In order to study the efficacy of retargeted oncolytic viruses (oHSV-HER2) able to selectively enter in tumor cells expressing the human epidermal growth factor receptor 2 (HER2), the aim of this research was to evaluate the use of immune competent C57BL/6 mice, engineered to be tolerant to the HER2 receptor. This mouse model was used to study the efficacy of two oHSV-HER2, R-LM113 and R-115, that expresses murine interleukin 12 (mIL-12). IL-12 is one of the most important anticancer cytokine able to enhance anticancer immune response. HER2-tyrosine kinase is a receptor overexpressed by some types of cancer cells, including human breast and ovary carcinomas. Only a subset of these tumors respond to the current therapy with HER2 targeted monoclonal antibodies, underlining the need for novel therapeutic approaches. To validate tolerance of HER2 transgenic mice, it was first demonstrated the ability of B16 and LLC1, two murine cancer cell lines (previously transduced to express HER2 and selected in vitro), to allow the development of tumors. We selected LLC1 cells to study the oncolytic and immunomodulatory activity of oHSV-HER2. C57Bl/6-HER2 mice were first injected subcutaneously with LLC1 cells, subsequently they were treated with R-LM113 or R-115. We monitored tumor development and observed that oHSV-HER2 treatment reduced or prevented the development of primary tumor. Treated mice, which have not developed primary tumor, were injected with a second inoculation of LLC1 cells on a distant site (challenge) to assess the development of a long-lasting and systemic immunity. Our study demonstrated that these mice are a reliable model for study HER2 tumors and an ideal system to investigate the activity of oncolytic HSV-1 retargeted to HER2 receptor. In effect, this mouse model is able to develop HER2 tumors and allow to study new targeted therapies in which the immune system has a key role.
Sanapo M., B.C. (2018). Immunocompetent C57BL/6 mouse, engineered to be tolerant to the human HER2 receptor, as a model for the study of retargeted fully-virulent oncolytic Herpes Virus (HSV).
Immunocompetent C57BL/6 mouse, engineered to be tolerant to the human HER2 receptor, as a model for the study of retargeted fully-virulent oncolytic Herpes Virus (HSV)
Sanapo M.;Barboni C.;Campadelli-Fiume MG;Mazza F;Leoni V;Zaghini A
2018
Abstract
In order to study the efficacy of retargeted oncolytic viruses (oHSV-HER2) able to selectively enter in tumor cells expressing the human epidermal growth factor receptor 2 (HER2), the aim of this research was to evaluate the use of immune competent C57BL/6 mice, engineered to be tolerant to the HER2 receptor. This mouse model was used to study the efficacy of two oHSV-HER2, R-LM113 and R-115, that expresses murine interleukin 12 (mIL-12). IL-12 is one of the most important anticancer cytokine able to enhance anticancer immune response. HER2-tyrosine kinase is a receptor overexpressed by some types of cancer cells, including human breast and ovary carcinomas. Only a subset of these tumors respond to the current therapy with HER2 targeted monoclonal antibodies, underlining the need for novel therapeutic approaches. To validate tolerance of HER2 transgenic mice, it was first demonstrated the ability of B16 and LLC1, two murine cancer cell lines (previously transduced to express HER2 and selected in vitro), to allow the development of tumors. We selected LLC1 cells to study the oncolytic and immunomodulatory activity of oHSV-HER2. C57Bl/6-HER2 mice were first injected subcutaneously with LLC1 cells, subsequently they were treated with R-LM113 or R-115. We monitored tumor development and observed that oHSV-HER2 treatment reduced or prevented the development of primary tumor. Treated mice, which have not developed primary tumor, were injected with a second inoculation of LLC1 cells on a distant site (challenge) to assess the development of a long-lasting and systemic immunity. Our study demonstrated that these mice are a reliable model for study HER2 tumors and an ideal system to investigate the activity of oncolytic HSV-1 retargeted to HER2 receptor. In effect, this mouse model is able to develop HER2 tumors and allow to study new targeted therapies in which the immune system has a key role.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
