Abstract 2406: Increased efficacy of combination of IL-13 receptor-targeted cytotoxin and DNA vaccine in murine tumor models

Abstract

Abstract Recent studies show that interleukin-13 receptor α2 chain (IL-13Rα2) is a tumor-associated antigen that is a promising potential target for immunotherapy. High levels of IL-13Rα2 are expressed on a variety of human tumors, but its precise role in tumor immunology is not known. IL13-PE, a targeted cytotoxin composed of IL-13 fused to mutated form of Pseudomonas exotoxin, induces specific killing of tumor cells expressing abundant levels of IL-13Rα2. In this study, we sought to determine the effect of IL13-PE in combination with DNA vaccination in murine MCA304 sarcoma and 4T1 breast carcinoma, which naturally over-express IL-13Rα2 antigen. Three intramuscular prophylactic IL-13Rα2 DNA immunizations in syngeneic mice (n=6) on −8, −4, and −2 weeks resulted in partial protection (382 mm3) against subcutaneous MCA304 tumor challenge compared to mock vector vaccine (1498 mm3) on day 21. Three additional intratumoral (i.t.) treatments of IL13-PE on day 4, 6 and 8 post-tumor challenge further decreased tumor burden (85 mm3) by 78%, measured on the same day (day 21) compared to DNA vaccination alone. In an established MCA304 tumor model, mice receiving three i.t. injections of IL13-PE (on day 7, 9, and 11) and four subsequent DNA vaccinations (on day 13, 18, 23 and 28) reduced tumor size to 44 mm3 (94% less) compared to DNA vaccination alone (693 mm3) on day 24. For comparison, the untreated control tumors had a size of 1579 mm3 on day 24. Interestingly, the combination therapy with IL13-PE and DNA vaccination produced 50% complete responders; however, tumors in remaining 50% partial responders grew slowly. Combination therapy prolonged the mean survival to 60 days compared to control (24 days) and DNA only vaccinated groups (36 days). Similar results were also observed in the 4T1 murine breast carcinoma model. Combination therapy group showed higher CTL activity and IFN-γ release from splenocytes compared to the single therapy groups in both tumor models. Immunohistochemical analysis showed the infiltration of CD4 and CD8 positive T cells and expression of IFN-γ-induced chemokines (CXCL9 and CXCL10) in tumor tissues of immunized mice. These results suggest that combination therapy with IL13-PE and IL-13Rα2 DNA vaccination inhibited tumor growth in a T cell dependent manner. In addition to the combination therapy strategy, elimination of immunosuppressive elements such as regulatory T cells and myeloid-derived suppressor cells may further enhance tumor immunity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2406.