Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus-1 with Integrin beta1 Blocking Antibody OS2966.

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Lee TJ, Nair M, Banasavadi-Siddegowda Y, Liu J, Nallanagulagari T, Jaime-Ramirez AC, Guo JY, Quadri H, Zhang J, Bockhorst KH, Aghi MK, Carbonell WS, Kaur B, Yoo JY

Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus-1 with Integrin beta1 Blocking Antibody OS2966.

Mol Cancer Ther. 2019 Jun;18(6):1127-1136. doi: 10.1158/1535-7163.MCT-18-0953. Epub 2019 Mar 29.

PubMed ID
30926634 [ View in PubMed
]
Abstract

Integrin beta1 receptor, expressed on the surface of tumor cells and macrophages in the tumor microenvironment (TME), has been implicated in both tumor progression and resistance to multiple modalities of therapy. OS2966 is the first clinical-ready humanized monoclonal antibody to block integrin beta1 and was recently orphan designated by the FDA Office of Orphan Products Development. Here, we tested therapeutic potential of OS2966-mediated integrin beta1 blockade to enhance the efficacy of oncolytic herpes simplex virus-1 (oHSV) through evaluation of virus replication, tumor cell killing efficiency, effect on the antiviral signaling pathway, co-culture assays of oHSV-infected cells with macrophages, and in vivo bioluminescence imaging on mammary fat pad triple-negative breast cancer xenograft and subcutaneous and intracranial glioma xenografts. OS2966 treatment decreased interferon signaling and proinflammatory cytokine induction in oHSV-treated tumor cells and inhibited migration of macrophages, resulting in enhanced oHSV replication and cytotoxicity. OS2966 treatment also significantly enhanced oHSV replication and oHSV-mediated antitumor efficacy in orthotopic xenograft models, including triple-negative breast cancer and glioblastoma. The results demonstrated the synergistic potential of the combinatory treatment approach with OS2966 to improve antitumor efficacy of conventional oHSV therapy.

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