Cytokine gene therapy for brain tumors using neural progenitor cells

使用神经祖细胞治疗脑肿瘤的细胞因子基因疗法

• 批准号: 13671422
• 负责人: IWADATE Yasuo
• 金额: $ 1.98万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671422/
• 关键词: Glioma; Cytokine; immune gene therapy; neural progenitor cell; Interleukin-2; Brain Neoplasm; Gene Therapy; Antitamor Immunity; Neural Progenitor Cell; IL-2; IL-4; GM-CSF

Cytokine gene therapy for the central nervous system tumors has proven to have significant potential, but it needs improvement in the process of antigen presentation and/or in insufficient recruitment of immunocompetent cells to achieve successful eradication of established brain tumors. We investigated the therapeutic potential of induced systemic immunity in peripheral tissues combined with the production of various cytokines in the vicinity of brain tumors to treat established brain tumors. Sequential magneti resonance image (MRI) monitoring showed that the combinatory therapy consisting of intracerebral (i.c.) transplantation of IL-2-producing syngeneic or xenogeneic cells and subcutaneous (s.c.) vaccination using irradiated 9L or 9L/IL-2 cells could cured 9L-bearing rats, whereas either the i.c. injection of IL-2-producers or the s.c. vaccination alone produced little or marginal anti-tumor effects, respectively. Other cytokines such as IL-4, IL-12, or GM-CSF could not induce sign … More ificant therapeutic effects against the established brain tumors. Glioma-specific CTL activity was equivalently induced in the rats vaccinated s.c. with irradiated 9L, irradiated IL-2-producing 9L cells or the mixed population of irradiated 9L and C1300/IL-2 cells, while the activity was relatively lower in the rats vaccinated with irradiated 9L cells mixed with either C1300/IL-4 or C1300/GM-CSF cells. In the rats immunized s.c. with irradiated 9L cells, i.c. 9L tumors implanted together with either C1300/IL-2 or C1300/IL-4 were completely rejected. Pre-established brain tumor also could be eliminated by the s.c. immunization of irradiated 9L cells and i.c. transplantation of IL-2-producers. Immunohistochemical analysis revealed that a number of CD4^+ and CD8^+ T cells infiltrated into the brain tumors which were treated with the combinatory therapy. The level of cell infiltration was similar to that found in s.c. 9L/IL-2 tumors which were subsequently rejected. These results suggest that glioma-specific CTLs could be effectively induced by s.c. immunization of irradiated wild-type tumor cells without artificial cytokine production. The combinatory strategy, i.c. grafting of IL-2-producing cells and s.c. immunization of irradiated whole tumor cell vaccine, is thus effective for recruiting activated T cells into the brain tumor site and could be a potential therapy for brain tumors. Less

细胞因子基因治疗中枢神经系统肿瘤已被证明具有显着的潜力，但它需要在抗原呈递和/或免疫活性细胞的募集不足的过程中进行改进，以实现成功根除已建立的脑肿瘤。我们研究了在外周组织中诱导的全身免疫结合在脑肿瘤附近产生各种细胞因子来治疗已建立的脑肿瘤的治疗潜力。磁共振成像（MRI）监测显示，脑内（i.c.）产生IL-2的同系或异种细胞的移植和皮下（s.c.）用辐照的9 L或9 L/IL-2细胞接种可治愈9 L荷瘤大鼠，而i.c.注射IL-2生产者或s.c.单独的疫苗接种分别产生很小或边缘的抗肿瘤作用。其他细胞因子如IL-4、IL-12或GM-CSF不能诱导体征， ...更多信息 对已建立的脑肿瘤有显著的治疗效果。胶质瘤特异性CTL活性在皮下接种的大鼠中同样诱导。照射9 L细胞、照射IL-2产生细胞、照射9 L细胞与C1300/IL-2细胞的混合群免疫大鼠，而照射9 L细胞与C1300/IL-4或C1300/GM-CSF细胞的混合群免疫大鼠的活性相对较低。在s.c.免疫的大鼠中，用辐照的9 L细胞，i.c.与C1300/IL-2或C1300/IL-4一起植入的9 L肿瘤被完全排斥。预先建立的脑肿瘤也可以通过皮下注射消除。照射的9 L细胞的免疫和i.c. IL-2生产者的移植。免疫组化结果显示，联合治疗组肿瘤内有大量CD 4 ^+和CD 8 ^+ T细胞浸润。细胞浸润水平与s.c. 9 L/IL-2肿瘤，随后被排斥。这些结果表明，胶质瘤特异性CTL可以有效地通过s.c.在没有人工细胞因子产生的情况下，对辐照的野生型肿瘤细胞进行免疫。组合策略，即。IL-2产生细胞的移植和s.c.因此，经照射的全肿瘤细胞疫苗的免疫对于将活化的T细胞募集到脑肿瘤部位是有效的，并且可能是脑肿瘤的潜在疗法。少

项目成果

Hiroki Nanba, Yasuo Iwadate, et al.: "Efficacy of the bystander effect in the horpes sinplex rirus thymidine binase-mediated gene therapy is…"Cancer Gene Therapy. 8. 414-420 (2001)

Hiroki Nanb​​a、Yasuo Iwadate 等人：“Horpes sinplex rirus 胸苷双酶介导的基因治疗中旁观者效应的功效是……”癌症基因治疗。

Iwadate, et al.: "Interleukin12-mediated induction of systemic immunity in the periphery and recruitment of activated T cells into the brain …"International Journal of Molecular Medicine. 10. 741-747 (2002)

Iwadate 等人：“白细胞介素 12 介导的外周系统免疫诱导以及将活化的 T 细胞招募到大脑中……”国际分子医学杂志 10. 741-747 (2002)。

Iwadate Y, et al.: "Induction of immunity in peripheral tissues combined with intracerebral transplantation of interleukin-2-producing cells eliminates established brain tumors"Cancer Research. 61. 8769-8774 (2001)

Iwadate Y 等人：“诱导外周组织免疫结合脑内移植白细胞介素 2 生成细胞可消除已形成的脑肿瘤”癌症研究。

Iwadate Y, Namba H, Sakiyama S, Yamaura A, Tagawa M: "Interleukin-12-mediated induction of systemic immunity in the periphery and recruitment of activated T cells into the brain produce limited antitumor effects compared with interleukin-2"Int J Mol Med.

Iwadate Y、Namba H、Sakiyama S、Yamaura A、Takawa M：“与白细胞介素 2 相比，白细胞介素 12 介导的外周系统免疫诱导以及将活化的 T 细胞招募到大脑中产生有限的抗肿瘤作用”Int J Mol

Namba H, Iwadate Y, Kawamura K, Sakiyama S, Tagawa M: "Efficacy of the bystander effect in the herpes simplex virus thymidine kinase-mediated gene therapy is influenced by the expression of connexin43 in the target cells"Cancer Gene Ther. 8. 414-420 (2001

Namba H、Iwadate Y、Kawamura K、Sakiyama S、Takawa M：“单纯疱疹病毒胸苷激酶介导的基因治疗中旁观者效应的功效受到靶细胞中连接蛋白 43 表达的影响”Cancer Gene Ther。