Abstract
Fully retargeted oncolytic herpes simplex viruses (o-HSVs) gain cancer-specificity from redirection of tropism to cancer-specific receptors, and are non-attenuated. To overcome the hurdles of systemic delivery, and enable oncolytic viruses (o-viruses) to reach metastatic sites, carrier cells are being exploited. Mesenchymal stromal cells (MSCs) were never tested as carriers of retargeted o-viruses, given their scarse-null expression of the cancer-specific receptors. We report that MSCs from different sources can be forcedly infected with a HER2-retargeted oncolytic HSV. Progeny virus spread from MSCs to cancer cells in vitro and in vivo. We evaluated the organ distribution and therapeutic efficacy in two murine models of metastatic cancers, following a single i.v. injection of infected MSCs. As expected, the highest concentration of carrier-cells and of viral genomes was in the lungs. Viral genomes persisted throughout the body for at least two days. The growth of ovarian cancer lung metastases in nude mice was strongly inhibited, and the majority of treated mice appeared metastasis-free. The treatment significantly inhibited also breast cancer metastases to the brain in NSG mice, and reduced by more than one-half the metastatic burden in the brain.
Highlights
Viruses belonging to different families have been chosen, and, in many cases, genetically modified to generate replicating oncolytic agents that target tumor cells with varying extent of cancer-specificity [1, 2]
Mesenchymal stromal cells (MSCs) cells were derived from human placenta, dental pulp, adipose tissue, bone marrow, as described [41,42,43]
The ones derived from placenta (FM-MSCs) were characterized as MSCs, based on expression of the stromal markers CD90, CD44, CD105, CD73, lack of expression of the CD34 and CD45 hematopoietic markers, as well as of HLA class II (Figure S1 A), and ability to undergo osteogenic, adipogenic, or chondrogenic differentiation upon appropriate treatments (Figure S1 B-E)
Summary
Viruses belonging to different families have been chosen, and, in many cases, genetically modified to generate replicating oncolytic agents that target tumor cells with varying extent of cancer-specificity [1, 2]. The first generation o-HSVs, in clinical trials, are conditional replication deletion or natural mutants Their replication occurs preferentially in subsets of cancer cells which are defective in specific branches of the innate response; their www.impactjournals.com/oncotarget replication in non-cancer cells is counteracted by the host defence. Their drawbacks are the attenuation introduced in order to confer cancer-specificity and for safety reasons, and their non-stringent cancer-specificity. To overcome these limitations, second generation o-HSVs encode the cytokines GM-CSF, or IL12, in order to stimulate the antitumor activity of the immune system of host [10,11,12,13]. In a phase 3 clinical trial, T-VEC led to an improved outcome in patients carrying metastatic melanoma and treated intratumorally [4]
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