APPLICATION OF GENETICALLY ENGINEERED TUMOR-SPECIFIC TH1 CELLS TO ADOPTIVE TUMOR IMMUNOTHERAPY

Abstract

CD4+ Th cells, in particular IFN-γ-producing Th1 cells, play a critical role in the activation and maintenance of CD8+ Tc1 cells that are essential for tumor eradication. Recent identification of MHC class II binding peptides derived from tumor antigens theoretically made possible to tumor-specific CD4+ T cells in addition to CD8+ T cells induced by MHC class I binding tumor antigen peptides. However, the generation of tumor-specific T cells is still a practically challenging and time-consuming procedure. This fact makes difficult the application of tumor-specific T cells to adoptive immunotherapy of cancer patients. Recently, novel methods have been developed to prepare tumor-specific T cells from nonspecifically activated T cells by gene transfer. Specifically, two types of genes were shown to be successful when they were introduced into nonspecific-T cells to generate genetically engineered tumor-specific T cells. One is the TCR α and β chain genes obtained from tumor-specific T cells, and the other is the chimeric immunoglobulin-T cell receptor (cIgTCR) gene which contains a single chain variable fragment from antitumor monoclonal antibody. In this review, we overviewed these methods briefly, and showed our recent results generating genetically engineered tumor-specific Th1 cells successfully by both these methods. In both mouse and human systems, non-specifically activated Th1 cells transduced with TCR genes specific for tumor antigen-derived peptide showed potent antitumor activity against tumor cells when they recognized tumor antigen peptide presented on MHC molecules. On the other hand, Th1 cells transduced with a cIgTCR gene specific for carcinoembryonic antigen, CEA, were shown to be reactive with cell surface CEA in an MHC independent manner. Taken together, these results strongly suggest that it is possible to prepare tumor-specific human Th1 cells by gene transfer technique that is applicable to adoptive tumor immunotherapy for cancer patients.