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Targeted Interleukin 2 Therapy Enhances Protective Immunity Induced by an Autologous Oral DNA Vaccine against Murine Melanoma¹

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037 [A. G. N., R. X., J. M. R., H. N. L., C. S. D., R. A. R.]; Lexigen Pharmaceuticals Corp., Lexington, Massachusetts 02173 [S. D. G.]; and Charité Children’s Hospital, 13353 Berlin, Germany [H. N. L.]

We demonstrate that a mouse-human chimeric anti-ganglioside GD2-interleukin (IL)-2 fusion protein (ch14.18-IL2) substantially amplifies tumor-protective immunity against murine melanoma induced by an autologous oral DNA vaccine containing the murine ubiquitin gene fused to murine melanoma peptide epitopes gp100_25–35 and TRP-2_181–188. This combination therapy led to the complete rejection of a lethal challenge with B78D14 murine melanoma cells in six of eight mice and a marked suppression of s.c. tumor growth in the two remaining animals. The tumor-protective immunity was mediated by MHC class I antigen- restricted CD8⁺ T cells together with CD4⁺ T cell help, which was required only for tumor cell killing in the effector phase of the immune response. A single oral vaccination with the DNA vaccine, which was carried by attenuated Salmonella typhimurium, was equally as effective as three such vaccinations applied at 2-week intervals. The immunological mechanisms involved in this antitumor effect were suggested by a decisively increased secretion of tumor necrosis factor TNFTnTNa and IFN- from CD4⁺ and CD8⁺ T cells and a markedly up-regulated expression on CD8⁺ T cells of high-affinity IL-2 receptor chain (CD25), costimulatory molecule CD28, and adhesion molecule lymphocyte function-associated antigen-2 (LFA-2/CD2). Additionally, the combination therapy induced increased expression of costimulatory molecules B7.1 and CD48 on murine antigen-presenting cells. Taken together, our results suggest that IL-2 targeted to the tumor microenvironment by a specific antibody-IL-2 fusion protein is a potent enhancer of tumor-protective immunity induced by an oral DNA vaccine that may ultimately enhance the chances of success in its clinical application.

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