Anti-Her-2/neu-IL-2 or heregulin-IL-2 fusions proteins redirect non-tumor specific CTL to the tumor site for tumor eradication

IL-2 is a T-cell growth factor that has pleiotropic functions on T cells, assisting in activating and expanding immune responses. Interestingly, we have previously found that in the presence of IL-2, CD4⁺ or CD8⁺ T cells kill tumor cells in an antigen-independent and non-MHC-restricted manner. In this study we took advantage of IL-2 capabilities to induce in this way the killing of tumor cells for immunotherpeutic purposes. We describe a novel mechanism where it is possible to bypass the usage of tumor-specific T cells for adoptive transfer by using non-tumor-specific T cells in combination with an anti-Her-2/neu-IL-2 (neu-Ab-IL-2) or heregulin-IL-2 fusion protein for tumor eradication. T cells in the presence of fusion proteins are capable of inducing the lysis of tumor cells in a non-MHC-restricted manner. This lysis is only observed in T cells that have been stimulated through the TCR, and it is mediated through the Fas-FasL pathway. Moreover, transfer of non-tumor-specific T cells in combination with the fusion proteins, induced the eradication of established Her-2, Her-3, and Her-4 expressing tumor cells in SCID mice. In contrast, the combination of non-tumor-specific T cells plus rIL-2 or irrelevant Ab-IL-2 (anti-hemagglutinin-IL-2) does not induce the elimination of tumors, indicating that the antitumor activity is dictated by the specificity of the fusion protein. These data demonstrate that neu-Ab-IL-2 or heregulin-IL-2 fusion proteins can direct the non-tumor-specific T cells to the tumor site and induce the elimination of tumors. Therefore, combination of non-tumor-specific T cells and antibody/ligand-IL-2 fusion proteins provides an alternative therapeutic strategy to control tumor growth in vivo.