Abstract
Pexa-Vec (pexastimogene devacirpvec; JX-594) has emerged as an attractive tool in oncolytic virotherapy. Pexa-Vec demonstrates oncolytic and immunotherapeutic mechanisms of action. But the determinants of resistance to Pexa-Vec are mostly unknown. We treated hemoatologic malignant cells with Pexa-Vec and examined the gene-expression pattern of sensitive and resistant cells. Human myeloid malignant cell lines (RPMI-8226, IM-9, K562, THP-1) and lymphoid cancer cell lines (MOLT4, CCRF-CEM, Ramos, U937) were treated with Pexa-Vec. Pexa-Vec was cytotoxic on myeloid cell lines in a dose-dependent manner, and fluorescent imaging and qPCR revealed that Pexa-Vec expression was low in RAMOS than IM-9 after 24 hrs and 48 hrs of infection. Gene expression profiles between two groups were analyzed by microarray. Genes with at least 2-fold increase or decrease in their expression were identified. A total of 660 genes were up-regulated and 776 genes were down-regulated in lymphoid cancer cell lines. The up- and down-regulated genes were categorized into 319 functional gene clusters. We identified the top 10 up-regulated genes in lymphoid cells. Among them three human genes (LEF1, STAMBPL1, and SLFN11) strongly correlated with viral replication. Up-regulation of PVRIG, LPP, CECR1, Arhgef6, IRX3, IGFBP2, CD1d were related to resistant to Pexa-Vec. In conclusion, lymphoid malignant cells are resistant to Pexa-Vec and displayed up-regulated genes associated with resistance to oncolytic viral therapy. These data provide potential targets to overcome resistance, and suggest that molecular assays may be useful in selecting patients for further clinical trials with Pexa-Vec.
Highlights
Oncolytic viruses (OVs) mediate tumor regression through selective replication in, and lysis of, tumor cells and induction of systemic anti-tumor immunity without damage to normal cells [1]
The cytotoxic effect of vaccinia virus on the myeloid leukemia cell lines was increased in a dosedependent manner for both viruses, with THP-1 cells more sensitive to NYCBH strain than Pexa-Vec (Figure 1)
Unlike other myeloid cell lines www.impactjournals.com/oncotarget examined, the viability of NYCBH infected THP-1 was significantly decreased compare to Pexa-Vec because Pexa-Vec was genetically attenuated virus by disrupting thymidine kinase region of the wild type virus
Summary
Oncolytic viruses (OVs) mediate tumor regression through selective replication in, and lysis of, tumor cells and induction of systemic anti-tumor immunity without damage to normal cells [1]. Natural or genetically engineered viruses are being investigated for the treatment of solid tumors. There was far less attention on hematologic malignancies, may be due to the disseminated nature of leukemia in contrast to discrete masses of solid tumor, inferring that leukemia is less suitable as a target of OVs [3]. Pexastimogene devacirepvec (Pexa-Vec; JX-594) is a cancer specific and transgene inserted oncolytic and www.impactjournals.com/oncotarget immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony-stimulating factor (GM-CSF) and β-galactosidase. Pexa-Vec has multiple mechanisms of action to destroy and eliminate cancer cells [4]. We have demonstrated that Pexa-Vec induces polyclonal antibody-mediated complement-dependent cytotoxicity (CDC) against various malignant cells both in rabbits and in cancer patients [5]. Pexa-Vec has induced objective responses in previous phase 1 or 2 clinical trials [6, 7]. No studies have used Pexa-Vec to treat hematologic malignancies
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