Development of novel immunogene therapy for hamatopietic malignancies

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We performed the series of experiments and obtained the following data. 1) Myeloma cells and lymphoma cells were both weakly positive for WT1 expression. However, only myeloma cells appeared to be sensitive to perforin-dependent cytotoxicity mediated by WT1-specific cytotoxic T lymphocytes (CTLs). These data suggest that susceptibility of membranes to perforin is an important factor determining the sensitivity of target cells to CTL-mediated cytotoxicity and that WT1 is an ideal target antigen for cellular immunotherapy of multiple myeloma..2) T-cell receptor (TCR) genes derived from HLA-A24-restricted WT1-specific CTL clone were transduced into CD4+ and CD8+ peripheral blood T lymphocytes. Consequently, TCR gene-transduced T lymphocytes could exert HLA-A24-restricted and WT1 specific reactivity. Thus, TCR gene-modified HLA-class I-restricted Th1 and Tc1 cells are a powerful strategy for the application to adoptive immunotherapy of human cancer. 3) Human hematopietic cells were transferred into new born NOD/SCID/IL2rgamma(null) mice. Human immune system was reconstituted in these mice. Thus, the NOD/SCID/IL2R gamma(null) newborn system might be an important experimental model to study the human hemato-lymphoid system. 4) We identified WT1-derived helper epitope which is recognized by HLA class II-restricted CD4+ CTLs. WT1-specific CD4+ T lymphocytes could directly recognized leukemia cells in an HLA class II-restricted manner. 5) We established CML66-specific and Aurora-A-specific CTL lines. Since these CTLs lysed leukemia cells in HLA-restricted manner, CML66 and Aurora-A appeared to be novel leukemia-associated antigens which are recognized by human CTLs. 6) Cancer peptide vaccination using WT1 peptide and hTERT peptide has been performed. No adverse event was detected, and apparent anti-cancer effect was observed in some patients.