Abstract
Background: 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. Methods: A fully virulent, tumor-targeted oncolytic Herpes simplex 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. Results: 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 (STING)-dependent pathway was engineered, to optimize viral yields. Conclusions: 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.
Highlights
Over the last two decades, the deep molecular characterization of tumors led to the development of targeted therapeutics for individualized approaches in cancer therapy
In the effort to generate an oncolytic Herpes simplex Virus 1 retargeted to mesothelinexpressing cells, we searched scientific literature for characterized antibody fragments, useful to retarget HSV-1 virus to human MSLN, by selecting the most appropriate protein epitope for viral entry; the insertion site for the scFvs was selected into a well characterized viral glycoprotein D deletion, which was proven to be effective for HER2 retargeting [7,17,18]
In this study we developed novel HSV-1 based oncolytic viruses targeting mesothelin, a tumor associated antigen (TAA) frequently expressed in triple-negative breast cancer, as well as in additional neoplasms, including the orphan disease mesothelioma
Summary
Over the last two decades, the deep molecular characterization of tumors led to the development of targeted therapeutics for individualized approaches in cancer therapy. A potential drawback of targeted therapy is the acquired resistance that relies on cancer evolution and immunoediting that drive the loss of target expression under the selective pressure of the treatment To overcome this limitation, a stronger contribution of the immune system is desirable, to elicit antitumor immunity against the targeted TAA and an epitope spreading to different tumor antigens and neoantigens. Methods: A fully virulent, tumor-targeted oncolytic Herpes simplex virus-1 (MSLN-THV) with a selectivity for mesothelin-expressing cancer cells was generated. Results: 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. Conclusions: 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
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