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In Situ Therapeutic Cancer Vaccination with an Oncolytic Virus Expressing Membrane-Tethered IL-2.

ABSTRACT: Successful in situ therapeutic vaccination would allow locally delivered oncolytic virus (OV) to exert systemic immunologic effects on metastases and improve survival. We have utilized bilateral flank tumor models to determine the most efficacious regimens of in situ vaccination. Intratumoral injection with membrane-tethered interleukin -2-armed OV (vvDD-mIL2) plus a Toll-like receptor 9 ligand (CpG) yielded systemic immunization and decreased tumor growth in a contralateral, noninjected tumor. Our main aims were to study the tumor immune microenvironment (TME) after vaccination and identify additional immune adjuvants that may improve the systemic tumor-specific immunity. Immunological profiles in the spleen showed an increased CD8+ T cell/regulatory T cell (Treg) ratio and increased CD11c+ cells after dual injection in one flank tumor. Concurrently, there was increased infiltration of tumor necrosis factor alpha (TNF-?)+CD8+ T cells and interferon gamma (IFN-?)+CD4+ T cells and reduced CTLA-4+PD-1+CD8+ T cells in the contralateral, noninjected tumor. The anti-tumoral activity depended on CD8+ T cells and IFN-?, but not CD4+ T cells. Based on the negative immune components still existing in the untreated tumors, we investigated additional adjuvants: clodronate liposome-mediated depletion of macrophages plus anti-PD-1 therapy. This regimen dramatically reduced the tumor burden in the noninjected tumor and increased median survival by 87%, suggesting that inhibition/elimination of suppressive components in the tumor microenvironment (TME) can improve therapeutic outcomes. This study emphasizes the importance of immune profiling to design rational, combined immunotherapy regimens ultimately to impact patient survival.

SUBMITTER: Liu W

PROVIDER: S-EPMC7210382 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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In Situ Therapeutic Cancer Vaccination with an Oncolytic Virus Expressing Membrane-Tethered IL-2.

Liu Weilin W Dai Enyong E Liu Zuqiang Z Ma Congrong C Guo Zong Sheng ZS Bartlett David L DL

Molecular therapy oncolytics 20200421

Successful in situ therapeutic vaccination would allow locally delivered oncolytic virus (OV) to exert systemic immunologic effects on metastases and improve survival. We have utilized bilateral flank tumor models to determine the most efficacious regimens of in situ vaccination. Intratumoral injection with membrane-tethered interleukin -2-armed OV (vvDD-mIL2) plus a Toll-like receptor 9 ligand (CpG) yielded systemic immunization and decreased tumor growth in a contralateral, nonin ...[more]

PMID: 32405533

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Project description:BACKGROUND:Despite advances in surgical aggressiveness and conventional chemotherapy, ovarian cancer remains the most lethal cause of gynecologic cancer mortality; consequently there is a need for new therapeutic agents and innovative treatment paradigms for the treatment of ovarian cancer. Several studies have demonstrated that ovarian cancer is an immunogenic disease and immunotherapy represents a promising and novel approach that has not been completely evaluated in ovarian cancer. Our objective was to evaluate the anti-tumor activity of an oncolytic herpes simplex virus "armed" with murine interleukin-12 and its ability to elicit tumor-specific immune responses. We evaluated the ability of interleukin-12-expressing and control oncolytic herpes simplex virus to kill murine and human ovarian cancer cell lines in vitro. We also administered interleukin-12-expressing oncolytic herpes simplex virus to the peritoneal cavity of mice that had developed spontaneous, metastatic ovarian cancer and determined overall survival and tumor burden at 95 days. We used flow cytometry to quantify the tumor antigen-specific CD8+ T cell response in the omentum and peritoneal cavity. RESULTS:All ovarian cancer cell lines demonstrated susceptibility to oncolytic herpes simplex virus in vitro. Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus demonstrated a more robust tumor antigen-specific CD8+ T-cell immune response in the omentum (471.6 cells vs 33.1 cells; p?=?0.02) and peritoneal cavity (962.3 cells vs 179.5 cells; p?=?0.05). Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus were more likely to control ovarian cancer metastases (81.2 % vs 18.2 %; p?=?0.008) and had a significantly longer overall survival (p?=?0.02). Finally, five of 6 mice treated with interleukin-12-expressing oHSV had no evidence of metastatic tumor when euthanized at 6 months, compared to two of 4 mice treated with sterile phosphate buffer solution. CONCLUSION:Our pilot study demonstrates that an interleukin-12-expressing oncolytic herpes simplex virus effectively kills both murine and human ovarian cancer cell lines and promotes tumor antigen-specific CD8+ T-cell responses in the peritoneal cavity and omentum, leading to reduced peritoneal metastasis and improved survival in a mouse model.

Dataset Information

In Situ Therapeutic Cancer Vaccination with an Oncolytic Virus Expressing Membrane-Tethered IL-2.

Publications

<i>In Situ</i> Therapeutic Cancer Vaccination with an Oncolytic Virus Expressing Membrane-Tethered IL-2.

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