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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Thursday, August 15, 2024
The combination of natural killer T-cell immunotherapy with enhanced oncolytic virotherapy demonstrated increased antitumor immune targeting of lung metastases in triple-negative mammary carcinoma models, according to Brent Johnston, PhD, of Dalhousie University, Halifax, Nova Scotia, Canada, and colleagues. Their findings, which were published in the journal Breast Cancer Research, offer a “promising” strategy for the treatment of metastatic breast cancer.
“Oncolytic vesicular stomatitis virus [VSV] is an attenuated negative-strand RNA virus… engineered with a methionine deletion in its matrix protein,” the investigators explained. “This inhibits the ability of VSV to block nuclear export of interferon (IFN)-beta mRNA and increases its sensitivity to type I interferons, thereby restricting replication to cancer cells, which commonly harbor defects in type I interferon signaling, and limiting off-target effects.”
The investigators conducted several laboratory experiments to examine the therapeutic effect of oncolytic VSV engineered to express either the reovirus-derived fusion-associated small transmembrane protein p14 (VSV-p14) or p15 (VSV-p15) in both primary and metastatic 4T1 triple-negative mammary carcinoma models. Virotherapy was administered alone or in combination with natural killer T-cell activation therapy and alpha-galactosylceramide–loaded dendritic cells.
Compared with control-treated and untreated mice, those injected with VSV-p14 or VSV-p15 alone into the primary tumor exhibited increased immunogenic tumor cell death, attenuated tumor growth, and enhanced immune cell infiltration and activation. Oncolytic VSV-p14 or VSV-p15 plus natural killer T-cell activation therapy was found to reduce metastatic lung burden to undetectable levels in all mice. The combination also appeared to generate immune memory, as evidenced by enhanced in vitro recall responses and impaired tumor growth upon rechallenge.
“Although we did not examine metastatic burden at [the lymph nodes, liver, brain, and bone], we expect our therapy targeted metastatic burden at these locations,” the investigators concluded. “It is also likely that our combined therapeutic approach will be effective in other cancers.”
Disclosure: Dr. Johnston reported no conflicts of interest. For full disclosures of the other study authors, visit breast-cancer-research.biomedcentral.com.
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