Generation of a Novel Mesothelin-Targeted Oncolytic Herpes Virus and Implemented Strategies for Manufacturing

HER2-based retargeted viruses are in advanced phases of preclinical development of breast cancer models. Mesothelin (MSLN) is a cell-surface tumor antigen expressed in different subtypes of breast and non-breast cancer. Its recent identification as a marker of some triple-negative breast tumors rend...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-01, Vol.22 (2), p.477
Main Authors: Froechlich, Guendalina, Gentile, Chiara, Infante, Luigia, Caiazza, Carmen, Pagano, Pasqualina, Scatigna, Sarah, Cotugno, Gabriella, D'Alise, Anna Morena, Lahm, Armin, Scarselli, Elisa, Nicosia, Alfredo, Mallardo, Massimo, Sasso, Emanuele, Zambrano, Nicola
Format: Article
Language:English
Subjects:
Antigens
Antiviral agents
Biotechnology
Breast cancer
Cancer therapies
Cell surface
Clinical trials
Cytotoxicity
ErbB-2 protein
Glycoprotein D
Glycoproteins
Herpes simplex
Herpes viruses
Immunotherapy
Interferon
Interleukin 1
Interleukin 12
Ligands
Lymphocytes
Lymphocytes T
malignant mesothelioma
Manufacturing
Medical prognosis
Monoclonal antibodies
MSLN
Nectin
Oncolysis
oncolytic virus
Pathogens
Proteins
Reproductive system
Selectivity
Stimulators
targeted therapy
triple negative breast cancer
Tumors
Viruses
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Summary:HER2-based retargeted viruses are in advanced phases of preclinical development of breast cancer models. Mesothelin (MSLN) is a cell-surface tumor antigen expressed in different subtypes of breast and non-breast cancer. Its recent identification as a marker of some triple-negative breast tumors renders it an attractive target, presently investigated in clinical trials employing antibody drug conjugates and CAR-T cells. The availability of MSLN-retargeted oncolytic viruses may complement the current immunotherapeutic panel of biological drugs against HER2-negative breast and non-breast tumors. A fully virulent, tumor-targeted oncolytic virus-1 (MSLN-THV) with a selectivity for mesothelin-expressing cancer cells was generated. Recombineering technology was used to replace an essential moiety of the viral glycoprotein D with antibody fragments derived from clinically validated MSLN monoclonal antibodies, and to allow IL12 cargo expression in infected cells. Panels of breast and female reproductive system cell lines were used to verify the oncolytic potential of the viral constructs. A platform for production of the retargeted viruses was developed in HEK 293 cells, providing stable expression of a suitable chimeric receptor. We demonstrated the selectivity of viral infection and cytotoxicity by MSLN-retargeted viruses in a panel of mesothelin-positive cancer cells, originating from breast and female reproductive system tumors. We also developed a second-generation oncolytic MSLN-THV, encoding IL12, to enhance the immunotherapeutic potential of the viral backbone. A non-tumor cell line expressing a chimeric MSLN/Nectin-1 receptor, de-sensitized from antiviral responses by genetic inactivation of the Stimulator of Interferon Genes ( )-dependent pathway was engineered, to optimize viral yields. Our proof-of-concept study proposes MSLN-retargeted herpesviruses as potential cancer immunotherapeutics for assessments in preclinical models of MSLN-positive tumors, complementing the available panel of oncolytic viruses to HER2-negative breast tumors.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms22020477