Enhanced antitumor efficacy of a novel oncolytic vaccinia virus encoding a fully monoclonal antibody against T-cell immunoglobulin and ITIM domain (TIGIT)

Abstract

Background Oncolytic virotherapy with vaccinia virus (VV) can lead to effective anti-tumor immunity by turning “cold” tumors into “hot” tumors. However, its therapeutic potential is affected by the tumor's local immunosuppressive tumor microenvironment (TME). Therefore, it is necessary to explore the use of immune checkpoint inhibitors to arm oncolytic VVs to enhance their anti-tumor efficacy. Methods A novel recombinant oncolytic VV, VV-α-TIGIT, which encoded a fully monoclonal antibody against T-cell immunoglobulin and ITIM domain (TIGIT) was generated by homologous recombination with a shuttle plasmid. The anti-tumor efficacy of the VV-α-TIGIT was investigated in several subcutaneous and ascites tumor models. Findings The functional α-TIGIT was sufficiently produced and secreted by tumor cells infected with VV-α-TIGIT, which effectively replicated in tumor cells leading to significant oncolysis. Intratumoral injection of VV-α-TIGIT improved anti-tumor efficacy in several murine subcutaneous tumor models compared to VV-Control (without α-TIGIT insertion). Intraperitoneal injection of VV-α-TIGIT achieved approximately 70% of complete tumor regression in an ascites tumor model. At the same time, treatment with VV-α-TIGIT significantly increased the recruitment and activation of T cells in TME. Moreover, the in vivo anti-tumor activity of VV-α-TIGIT was largely dependent on CD8 + T cell-mediated immunity. Finally, the tumor-bearing mice cured of VV-α-TIGIT treatment resisted rechallenge with the same tumor cells, suggesting a long-term persistence of tumor-specific immunological memory. Interpretation The recombinant oncolytic virus VV-α-TIGIT successfully combines the advantages of oncolytic virotherapy and intratumorally expression of immune checkpoint inhibitor against TIGIT. This novel strategy can provide information on the optimal design of novel antibody-armed oncolytic viruses for cancer immunotherapy. Funding This work was supported by the National Natural Science Foundation of China (81773255, 81472820, and 81700037), the Science and Technology Innovation Foundation of Nanjing University (14913414), and the Natural Science Foundation of Jiangsu Province of China (BK20171098).

Viro-antibody therapy: engineering oncolytic viruses for genetic delivery of diverse antibody-based biotherapeutics

“… 106 Furthermore, OVs encoding an anti-murine PD-1, CTLA-4 or TIGIT antibody enabled tumor growth inhibition and survival superior to parental virus and for the PD-1 virus similar to combined parental virus with repeated high dose systemic mAb. 103 , 105 , 117 Similar results were obtained for an oncolytic HSV-2 encoding an anti-human PD-1 antibody in a mouse model with humanized PD-1. 92 …”

“…These studies included a model antibody to demonstrate proof-of-principle, 117 an experimental therapeutic antibody targeting the tumor vascular antigen fibronectin extradomain B, 121 IgGs with specificity for tumor targets (CD147), 122 or targets of approved mAbs (CTLA-4, PD-1, VEGF), 92 , 103 , 106 , 111 and the approved antibody trastuzumab. 108 Overall, the reports established that the genetic delivery of full-length IgGs is feasible for both RNA viruses, as reported for NDV 121 , 122 and influenza A, 117 and for DNA viruses, reported for Ad, 106–108 , 111 VV, 103 , 105 and HSV. 92 Strategies for the required co-expression of IgG heavy and light chains were the insertion of two separate transcription units for NDV and VV, fusion to two viral ORFs of different gene segments using viral 2A sequences for influenza A virus or co-expression via an IRES or a 2A sequence for Ads.…”

Kickstarting Immunity in Cold Tumours: Localised Tumour Therapy Combinations With Immune Checkpoint Blockade

“…Treatment stimulated a CD8 T cell-mediated anti-tumour response with evidence of immune memory and protection from re-challenge. High levels of anti-TIGIT mAb were seen in tumour tissue, but not in blood from treated mice ( 66 ). A TK-gene deleted oVV expressing anti-PD-1 and an anti-4-1BB co-stimulatory receptor agonist was also shown to suppress tumour growth in mouse models of liver and pancreatic cancer ( 67 ).…”

Strategies to Optimise Oncolytic Viral Therapies: The Role of Natural Killer Cells

“…Arming HSV with secreted chimeric molecules to induce innate immune cell killing of infected tumours has also been explored [ 79 ]. In contrast, as NK cells were shown to augment oncolytic vaccinia virus activities [ 4 ], engineering expression of a monoclonal antibody against TIGIT was able to enhance preclinical effectiveness [ 80 ]. Similarly, an adenovirus expressing fusion protein PD-1/CD137L demonstrated anti-tumoural response in murine hepatocellular carcinoma [ 81 ].…”