Novel immunogene therapy for hematopoietic malignancies

我们进行了免疫基因治疗造血恶性肿瘤的研究。从这一系列的研究中得到的数据如下。1)骨髓瘤细胞对wt1特异性细胞毒性T淋巴细胞（ctl）介导的穿孔依赖性细胞毒性敏感。2) CD4^+和CD8^+ ctl对穿孔素表达的控制存在差异；也就是说，穿孔素在记忆性CD8^+ ctl中组成性表达，但依赖于记忆性CD4^+ ctl中的细胞活化。3)从hla - a24受限的WT1肽特异性CTL克隆中获得的T细胞受体(TCR) α和β基因被慢病毒转导到多克隆活化的T淋巴细胞上。TCR基因转导的CD4+和CD8+ T淋巴细胞对白血病细胞表现出hla - a24限制性和wt1特异性反应性。4)鉴定出hla - dp5限制性CD4+ t细胞克隆识别的wt1源性表位。wt1特异性CD4+ t细胞克隆对白血病细胞具有穿孔依赖的细胞毒性。5)使用wt1衍生肽和htert衍生肽的癌症肽疫苗的I期临床研究仍在继续。6)通过移植人造血干细胞在新型免疫缺陷小鼠体内构建人免疫系统。

We performed studies on immunogene therapy for hematopoietic malignanicies. The data obtained from the series of study are as follows. 1) Myeloma cells are sensitive to perforin-dependent cytotoxicity mediated by WT1-specifici cytotoxic T lymphocytes (CTLs). 2)There is a difference in the control of perforin expression between CD4^+ and CD8^+ CTLs ; that is, perforin is expressed constitutively in memory CD8^+ CTLs, but is dependent on cell activation in memory CD4^+ CTLs. 3)T-cell receptor (TCR) α and β genes obtained from an HLA-A24-restricted, WT1 peptide-specific CTL clone were lentivirally transduced to polyclonally-activated T lymphocytes. TCR gene-transduced CD4+ and CD8+ T lymphocytes showed HLA-A24-restricted and WT1-specific reactivity against leukemia cells. 4)The WT1-derived epitope recognized by HLA-DP5-restricted CD4+ T-cell clone was identified. WT1-specific CD4+ T-cell clone exerted the perforin-dependent cytotoxicity against leukemia cells. 5)Phase I clinical study of cancer peptide vaccine using WT1-derived and hTERT-derived peptides has been continued. 6) Human immune system was constructed in the novel immundeficient mice by transplantation of human hematopoietic stem cells.