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.
Lustgarten
Joseph
J
Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121, USA. jlustgarten@skcc.org
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control; D020890:Neuregulin-1 / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
D000911:Antibodies, Monoclonal; D053222:Fas Ligand Protein; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; C505661:FASLG protein, human; C505658:Fasl protein, mouse