Vaccinia virus armed with IL-21 can cure murine colorectal cancer liver metastases via intravenous administration.

[BACKGROUND] Liver metastases of colorectal cancer are one of the leading causes of mortality in patients with colorectal cancer. Oncolytic virus immunotherapy has demonstrated significant potential in tumor treatment; however, most oncolytic viruses are currently administered via intratumoral injection, limiting their broader clinical application.

[METHODS] In this study, we used an oncolytic vaccinia virus VVLΔTK-STCΔN1L-mIL21 expressing interleukin-21 to treat a male BALB/c murine model of colorectal cancer liver metastases (CRLM) via intravenous administration. This approach aimed to explore the feasibility of oncolytic viruses reaching distant tumors through systemic delivery and exerting therapeutic effects, thereby broadening the application scope of oncolytic viruses. We examined the effects of intravenous vaccinia virus treatment on the survival of mice with colorectal cancer liver metastases. Furthermore, we performed comprehensive analyses of the impacts of vaccinia virus therapy on T lymphocytes in these mice using flow cytometry, in vitro interferon (IFN)-γ release assays, and RNA sequencing.

[RESULTS] Our findings revealed that VVLΔTK-STCΔN1L-mIL21, when administered intravenously, successfully reached liver tumor foci and persisted for an extended period, significantly prolonging the survival of mice with CRLM. Further analysis showed that VVLΔTK-STCΔN1L-mIL21 treatment promoted the expansion of CD8 T cells and effector memory T cells (CD8CD44CD62L T) while reducing regulatory T cells. It also enhanced the secretion of IFN-γ by splenic CD45 lymphocytes in vitro, inhibited the expression of immune checkpoint molecules and effector molecules on CD8 T cells, and promoted the generation of T follicular helper cells.

[CONCLUSIONS] VVLΔTK-STCΔN1L-mIL21 can effectively reach liver metastases via tail vein injection and exert potent antitumor effects, significantly extending the survival of mice.