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Using Genetically Modified Microvascular Free Flaps to Deliver Local Cancer Immunotherapy with Minimal Systemic Toxicity

Dempsey, Marlese P. A.F.R.C.S.I.; Hamou, Cynthia M.D.; V, Joseph Michaels M.D.; Ghali, Shadi M.R.S.C.; Jazayeri, Leila B.S., B.A.; Grogan, Raymon H. M.D.; Gurtner, Geoffrey C. M.D.

Plastic and Reconstructive Surgery: May 2008 - Volume 121 - Issue 5 - p 1541-1553
doi: 10.1097/PRS.0b013e31816ff6aa
EXPERIMENTAL: ORIGINAL ARTICLES
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Background: Clinical use of cancer gene therapy has been prevented by the inability to deliver high levels of local transgene expression with acceptable host toxicity. The authors’ laboratory has developed an ex vivo technique to genetically modify free flaps to deliver immunotherapy locally without systemic toxicity.

Methods: Superficial inferior epigastric flaps were dissected in Fischer rats, perfused with a viral vector expressing the antitumor interleukin-12 (IL-12) for 1 hour, and re-anastomosed. Beneath the flaps was a bolus of 1 × 106 beta-human chorionic gonadotropin–secreting MADB-106 tumor cells. Tumor growth was monitored using beta-human chorionic gonadotropin levels (secreted by the tumor) and size. IL-12 expression in tissue was assessed by enzyme-linked immunosorbent assay. Tumor inflammatory infiltrate was assessed using immunohistologic staining (CD8 and CD161) and enzyme-linked immunosorbent assay (interferon-γ). Serum levels of liver enzymes and histologic analysis were used to assess systemic toxicity.

Results: IL-12 expression was confirmed in the flap and surrounding tissue. The rate of tumor growth in the IL-12–treated group was significantly suppressed compared with the control group (p < 0.001). Liver enzyme levels remained normal, and histological evaluation of the liver, lung, and spleen revealed no evidence of inflammation in the treated group.

Conclusions: Using genetically modified free flaps, the authors were able to deliver IL-12 directly into the local environment of a tumor and suppress its growth without eliciting toxic systemic effects. This technique could provide valuable adjuvant treatment after oncologic surgery for soft-tissue cancers, with the transduced flap reconstructing the defect and supplying a therapeutic agent to the resected tumor bed.

Stanford, Calif.

From the Department of Surgery, Division of Plastic Surgery, Stanford University School of Medicine.

Received for publication September 25, 2007; accepted January 7, 2008.

The first three authors contributed equally to this work.

Presented at the 2006 Plastic Surgery Research Council meeting, in Dana Point, California, May 17 through 20, 2006.

Geoffrey C. Gurtner, M.D.; Department of Surgery; Division of Plastic Surgery; 257 Campus Drive, GK-201; Stanford, Calif. 94305-5148; ggurtner@stanford.edu

Disclosure:None of the authors has a financial interest in any of the products, drugs, or devices described in the article.

©2008American Society of Plastic Surgeons