1. Retargeted and Multi-cytokine-Armed Herpes Virus Is a Potent Cancer Endovaccine for Local and Systemic Anti-tumor Treatment
- Author
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Gabriella Campadelli-Fiume, Gabriella Cotugno, Irene Garzia, Alfredo Nicosia, Maria De Lucia, Francesca Langone, Emanuele Sasso, Guendalina Froechlich, Chiara Gentile, Biljana Petrovic, Anna Morena D'Alise, Nicola Zambrano, Simona Pepe, Veronica Bignone, Elisa Scarselli, Linda Nocchi, De Lucia, M., Cotugno, G., Bignone, V., Garzia, I., Nocchi, L., Langone, F., Petrovic, B., Sasso, E., Pepe, S., Froechlich, G., Gentile, C., Zambrano, N., Campadelli-Fiume, G., Nicosia, A., Scarselli, E., and D'Alise, A. M.
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,medicine.disease_cause ,lcsh:RC254-282 ,Virus ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,medicine ,cytokine ,cancer ,Pharmacology (medical) ,immune checkpoint ,retargeted Herpes virus ,oncolytic virus ,Tumor microenvironment ,business.industry ,GM-CSF ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immune checkpoint ,cytokines ,Oncolytic virus ,030104 developmental biology ,Herpes simplex virus ,Oncology ,oncolytic viru ,IL-12 ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Original Article ,business ,endovaccine - Abstract
Oncolytic viruses (OVs) are novel anti-tumor agents with the ability to selectively infect and kill tumor cells while sparing normal tissue. Beyond tumor cytolysis, OVs are capable of priming an anti-tumor immune response via lysis and cross-presentation of locally expressed endogenous tumor antigens, acting as an “endovaccine.” The effectiveness of OVs, similar to other immunotherapies, can be hampered by an immunosuppressive tumor microenvironment. In this study, we modified a previously generated oncolytic herpes simplex virus (oHSV) retargeted to the human HER2 (hHER2) tumor molecule and encoding murine interleukin-12 (mIL-12), by insertion of a second immunomodulatory molecule, murine granulocyte-macrophage colony-stimulating factor (mGM-CSF), to maximize therapeutic efficacy. We assessed the efficacy of this double-armed virus (R-123) compared to singly expressing GM-CSF and IL-12 oHSVs in tumor-bearing mice. While monotherapies were poorly effective, combination with α-PD1 enhanced the anti-tumor response, with the highest efficacy of 100% response rate achieved by the combination of R-123 and α-PD1. Efficacy was T cell-dependent, and the induced immunity was long lasting and able to reject a second contralateral tumor. Importantly, systemic delivery of R-123 combined with α-PD1 was effective in inhibiting the development of tumor metastasis. As such, this approach could have a significant therapeutic impact paving the way for further development of this platform in cancer immunotherapy., Graphical Abstract, Fully virulent tumor retargeted HSV oncolytic viruses (THVs) are novel immunotherapeutic agents with increased specificity, safety, and potency. De Lucia et al. propose the use of a hHER2 THV expressing IL-12 and GM-CSF as a strategy to potentiate anti-tumor efficacy in combination with anti-PD1, opening future perspectives for local and systemic treatment.
- Published
- 2020