Antitumor efficacy of oncolytic herpes simplex virus adsorbed onto antigen-specific lymphocytes.
ABSTRACT Although several studies have reported that locally administering oncolytic viruses effectively targets malignancies, the efficacy of systemically administered oncolytic viruses is restricted. Recently, however, it was reported that systemic administration of oncolytic vesicular stomatitis virus adsorbed onto antigen-specific lymphocytes was effective against malignancies. We hypothesized that intravenously administering such virus might have significant potential in treatment of the malignant tumors. We adsorbed oncolytic herpes simplex virus-1 mutant R3616 onto lymphocytes harvested from mice with acquired antitumor immunity. We administered adsorbed R3616 to peritoneally disseminated tumors and analyzed the efficacy of this treatment. Mice administered adsorbed R3616 survived significantly longer than mice administered R3616 adsorbed onto non-specific lymphocytes, or mice administered either virus or tumor antigen-specific lymphocytes alone. In this context, herpes oncolytic virus is a promising treatment not only for primary lesions, but also for multiple metastasizing lesions. This treatment strategy may become one of the most effective methods for systemic virus delivery.
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ABSTRACT: Adoptive T-cell transfer has achieved significant clinical success in advanced melanoma. However, therapeutic efficacy is limited by poor T-cell survival after adoptive transfer and by inefficient trafficking to tumor sites. Here, we report that intratumoral expression of the chemokine CCL21 enhances the efficacy of adoptive T-cell therapy in a mouse model of melanoma. Based on our novel observation that CCL21 is highly chemotactic for activated OT-1 T cells in vitro and down-regulates expression of CD62L, we hypothesized that tumor cell-mediated expression of this chemokine might recruit, and retain, adoptively transferred T cells to the sites of tumor growth. Mice bearing metastatic tumors stably transduced with CCL21 survived significantly longer following adoptive T-cell transfer than mice bearing non-CCL21-expressing tumors. However, although we could not detect increased trafficking of the adoptively transferred T cells to tumors, tumor-expressed CCL21 promoted the survival and cytotoxic activity of the adoptively transferred T cells and led to the priming of antitumor immunity following T-cell transfer. To translate these observations into a protocol of real clinical usefulness, we showed that adsorption of a retrovirus encoding CCL21 to OT-1 T cells before adoptive transfer increased the therapeutic efficacy of a subsequently administered dose of OT-1 T cells, resulting in cure of metastatic disease and the generation of immunologic memory in the majority of treated mice. These studies indicate a promising role for CCL21 in enhancing the therapeutic efficacy of adoptive T-cell therapy.Cancer Research 02/2007; 67(1):300-8. · 8.65 Impact Factor
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ABSTRACT: Oncolytic viral therapy is a newly developed modality for treating tumors. Many clinical trials using oncolytic virus have been performed worldwide, but most of them have used local injection in the tumor. Determination of the effect and safety of intravascular virus injection instead of local injection is necessary for clinical use against multiple liver metastases and systemic metastases. To evaluate the efficacy and safety of intravascular virus therapy, mice bearing multiple liver metastases were treated by intraportal or intravenous administration of the herpes simplex virus type 1 (HSV-1) mutant, hrR3. Mice treated with hrR3 were killed and organs were harvested for lacZ staining and PCR analysis. Inactivation of oncolytic virus in bloodstream was assessed by neutralization assay in vitro. Infectious activity of hrR3 with vascular endothelial cells was evaluated by replication and cytotoxicity assay. The survival rate of animals treated by hrR3 was significantly improved compared with the untreated group. lacZ staining and PCR analysis demonstrated detectable virus in the tumor but not in normal tissue or other organs except for the adrenal glands. We also showed that vascular endothelial cells allowed virus replication, while normal hepatocytes did not, and human anti-HSV antibody revealed attenuation of the infectious activity of hrR3. Intravascular delivery of hrR3 is effective in treating multiple liver metastases, however, several points must be kept in mind at the time of human clinical trials using intravascular virus administration in order to avoid critical side effects.Cancer Chemotherapy and Pharmacology 07/2008; 63(2):321-30. · 2.80 Impact Factor
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ABSTRACT: The ability to specifically target a cell-type is important for the development of vectors for in vivo gene therapy. In order to produce retrovirus vectors targeting ovarian cancer cells, which specifically overexpress alpha folate receptor (alphaFR), a single chain antibody was fused as an N-terminal extension of the ecotropic and amphotropic murine leukemia virus (MLV) envelope glycoproteins. Vector particles bearing the modified glycoproteins were produced and analysed. Although conventional FACS studies indicated that viral particles bearing the modified Env could bind to ovarian cancer cells, targeted infection was not achieved. The initial step of virus-cell interaction was further studied using an immunofluorescence technique, which allows visualisation of single retrovirus particles. Vectors bearing chimeric or wild-type glycoproteins bound equally well to cells with or without the targeted receptor, although soluble chimeric glycoproteins bound specifically to FBP. Our results indicate that the incorporation of specific ligands to the virus envelope does not necessarily result in significant enhancement of vector particle binding. A similar interaction was also observed using Env-defective virus particles, suggesting that cellular factors incorporated into the lipid envelope play a dominant role in promoting initial adsorption of virus particles to cells. Significant implications arise from these observations on the interpretation of previous reports on 'targeted' vectors, and for the development of vectors for in vivo gene therapy protocols.Gene Therapy 08/2001; 8(14):1088-96. · 4.32 Impact Factor