The combination of immunosuppression and carrier cells significantly enhances the efficacy of oncolytic poxvirus in the pre-immunized host

• Published in: Gene therapy Vol. 17; no. 12; pp. 1465 - 1475
• Main Authors: Guo, Z S, Parimi, V, O'Malley, M E, Thirunavukarasu, P, Sathaiah, M, Austin, F, Bartlett, D L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2010; Nature Publishing Group
• Subjects: 631/250/251/1574; 631/326/596/1746; 631/61/2300; 692/699/67; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Animals; Antibodies; Antibodies, Neutralizing - blood; Antibodies, Viral - immunology; Applied cell therapy and gene therapy; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; Carcinoma - drug therapy; Cell Biology; Cell Line, Tumor; Cell physiology; Cell survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular biology; DNA viruses; Female; Fundamental and applied biological sciences. Psychology; Gastric cancer; Gene Expression; Gene Therapy; Genetic aspects; Haplorhini; Health aspects; Health. Pharmaceutical industry; HeLa Cells; Human Genetics; Humans; Immunity; Immunology; Immunosuppression; Immunosuppressive agents; Immunosuppressive Agents - analysis; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Industrial applications and implications. Economical aspects; Infection; Kaplan-Meier Estimate; Lymphocytes B; Macrophages; Medical sciences; Methylprednisolone; Mice; Mice, Inbred C57BL; Mice, Knockout; Microenvironments; Molecular and cellular biology; Mycophenolate mofetil; Mycophenolic acid; Nanotechnology; Oncology; Oncolysis; Oncolytic Virotherapy; Oncolytic Viruses - genetics; Oncolytic Viruses - immunology; Oncolytic Viruses - physiology; original-article; Patients; Peritoneal Neoplasms - drug therapy; Peritoneum; Phenotypes; Physiological aspects; Poxvirus; Replication; Sodium succinate; Tacrolimus; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Tumor cells; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumors; Vaccinia virus; Vaccinia virus - genetics; Vaccinia virus - immunology; Vaccinia virus - physiology; Virus Replication - drug effects; Viruses; Xenograft Model Antitumor Assays; United States; immunosuppression; carrier cells; vaccinia virus; pre-immunized host; tumor-associated macrophages; Chordopoxvirinae; Orthopoxvirus; Virus; Vaccinia virus; Immunosuppression; Poxviridae; Tumor; Carrier; Gene therapy; Macrophage
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2010.104

Pre-existing antipoxvirus immunity in cancer patients presents a severe barrier to poxvirus-mediated oncolytic virotherapy. We have explored strategies of immunosuppression (IS) and/or immune evasion for efficient delivery of an oncolytic double-deleted vaccinia virus (vvDD) to tumors in the pre-immunized mice. Transient IS using immunosuppressive drugs, including tacrolimus, mycophenolate mofetil and methylprednisolone sodium succinate, have been used successfully in organ transplantation. This drug cocktail alone did not enhance viral recovery from subcutaneous tumor after systemic viral delivery. Using B-cell knockout mice, we confirmed that the neutralizing antibodies had a significant role in preventing poxvirus infection. Using a MC38 peritoneal carcinomatosis model, we found that the combination of IS and tumor cells as carriers led to the most effective viral delivery, viral replication and viral spread inside the tumor mass. We found that our immunosuppressive drug cocktail facilitated recruitment of tumor-associated macrophages and conversion into an immunosuppressive M2 phenotype (interleukin (IL)-10
hi
/IL-12
low
) in the tumor microenvironment. A combination of IS and carrier cells led to significantly prolonged survival in the tumor model. These results showed the feasibility of treating pre-vaccinated patients with peritoneal carcinomatosis using an oncolytic poxvirus and a combined immune intervention strategy.