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Retargeted and Multi-cytokine-Armed Herpes Virus Is a Potent Cancer Endovaccine for Local and Systemic Anti-tumor Treatment

Authors :
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.
D'Alise, A. M.
Source :
Molecular Therapy: Oncolytics, Vol 19, Iss, Pp 253-264 (2020), Molecular Therapy Oncolytics
Publication Year :
2020
Publisher :
Elsevier, 2020.

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.<br />Graphical Abstract<br />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.

Details

Language :
English
ISSN :
23727705
Volume :
19
Database :
OpenAIRE
Journal :
Molecular Therapy: Oncolytics
Accession number :
edsair.doi.dedup.....33e0ff896c974912e12b86497d6ded08