Development of new immunogene therapy for refractory leukemia and lymphoma

难治性白血病和淋巴瘤的新型免疫基因疗法的开发

• 批准号: 10470208
• 负责人: TANI Kenzaburo
• 金额: $ 8.26万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470208/
• 关键词: Immunogene therapy; GM-CSF; CD34; Leukemia; Tumor vaccination; SAGE method; WEHI; 3B Cells; Balb; c mouse; WEHI3B細胞; MFGレトロウイルスベクター; 造腫瘍抑制効果; IL-11; MIF; BALB; c

We have treated 3 renal cancer patients using granulocyte macrophage colony stimulating factor (GM-CSF) gene-transduced autologous renal cancer cells as clinical trials. To develop more efficient immunogene therapy for malignacy in future, we have been trying to determine the most powerful effector molecules functioning in rejecting leukemia cells from normal immune mice. Our previous observation demonstrated that GM-CSF transduced WEHI3B, mouse leukemia cells induced strong antitumor immunity in Balb/c mice, on the other hand, wild WEHI3B cells made tumor in Balb/c mice and nude mice. Using SAGE (sequence analysis of gene expression) method, we screened 30,000 mRNA fragments, tag sequences, which speciflically expressed at the sites of WEHI3B cells injected to Balb/c or nude mice as well as WEHI3B/GM-CSF cells injected to Balb/c mice. 9 candidate fragments, which were specifically expressed in WEHI3B cells rejection system, were obtained in this study and precise analysis has been under way to characterize these newly identified genes from the standpoint of immunogene therapy for malignancies.

我们用粒细胞巨噬细胞集落刺激因子（GM-CSF）基因转导的自体肾癌细胞治疗3例肾癌患者作为临床试验。为了在未来开发更有效的恶性肿瘤免疫基因治疗，我们一直在试图确定在正常免疫小鼠中排斥白血病细胞的最强大的效应分子。我们前期的观察表明，GM-CSF转导的WEHI3B，小鼠白血病细胞在Balb/c小鼠体内产生较强的抗肿瘤免疫，而野生WEHI3B细胞在Balb/c小鼠和裸鼠体内产生肿瘤。采用SAGE （sequence analysis of gene expression）方法，我们筛选了3万个mRNA片段和标记序列，这些mRNA片段和标记序列在注射到Balb/c或裸小鼠的WEHI3B细胞以及注射到Balb/c小鼠的WEHI3B/GM-CSF细胞的位点特异表达。本研究获得了在WEHI3B细胞排斥系统中特异性表达的9个候选片段，并从免疫基因治疗恶性肿瘤的角度对这些新发现的基因进行了精确的分析。

项目成果

Ohata,J.,Tani,K.,et al.: "CD4/CD8 double-positive adult T cell leukemia With preceding cytomegaloviral gastroenterocolitis"Int J Hematol.. 69. 1-5 (1999)

Ohata,J.,Tani,K.,et al.：“CD4/CD8 双阳性成人 T 细胞白血病伴有巨细胞病毒性胃肠结肠炎”Int J Hematol.. 69. 1-5 (1999)

Koseki,S.,Tani,K.,et al.: "Factors governing the activity in vivo of ribozymes transcribed by RNA polymerase III."J Virol. 73. 1868-1877 (1999)

Koseki,S.,Tani,K.,et al.：“控制 RNA 聚合酶 III 转录的核酶体内活性的因素。”J Virol。

Hibino,H.,Tani,K.,et al.: "Common Marmoset as a Target Preclinical Primate for Cytokine and Gene Therapy Studies"Blood. 93. 2829-2838 (1999)

Hibino, H., Tani, K., et al.：“普通狨猴作为细胞因子和基因治疗研究的临床前灵长类动物目标”血液。

Tani, K., et al.: "Molecular Biology of Hematopoiesis"Kluwer Academic/Plenum Publishers. 307-319 (1999)

Tani, K. 等人：“造血的分子生物学”Kluwer Academy/Plenum 出版社。

谷 憲三郎: "血液悪性腫瘍に対する遺伝子治療"臨床病理. 793-803 (1999)

Kenzaburo Tani：“血液恶性肿瘤的基因治疗”临床病理学 793-803 (1999)。