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

Abstract

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.

Strategies for Gene Transfer to Vascularized Composite Allografts

“…This group coined the term "biologic brachytherapy" to describe the localized delivery of a biologically active molecule using gene transduction of a graft. They were able to demonstrate the ability of the antimicrobial peptide to decrease bacterial loads, and even more exciting from the transplant perspective, they were able to decrease breast cancer growth rates by expressing IL-12 and increasing the inflammatory environment [61]. Presumably, if gene therapy can be used to express pro-inflammatory cytokines, it should be possible to do the reverse by expressing inhibitory cytokines.…”

“…It is through the recognition of donor MHC class I or MHC class II peptides by recipient immune cells, the recipient immune system will initiate a "major" immune response in an effort to prevent donor immune cells from commencing an immune response against native recipient tissues, commonly seen in graft-versus-host disease (GVHD) [4,6,61,62]. Understanding how immune response element kinetics command and propagate a variety of reactions to the presence of alloantigen within the system and how certain successive on/off rejection pathway switches coordinate either rejection or tolerance provides those advocating for gene therapy with initial targets of interest.…”

Cellular and Molecular Bioengineering: A Tipping Point

“…CMBE studies have demonstrated that free flaps (explanted vascular beds) represent a microcosm of the circulatory system, which can be harnessed as the scaffold for tissue engineering purposes [30]. Free flaps can be sustained ex vivo in a bioreactor and seeded with stem cells or engineered to express proteins in a targeted fashion [30-32]. Furthermore, the potential uses of free flaps are not restricted only to restoring form and function, but can also be used as a vector for targeted delivery of gene therapy [33].…”

Adenovirally Delivered Enzyme Prodrug Therapy with Herpes Simplex Virus–Thymidine Kinase in Composite Tissue Free Flaps Shows Therapeutic Efficacy in Rat Models of Glioma

“…Ex vivo gene therapy in free flaps has been described previously (9)(10)(11)(12) and a variety of gene therapy strategies may be applied to deliver targeted cancer therapies to microscopic residual disease at the tumour bed (12). We have previously shown that the intra-vascular administration of viral vectors into flaps achieves greater transfection efficiencies than nonviral and percutaneous modalities of delivery (13), although topical viral administration has been successful in other contexts (14)(15)(16).…”

“…We have previously shown that the intra-vascular administration of viral vectors into flaps achieves greater transfection efficiencies than nonviral and percutaneous modalities of delivery (13), although topical viral administration has been successful in other contexts (14)(15)(16). Free flap-mediated immunostimulatory approaches (10) to eradicate microscopic residual disease have previously been described, for example, through the over-expression of interleukin-12 (IL-12) (17)(18)(19)(20)(21)(22) and have shown retardation of tumour growth by therapeutic flaps. In this study, we chose to investigate the utility of an alternative gene therapy strategy to treat residual disease: virally delivered enzyme/prodrug therapy (VDEPT).…”