Redirecting effector T cells through their IL-2 receptors

Fusion proteins constructed of a tumor-specific Ab joined to IL-2 (Ab-IL-2) have been used in the past to deliver cytokine directly to the site of tum or cells in vivo. These molecules mimic the activity of IL-2 and assist in activating and expanding antitumor effector cells, To enhance the cytolytic activity of CTL specific for peptide epitopes of the Her-2/neu tumor Ag pr esented by HLA-A*0201 molecules, a fusion protein was constructed consistin g of a single chain Ab specific for Her-2/neu, linked to IL-2 (neu-Ab-IL-2) . When added to a mixture of tumor cells and Her-2/neu-specific CTL, the pr otein was found to augment lysis of tumor cells, Tn addition, the hybrid mo lecule also promoted lysis of Her-2/neu expressing tumors by non-tumor-spec ific cloned T cell lines, including Th1 CD4 cells, Analysis of the mechanis m of cytotoxicity revealed that the fusion protein mediates the formation o f stable conjugates between T cells expressing IL-2R and tumor cells expres sing Her-2/neu, resulting in lysis through the Pas-Fas ligand pathway. Lysi s induction was independent of specific engagement by the TCR, When tested for its ability to enhance tumor cell eradication by Her-2/neu-specific CD8 (+) T cells in an adoptive transfer model in SCI, mice, neu-Ab-IL-2 facilit ated the elimination of tumor cells in vivo. Surprisingly, the combination of non-tumor-specific CD8(+) T cells and fusion protein also induced a sign ificant delay of tumor growth, This represents a novel approach for redirec ting non-tumor-specific T cells to eliminate tumors.