An engineered oncolytic vaccinia virus encoding a single-chain variable fragment against TIGIT induces effective antitumor immunity and synergizes with PD-1 or LAG-3 blockade

Abstract

BackgroundIn addition to directly lysing tumors, oncolytic viruses also induce antitumor immunity by recruiting and activating immune cells in the local tumor microenvironment. However, the activation of the immune cells induced by oncolytic viruses is always accompanied by high-level expression of immune checkpoints in these cells, which may reduce the efficacy of the oncolytic viruses. The aim of this study is to arm the oncolytic vaccinia virus (VV) with immune checkpoint blockade to enhance its antitumor efficacy.MethodsThrough homologous recombination with the parental VV, an engineered VV-scFv-TIGIT was produced, which encodes a single-chain variable fragment (scFv) targeting T-cell immunoglobulin and ITIM domain (TIGIT). The antitumor efficacy of the VV-scFv-TIGIT was explored in several subcutaneous and ascites tumor models. The antitumor efficacy of VV-scFv-TIGIT combined with programmed cell death 1 (PD-1) or lymphocyte-activation gene 3 (LAG-3) blockade was also investigated.ResultsThe VV-scFv-TIGIT effectively replicated in tumor cells and lysed them, and prompt the infected tumor cells to secret the functional scFv-TIGIT. Compared with control VV, intratumoral injection of VV-scFv-TIGIT in several mouse subcutaneous tumor models showed superior antitumor efficacy, accompanied by more T cell infiltration and a higher degree of CD8+ T cells activation. Intraperitoneal injection of VV-scFv-TIGIT in a mouse model of malignant ascites also significantly improved T cell infiltration and CD8+ T cell activation, resulting in more than 90% of the tumor-bearing mice being cured. Furthermore, the antitumor immune response induced by VV-scFv-TIGIT was dependent on CD8+ T cells which mediated a long-term immunological memory and a systemic antitumor immunity against the same tumor. Finally, the additional combination of PD-1 or LAG-3 blockade further enhanced the antitumor efficacy of VV-scFv-TIGIT, increasing the complete response rate of tumor-bearing mice.ConclusionsOncolytic virotherapy using engineered VV-scFv-TIGIT was an effective strategy for cancer immunotherapy. Administration of VV-scFv-TIGIT caused a profound reshaping of the suppressive tumor microenvironment from ‘cold’ to ‘hot’ status. VV-scFv-TIGIT also synergized with PD-1 or LAG-3 blockade to achieve a complete response to tumors with poor response to VV or immune checkpoint blockade monotherapy.

Improvement of the anticancer efficacy of PD-1/PD-L1 blockade via combination therapy and PD-L1 regulation

“…Engineered oncolytic viruses recombinantly expressing monoclonal antibodies against the immunosuppressive molecule TIGIT have been constructed in a previous study. These recombinant oncolytic viruses could turn the “cold” TME to “hot” and induce an effective anti-tumor immune response [ 228 ]. In addition, combination of these viruses with PD-1 inhibitors or LAG-3 inhibitors resulted in better efficacy and caused tumor regression.…”

Oncolytic vaccinia virus expressing a bispecific T-cell engager enhances immune responses in EpCAM positive solid tumors

“…Even so, solitomab, an EpCAM-CD3 BiTE, was still reported to damage healthy EpCAM + tissues in phase I clinical trials ( 36 , 37 ). Therefore, local administration via an oncolytic virus can avoid the side effects of BiTE ( 38 ). In our study, no significant toxicity was observed during the treatment as monitored by mouse body weight.…”

“…As reported, the WR strain is the most tumourolytic VV strain in animal models, and 10 6 pfu of WR strain vaccinia virus can rapidly cause subcutaneous necrotic ulcers in rhesus monkeys with no systemic transmission of the virus ( 40 ). Our laboratory uses the WR strain and enhances the tumor-specific selection of vaccinia virus by deleting the thymidine kinase (TK) gene ( 14 , 38 ). Vaccinia viruses lacking the TK gene have been shown to be injected intravenously or intraperitoneally and are carried into subcutaneous tumors where they replicate and cause an anti-tumor response ( 41 ).…”

Lung cancer and oncolytic virotherapy——enemy's enemy

“…A novel recombinant oncolytic virus VV, VV-α-TIGIT, encoding a fully monoclonal antibody against T cell immunoglobulin and ITIM domain (TIGIT) significantly increased T cell recruitment and activation in the tumor microenvironment [60] . Another engineered oncolytic vaccinia virus, VV-scFv-TIGIT, encoding a single-chain variable fragment (scFv) targeting T-cell immunoglobulin and ITIM domain, induces potent antitumor immunity [61] . Oncolytic viruses expressing antibodies against immune checkpoint domains successfully combine the advantages of OV with an intratumoral expression of ICIs to enhance antitumor efficacy.…”