TY - JOUR
T1 - Enhancing therapeutic efficacy of oncolytic herpes simplex virus-1 with integrin B1 blocking antibody OS2966
AU - Lee, Tae Jin
AU - Nair, Mitra
AU - Banasavadi-Siddegowda, Yeshavanth
AU - Liu, Joseph
AU - Nallanagulagari, Tejaswini
AU - Jaime-Ramirez, Alena Cristina
AU - Guo, Jeffrey Yunhua
AU - Quadri, Haroon
AU - Zhang, Jianying
AU - Bockhorst, Kurt H.
AU - Aghi, Manish K.
AU - Shawn Carbonell, W.
AU - Kaur, Balveen
AU - Yoo, Ji Young
N1 - Funding Information:
This study was supported in part by ACS grant IRG-67-003-50 to J.Y. Yoo; NIH grant P30 DK056338 to T.J. Lee; and NIH grants R01 NS064607, R01 CA150153, and P01CA16320 to B. Kaur. We would like to acknowledge Dr. Joanna O'Leary for critical reading of the manuscript.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - Integrin b1 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 b1 and was recently orphan designated by the FDA Office of Orphan Products Development. Here, we tested therapeutic potential of OS2966-mediated integrin b1 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 proin-flammatory 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.
AB - Integrin b1 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 b1 and was recently orphan designated by the FDA Office of Orphan Products Development. Here, we tested therapeutic potential of OS2966-mediated integrin b1 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 proin-flammatory 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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U2 - 10.1158/1535-7163.MCT-18-0953
DO - 10.1158/1535-7163.MCT-18-0953
M3 - Article
C2 - 30926634
AN - SCOPUS:85067217149
SN - 1535-7163
VL - 18
SP - 1127
EP - 1136
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 6
ER -