Abstract
BackgroundDespite 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.ResultsAll 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.ConclusionOur 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.
Highlights
Despite advances in surgical aggressiveness and conventional chemotherapy, ovarian cancer remains the most lethal cause of gynecologic cancer mortality; there is a need for new therapeutic agents and innovative treatment paradigms for the treatment of ovarian cancer
Oncolytic herpes simplex viruses Wild-type herpes simplex virus (HSV) causes potentially life-threatening encephalitis, attenuation is a prerequisite of oncolytic HSV development
Results oncolytic herpes simplex viruses (oHSV) demonstrate broad cytotoxicity against in vitro models of ovarian cancer We evaluated the capacity of several oHSV (R3659, G207, Human interleukin-12 expressing oncolytic herpes simplex virus (M032), and Murine interleukin-12 expressing oncolytic herpes simplex virus (M002)) at various dose concentrations to achieve oncolysis in a variety of mouse and human ovarian cancer cell lines
Summary
Despite advances in surgical aggressiveness and conventional chemotherapy, ovarian cancer remains the most lethal cause of gynecologic cancer mortality; 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 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. Ovarian cancer is an immunogenic disease as demonstrated by the expression of tumor-associated antigens such as mesothelin, CA-125, MUC-1, NY-ESO-1, and HER2/NEU, along with the discovery of antibodies and T-cells isolated from peripheral blood of ovarian cancer patients that react with these antigens [3]. It is our contention that oncolytic HSV that expresses a potent cytokine, Interleukin-12, would accomplish three important intratumoral changes: i) direct tumor cell lysis by the virus, ii) generation of a tumor debris field and increased exposure of tumor-associated antigens to immune effector cells allowing for Matzinger “danger signal” immune activation, and iii) augmentation of TH1-type anti-tumor response to antigen and co-stimulation by intratumoral IL-12 expression (Signal 3) [12,13,14]
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