetuale per l'integrazione lavorativa di giovani adulti con disabilit\ue

\u3b1v\u3b23-integrin regulates PD-L1 expression and is involved in cancer immune evasion

Tumors utilize a number of effective strategies, including the programmed death 1/PD ligand 1 (PD-1/PD-L1) axis, to evade immune-mediated control of their growth. PD-L1 expression is mainly induced by IFN receptor signaling or constitutively induced. Integrins are an abundantly expressed class of proteins which play multiple deleterious roles in cancer and exert proangiogenic and prosurvival activities. We asked whether \u3b1v\u3b23-integrin positively regulates PD-L1 expression and the anticancer immune response. We report that \u3b1v\u3b23-integrin regulated constitutive and IFN-induced PD-L1 expression in human and murine cancerous and noncancerous cells. \u3b1v\u3b23-integrin targeted STAT1 through its signaling C tail. The implantation of \u3b23-integrin-depleted tumor cells led to a dramatic decrease in the growth of primary tumors, which exhibited reduced PD-L1 expression and became immunologically hot, with increased IFN\u3b3 content and CD8+ cell infiltration. In addition, the implantation of \u3b23-integrin-depleted tumors elicited an abscopal immunotherapeutic effect measured as protection from the challenge tumor and durable splenocyte and serum reactivity to B16 cell antigens. These modifications to the immunosuppressive microenvironment primed cells for checkpoint (CP) blockade. When combined with anti-PD-1, \u3b23-integrin depletion led to durable therapy and elicited an abscopal immunotherapeutic effect. We conclude that in addition to its previously known roles, \u3b1v\u3b23-integrin serves as a critical component of the cancer immune evasion strategy and can be an effective immunotherapy target

Immunotherapeutic Efficacy of Retargeted oHSVs Designed for Propagation in an Ad Hoc Cell Line

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 3rd 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 1st 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 3rd generation viruses. They are effective as immunotherapeutic agents against primary tumors and as antigen-agnostic vaccines

Immunotherapeutic Efficacy of Retargeted oHSVs Designed for Propagation in an Ad Hoc Cell Line

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 3rd 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 1st 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 3rd generation viruses. They are effective as immunotherapeutic agents against primary tumors and as antigen-agnostic vaccines