Vesicular stomatitis virus (VSV) is being developed for cancer therapy. We created a recombinant replicating VSV (rrVSV) that preferentially infected Her2/neu expressing breast cancer cells. We now used this rrVSV to treat macroscopic peritoneal tumor implants of a mouse mammary tumor cell line stably transfected to express Her2/neu. rrVSV therapy alone prolonged survival but did not cure any animals. rrVSV therapy combined with antibody to TGFb or antibody to IL-10 receptor (IL-10R) each produced cure in one of six animals. Strikingly, rrVSV therapy combined with anti-CTLA4 monoclonal antibody (MAb) produced cure in four of five animals. Anti-CTLA4 MAb was only effective when administered within one day of rrVSV therapy. Cure required CD4 T-cells early (o7 days) and late (47 days) after rrVSV therapy whereas CD8 T-cells were required only late (47 days) after rrVSV therapy. Surviving animals were resistant to re-challenge with D2F2/E2 suggesting a memory immune response. Histopathologic analysis demonstrated a dense inflammatory infiltrate of tumor nodules within days of therapy and foamy histiocytes replacing the tumor nodules 2 weeks following therapy. These studies demonstrate that targeted rrVSV combined with anti-CTLA4 MAb can eliminate established macroscopic tumor implants by eliciting an anti-tumor CD4 and CD8 T-cell immunologic response.

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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.

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