A Single Intramuscular Injection of AAV-8 Vector Expressing MDA7/IL-24 Efficiently Suppresses Tumor Growth Mediated by Multiple Anti-Cancer Mechanisms In Lymphoma Model Mice.

Abstract 1474

Melanoma differentiation-associated gene-7/interleukin-24 (MDA7/IL-24) selectively induces apoptosis in cancer cells without harming normal cells. It also exerts immunomodulatory and anti-angiogenic effects, as well as potent antitumor bystander effects, making it an ideal candidate for use in a new anticancer gene therapy. To examine the feasibility of adeno-associated virus (AAV) vectors expressing MDA7/IL-24 in systemic cancer gene therapy for lymphoma, we generated an AAV type 8 vector expressing MDA7/IL-24 (AAV-IL24). In vitro studies showed that medium conditioned by AAV-IL24-transduced C2C12 cells induces tumor cell-specific apoptosis against murine lymphoma cell line (A20 cell). To assess the in vivo effects of muscle targeted AAV-mediated systemic delivery of MDA7/IL-24 we established a lymphoma murine model in which the A20 cells expressing luciferase gene was inoculated into the caudal vein of BALB/C. Using this lymphoma murine model, we can detect the tumor growth and metastases by a real-time in vivo imaging analyze system (IVIS). After single injection of AAV-IL24 (1.5×10¹¹ vg/body) into the right quadriceps muscle of the lymphoma model mice, tumor cell growth was monitored by IVIS. ELISA analysis showed high level of IL-24 was detected in plasma of treated mice (263±16 ng/ml). Suppression of tumor growth was observed in AAV-IL24 injected mice compared to control GFP expressing AAV injected mice (1.3×10⁸vs.2.6×10⁸ photon/sec; p<0.05). Survival effect was also detected in AAV-IL24 mice (66±6 vs. 47±5 days; p<0.03). In addition, TUNEL analyses showed significant induction of tumor cell-specific apoptosis within the tumors and suppression of angiogenesis was also detected in AAV-IL24 treated mice. Finally, immune modulating activity of induction of Th1 cytokines (IL-6, TNFα, IFNγ) secretion was observed after AAV-IL24 injection. These results clearly demonstrate that continuous systemic delivery of MDA7/IL-24 can serve as an effective treatment for lymphoma. Thus, AAV type 8 vector-mediated systemic deliverY of MDA7/IL-24 represents a potentially promising new approach to treat lymphoma.