Scientific Publications by FDA Staff

J Transl Med 2010 Nov 10;8:116

Interleukin-13 receptor alpha2 DNA prime boost vaccine induces tumor immunity in murine tumor models.

Nakashima H, Fujisawa T, Husain SR, Puri RK

BACKGROUND: DNA vaccines represent an attractive approach for cancer treatment by inducing active T cell and B cell immune responses to tumor antigens. Previous studies have shown that interleukin-13 receptor a2 chain (IL-13Ra2), a tumor-associated antigen is a promising target for cancer immunotherapy as high levels of IL-13Ra2 are expressed on a variety of human tumors. To enhance the effectiveness of DNA vaccine, we used extracellular domain of IL-13Ra2 (ECDa2) as a protein-boost against murine tumor models. METHODS: We have developed murine models of tumors naturally expressing IL-13Ra2 (MCA304 sarcoma, 4T1 breast carcinoma) and D5 melanoma tumors transfected with human IL-13Ra2 in syngeneic mice and examined the antitumor activity of DNA vaccine expressing IL-13Ra2 gene with or without ECDa2 protein mixed with CpG and IFA adjuvants as a boost vaccine. RESULTS: Mice receiving IL-13Ra2 DNA vaccine boosted with ECDa2 protein were superior in exhibiting inhibition of tumor growth, compared to mice receiving DNA vaccine alone, in both prophylactic and therapeutic vaccine settings. In addition, prime-boost vaccination significantly prolonged the survival of mice compared to DNA vaccine alone. Furthermore, ECDa2 booster vaccination increased IFN-¿ production and CTL activity against tumor expressing IL-13Ra2. The immunohistochemical analysis showed the infiltration of CD4 and CD8 positive T cells and IFN-¿-induced chemokines (CXCL9 and CXCL10) in regressing tumors of immunized mice. Finally, the prime boost strategy was able to reduce immunosuppressive CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in the spleen and tumor of vaccinated mice. CONCLUSION: These results suggest that immunization with IL-13Ra2 DNA vaccine followed by ECDa2 boost mixed with CpG and IFA adjuvants inhibits tumor growth in T cell dependent manner. Thus our results show an enhancement of efficacy of IL-13Ra2 DNA vaccine with ECDa2 protein boost and offers an exciting approach in the development of new DNA vaccine targeting IL-13Ra2 for cancer immunotherapy.