Inflammation, apoptosis, and necrosis induced by neoadjuvant fas ligand gene therapy improves survival of dogs with spontaneous bone cancer

Jaime F. Modiano, Donald Bellgrau, Gary R. Cutter, Susan E. Lana, Nicole P. Ehrhart, Ej Ehrhart, Vicki L. Wilke, J. Brad Charles, Sibyl Munson, Milcah C. Scott, John Pozniak, Cathy S. Carlson, Jerome Schaack, Richard C. Duke

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Fas ligand (FasL) gene therapy for cancer has shown promise in rodents; however, its efficacy in higher mammals remains unknown. Here, we used intratumoral FasL gene therapy delivered in an adenovirus vector (Ad-FasL) as neoadjuvant to standard of care in 56 dogs with osteosarcoma. Tumors from treated dogs had greater inflammation, necrosis, apoptosis, and fibrosis at day 10 (amputation) compared to pretreatment biopsies or to tumors from dogs that did not receive Ad-FasL. Survival improvement was apparent in dogs with inflammation or lymphocyte-infiltration scores >1 (in a 3-point scale), as well as in dogs that had apoptosis scores in the top 50th percentile (determined by cleaved caspase-3). Survival was no different than that expected from standard of care alone in dogs with inflammation scores 1 or apoptosis scores in the bottom 50th percentile. Reduced Fas expression by tumor cells was associated with prognostically advantageous inflammation, and this was seen only in dogs that received Ad-FasL. Together, the data suggest that Ad-FasL gene therapy improves survival in a subset of large animals with naturally occurring tumors, and that at least in some tumor types like osteosarcoma, it is most effective when tumor cells fail to express Fas.

Original languageEnglish (US)
Pages (from-to)2234-2243
Number of pages10
JournalMolecular Therapy
Volume20
Issue number12
DOIs
StatePublished - Dec 2012

Bibliographical note

Funding Information:
The authors thank Susan Plaza, Amy Cunkelman, Kelly Carlsten, and Kristen Grunerud (Colorado State University), as well as Marianne Robeck, and Megan Duckett (University of Minnesota) for technical assistance; Stewart Ryan (Colorado State University)for performing many of the injection procedures; Mitzi Lewellen and Kathy Stuebner (University of Minnesota), and Lynda Reed (Colorado State University) for assistance with project coordination; and John Ohlfest (University of Minnesota), Kristin Bloink (Novartis Animal Health), and Stephen Withrow for helpful discussions and critical review of the manuscript. This work was supported in part by grant 1R43 CA119840 from the National Cancer Institute of the National Institutes of Health and by grant CHF 982 from the AKC Canine Health Foundation (to J.F.M., D.B., and R.C.D.). J.F.M., D.B., and R.C.D. are cofounders of ApopLogic Pharmaceuticals, Inc. JFM holds an equity interest in—and serves as a consultant for—ApopLogic Pharmaceuticals, Inc., the developer of Fasaret, a product that was the subject of the research described in this report. These relationships have been reviewed and managed by the University of Minnesota in accordance with its conflict of interest policies. The remaining authors report no conflict of interest.

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