High Therapeutic Potential for Systemic Delivery of a Liposomeconjugated Herpes Simplex Virus

T.      Shikano; H.      Kasuya; T.      T. Sahin; N.      Nomura; A.      Kanzaki; M.      Misawa; Y.      Nishikawa; T.      Shirota; S.      Yamada; T.      Fujii; H.      Sugimoto; N.      Kanazumi; S.      Nomoto; S.      Takeda; A.      Nakao

Abstract

Purpose: Oncolytic viral therapy is a newly developed modality to treat tumors. Many clinical trials worldwide have examined the efficacy of locally injected oncolytic viruses. However, systemic intravascular injections are limited by the humoral immune response, which dramatically decreases the level of infection. To overcome this limitation, we encapsulated the oncolytic virus in liposomes. Methods: The infectious properties of the herpes simplex virus type 1 (HSV-1) mutant, hrR3, with or without liposomes in the presence of neutralizing antibodies were evaluated using replication and cytotoxicity assays in vitro. To evaluate the efficacy of intravascular virus therapy with liposomes in the presence of neutralizing antibodies, immunized mice bearing multiple liver metastases were intraportally or peritoneally administered hrR3 or hrR3 complexed with liposomes. Results: Anti-HSV antibodies attenuated the infectiousness and cytotoxicity of hrR3, whereas hrR3/liposome complexes were not attenuated by these anti-HSV antibodies. Although the survival rate of non-immunized mice treated with hrR3 alone was similar to that of mice treated with the hrR3/liposome complexes, the survival rates of immunized mice treated with hrR3 alone were significantly reduced compared to mice treated with the hrR3/liposome complexes. Conclusions: This systemic intravascular delivery of hrR3/liposome complexes in the presence of pre-existing neutralizing antibodies is effective to treat multiple liver metastases.

Keywords: Onocolytic viral therapy, herpes simplex virus, hrR3, neutralizing antibody, immune response, liposome, adenovirus, herpes, vaccinia virus, disease virus, cancer gene therapy, infection, antibodies, mmune-competent, anti-herpes drugs, DNA, oncolytic viral therapy, lungs, peritoneum, colon carcinomas, squamous cell carcinoma, humoral immune response, blood stream, liposomes, kidney cell line, ribonucleotide, Lipofectamine Formulations, Lipofectamine, eukaryotic cel, ipid dioleoyl phosphatidylethanolamine (DOPE), Liposome Complexes, aqueous uranyl acetate solution, electron microscope, -Galactosidase, Histochemistry, X-gal solution, random hyper fields, Viral Antigenicity, IgG, IgM, plaques, neutralization, microliters of serum, colorimetric, liver tumor, photomicrographs, neurological symptoms, toxic side effects, antigenicity, oncolytic viral, intraneoplastically, cationic liposome-conjugated adenoviral, obstacle, virotherapy, lesions