Cytokine-secreting herpes viral mutants effectively treat tumor in a murine metastatic colorectal liver model by oncolytic and T-cell-dependent mechanisms

Abstract

In this model of hepatic micrometastases, the antitumor efficacy and role of the T-cell and natural killer (NK) cell populations were studied for oncolytic herpes simplex virus type-1 (HSV-1) viral mutants containing the granulocyte-monocyte colony stimulating factor (GM-CSF (NV1034)) or interluken-12 (IL-12 (NV1042)) cytokine genes. These were compared to saline and control virus (NV1023) in vitro and in vivo. HSV-1 mutants were assessed for cytotoxicity, replication and cytokine expression in CT-26 cells. A syngeneic micrometastatic liver model was then established in naive and immune cell-depleted animals to assess the antitumor efficacy of these viruses. In vitro cytotoxicity and viral replication were similar for each virus, resulting in greater than 80 and 98% cytotoxicity at multiplicity of infection of 1 and 10, respectively. Peak viral titers were 25-to 50-fold higher than initial titer and were not significantly different between viruses. In vivo, all three viruses reduced metastases relative to control, but cytokinesecreting viruses did so with greater efficacy compared to NV1023. This effect was abrogated by T-cell depletion, but not NK-cell depletion. Single-agent therapy with oncolytic viral agents containing GM-CSF or IL-12 is effective in a murine model of liver metastases and likely involves direct viral oncolysis and actions of specific immune effector cells.

Oncolytic measles virus encoding interleukin-12 mediates potent antitumor effects through T cell activation

“…26 We have studied measles virus encoding anti-PD-L1 previously. 13 Other oncolytic vectors encoding IL-12, such as vesicular stomatitis virus, 27 adenovirus 28 and herpes virus 29 have been developed, but to our knowledge this is the first report of MeV encoding IL-12 for cancer therapy. We demonstrated that MeVac-encoded immunomodulators are expressed and functional.…”

Advance in herpes simplex viruses for cancer therapy

“…HSV armed with IL-12 showed enhanced oncolytic effects on squamous cell carcinoma. In a murine model of squamous cell carcinoma or micro-metastatic liver disease, NV1042 expressing IL-12 displayed significantly stronger anti-tumor in comparison with its non-IL-12-expressing analog, NV1023 [71][72][73]. Moreover, NV1042 also exhibited more efficacious effects than GM-CSF-expressing NV1034 [74].…”

“…GM-CSF may exert cytotoxic effects on tumor cells by activating T cells. Depletion of T cells inhibited the efficacy of NV1034, and eliminated the statistical difference in antitumor between animals treated with NV1034 and NV1023 [72]. It is reported that high dose of GM-CSF was toxic and brought immuno-suppressive effects [76].…”

Colorectal Cancer Immunotherapy: Current State and Prospects (Review)

“…The administration of a modified NDV expressing IL-2 resulted in tumor growth inhibition up to total regression in most tumor-bearing mice with a grafted CT26 [88]. The same model was used to demonstrate the more effective (compared to a non-modified virus) reduction of liver metastases when animals are infected with herpes simplex virus of type 1 (HSV-1) expressing IL-2 or GM-CSF [89], as well as the enhancement of an anti-tumor immune response in the administration of vesicular stomatitis virus expressing IL-15 [90]. However, it is unknown if there are successful clinical trials on targeted delivery of anticancer cytokines in colorectal carcinoma.…”