Therapeutic HER2/Neu DNA Vaccine Inhibits Mouse Tumor Naturally Overexpressing Endogenous Neu

Abstract

The therapeutic efficacy of HER2/c-erbB-2/neu DNA immunization on mouse tumor cells expressing exogenous human or rat p185^neu but not on mouse tumor cells naturally expressing mouse p185^neu has been demonstrated. We investigated the feasibility of using N-terminal rat neu DNA immunization on mouse tumor overexpressing endogenous p185^neu and enhancing the therapeutic efficacy of this vaccine by fusion to various cytokine genes, including interleukin-2 (IL-2), interleukin-4 (IL-4), or granulocyte–macrophage colony-stimulating factor. In a therapeutic model, N′-neu-IL-2 DNA vaccine was significantly better than N′-neu DNA vaccine, and N′-neu DNA vaccine was significantly better than control DNA or N′-neu-IL-4 DNA vaccine. The therapeutic efficacy of DNA vaccines was correlated with tumor infiltration of CD8⁺ T cells. Depletion of CD8⁺ T cells completely abolished the therapeutic effects of N′-neu-IL-2 DNA vaccine and N′-neu DNA vaccine. Depletion of CD4⁺ T cells after tumor implantation had no influence on N′-neu-IL-2 DNA vaccine, but enhanced the therapeutic efficacy of N′-neu DNA vaccine. Our results demonstrate that rat N′-neu DNA vaccine has a therapeutic effect on established tumor through the CD8⁺ T-cell-dependent pathway. Depletion of CD4⁺ T cells or fusion to the IL-2 gene can thus further enhance the therapeutic effects of N′-neu DNA immunization on mouse tumor expressing endogenous p185^neu.