A T-cell engager-armed oncolytic vaccinia virus to target the tumor stroma
Feng Yu1, Bangxing Hong1, Xiao-Tong Song2
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
Center for Cell and Gene Therapy, Baylor College of Medicine, 1102 Bates Street, Suite 1770, Houston, TX 77030-2316
Source of Support: None, Conflict of Interest: None
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.