Therapeutic Breast Reconstruction Using Gene Therapy-Delivered IFN gamma Immunotherapy

After mastectomy, breast reconstruction is increasingly performed using autologous tissue with the aim of improving quality of life. During this procedure, autologous tissue is excised, relocated, and reattached using microvascular anastomoses at the site of the extirpated breast. The period during which the tissue is ex vivo may allow genetic modification without any systemic exposure to the vector. Could such access permit delivery of therapeutic agents using the tissue flap as a vehicle? Such delivery may be more targeted and oncologically efficient than systemic therapy, and avoid systemic complications. The cytokine IFN gamma has antitumor effects, and systemic toxicity could be circumvented by localized delivery of the IFN gamma gene via gene therapy to autologous tissue used for breast reconstruction, which then releases IFN gamma and exerts antitumor effects. In a rat model of loco-regional recurrence (LRR) with MADB-106-Luc and MAD-MB-231-Luc breast cancer cells, autologous tissue was transduced ex vivo with an adeno-associated viral vector encoding IFN gamma. The "Therapeutic Reconstruction" released IFN gamma at the LRR site and eliminated cancer cells, significantly decreased tumor burden, and increased survival compared with sham reconstruction (P < 0.05). Mechanistically, localized IFN gamma immunotherapy stimulated M1 macrophages to target cancer cells within the regional confines of the modified tumor environment. This concept of "Therapeutic Breast Reconstruction" using ex vivo gene therapy of autologous tissue offers a new application for immunotherapy in breast cancer with a dual therapeutic effect of both reconstructing the ablative defect and delivering local adjuvant immunotherapy.