Mitigating late adverse effects in free flaps following radiotherapy: an immunomodulatory gene therapy strategy (360G-Wellcome-200175_Z_15_Z)

Mastectomy and immediate, autologous breast reconstruction, using a free flap, is now standard-of-care in breast cancer. Approximately half of these, high-risk, patients will require adjuvant radiotherapy to the chest wall resulting in irradiation of the free flap. This is detrimental to flaps and leads to late adverse effects (LAEs) within flap tissues resulting in wound breakdown, fat necrosis, fibrosis and distortion. Up to 25% of these patients will require salvage reconstruction and, in extreme cases, a further free flap. The over-arching goal of this proposal is to combine radioprotective gene therapies with microvascular surgical techniques to give cancer patients a more durable reconstruction. Gene therapies can be delivered into flaps using viral vectors, administered ex vivo, during the flaps ischaemic interval. We have identified the CXCL12-CXCR4 axis as an immunological link between radiation damage and LAEs, and in particular fibrosis. This proposal aims to investigate the involvement of the innate immune system in the development of LAEs within irradiated flap tissues. Using a small animal model of free flap irradiation, I aim to manipulate therapeutically the LAE phenotype using a lentivirally-delivered, RNA-interference strategy to silence CXCL12 expression. Finally, this work will evaluate the oncological safety of the proposed therapeutic strategy.