Treatment of implanted mammary tumors with recombinant vesicular stomatitis virus targeted to Her2/neu

Abstract

Vesicular stomatitis virus (VSV) is being developed for cancer therapy. We have created a recombinant replicating VSV (rrVSV) that targeted to Her2/neu expressing breast cancer cells and expresses mouse GM‐CSF. We now tested the efficacy of this rrVSV in the treatment of peritoneal tumor implants of D2F2/E2 cells, a BALB/c mouse mammary tumor cell line, which was stably transfected to express Her2/neu. Mice were treated 1 day following tumor implantation with either 2 × 108 infectious doses rrVSV or conditioned media (CM). All control animals developed massive peritoneal tumor with a median survival of 16 days. Nine of 10 rrVSV treated mice survived long term with no evidence of tumor. rrVSV had much less efficacy in treating implants of the parent D2F2 cells that did not express Her2/neu. The median survival was 13.5 days in mice treated with CM and 21 days in those treated with rrVSV. There was one long term survivor in the rrVSV treated group. None of the rrVSV treated animals showed evidence of viral toxicity. Three of 7 long term survivors did not develop tumor when rechallenged first with D2F2/E2 and then with D2F2 cells. Both successful therapy and resistance to rechallenge were T‐cell dependent. These studies demonstrate that targeted rrVSV eliminated peritoneal implants of Her2/neu expressing tumor and elicited an anti‐tumor T‐cell immunologic response. © 2007 Wiley‐Liss, Inc.

Vesiculovirus Neutralization by Natural IgM and Complement

“…The high sensitivity of VSV to innate interferon responses and its lack of pathogenicity to humans have made it an attractive oncolytic platform that has been extensively investigated and has been shown to kill cancer cells selectively, particularly when they have a disrupted interferon response (28)(29)(30)(31)(32)(33)(34). Preclinical studies show that VSV is promising for the treatment of a variety of human cancers (10,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). However, efficient intravenous delivery will be critical for its successful clinical application.…”

“…VSV is a Vesiculovirus of the family Rhabdoviridae with a negative-sense RNA genome (16,17). VSV is a preferred candidate as a platform for oncolytic virus development against a variety of cancers (10,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), primarily due to its very broad tropism infecting a wide variety of animals and different cells, its short replication cycle, and high sensitivity to host interferon-mediated antiviral activity (28)(29)(30)(31)(32)(33)(34)(35). Tumor-selective tropism can be further enhanced by mutating the M protein or engineering the virus to encode beta interferon (IFN-␤).…”

Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells

“…Also, the majority of patients who initially respond to trastuzumab become resistant within 1 year of treatment initiation (18). Although there is a pressing need for novel therapeutic approaches, so far, few efforts were undertaken to generate HER-2-specific oncolytic viruses or lytic immune cells (19,39). Such viruses share their target with small molecule inhibitors (SMI) and, particularly, mAbs.…”

“…However, only a subset responds to current targeted therapy, mainly because of alterations in HER-2 signaling pathway; thus, illustrating the pressing need for novel therapeutic approaches against this tumor target (18). Despite its clinical relevance, few efforts were made so far to generate HER-2 specific oncolytic viruses (19,20).…”

Evaluation of an Attenuated Vesicular Stomatitis Virus Vector Expressing Interferon-β for Use in Malignant Pleural Mesothelioma: Heterogeneity in Interferon Responsiveness Defines Potential Efficacy

“…VSV replicates more efficiently in tumor cells compared with normal ''nontransformed'' cells, which is attributable to flaws in cancer cells' innate immune responses involving the IFN system, tumor-related defects in translational regulation, and abnormal signaling pathways in cancer cells that support viral replication (Balachandran and Barber, 2000;Stojdl et al, 2000;Balachandran et al, 2001). VSV has shown significant promise in a variety of preclinical tumor models, such as melanoma, squamous cell cancer, ovarian cancer, colorectal carcinoma, prostate cancer, breast cancer, rhabdoid tumors, leukemia, hepatocellular carcinoma, and glioblastoma (Ebert et al, , 2005Huang et al, 2003;Stojdl et al, 2003;Ahmed et al, 2004;Shinozaki et al, 2004;Lun et al, 2006;Bergman et al, 2007;Diaz et al, 2007;Sung et al, 2008;Wu et al, 2008).…”