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ORIGINAL ARTICLE
Year : 2017  |  Volume : 3  |  Issue : 4  |  Page : 122-132

A T-cell engager-armed oncolytic vaccinia virus to target the tumor stroma


1 Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX, USA
2 Center for Cell and Gene Therapy, Texas Children’s Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX; Texas Children’s Cancer Center, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA

Correspondence Address:
Xiao-Tong Song
Center for Cell and Gene Therapy, Baylor College of Medicine, 1102 Bates Street, Suite 1770, Houston, TX  77030-2316
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_13_17

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Aim: Cancer-associated fibroblasts (CAFs) are the key cellular components of the tumor stroma. CAFs express fibroblast activation protein (FAP) and FAP-targeted immunotherapies have shown potent antitumor effects in preclinical mouse studies, highlighting their central role in tumorigenesis. However, safety concerns have been raised in regard to FAP-targeted immunotherapies since bone marrow failure and cachexia were observed in transgenic models and preclinical studies. Here, we describe a novel oncolytic virotherapy by locally targeting FAP within tumor tissue. Methods: T-cell engager-armed oncolytic vaccinia virus (TEA-VV) that encodes a secretory bi-specific T-cell engager consisting of two single-chain variable fragments specific for murine CD3 and fibroblast activation protein (mFAP-TEA-VV) was generated. The antitumor effects of mFAP-TEA-VV were compared to unmodified VVs using standard in vitro immunological assays and an immunocompetent B16 melanoma mouse model. Results: In vitro, the ability of mFAP-TEA-VV to replicate within tumor cells and induce oncolysis was similar to that of unmodified VVs. However, in co-culture assays, only mFAP-TEA-VV induced bystander killing of noninfected FAP-expressing cells in the presence of murine T-cells. In vivo, mFAP-TEA-VV enhanced viral titer within the tumor and had potent antitumor activity in comparison to control VVs in an immunocompetent B16 melanoma mouse model. Importantly, the improved viral spread of mFAP-TEA-VV correlated with the destruction of tumor stroma. Conclusion: Arming oncolytic VVs with an FAP-targeted T-cell engager may be a promising improvement to oncolytic virus therapy for solid tumors.


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