BIOLOGICAL EFFECTS OF RHIL-12

RHIL-12 的生物学效应

• 批准号: 2770000
• 负责人: JAMES W MIER
• 金额: $ 16.61万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-22 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2770000
• 关键词: T lymphocyte; apoptosis; biological signal transduction; clinical research; clinical trial phase I; cytokine receptors; drug screening /evaluation; enzyme activity; human subject; interferon gamma; interleukin 12; mitogen activated protein kinase; neoplasm /cancer immunotherapy; polymerase chain reaction; receptor expression; recombinant proteins; tumor necrosis factor alpha

The studies proposed in this application will explore several issues pertinent to the use of recombinant Interleukin-12 (rhIL-12) in patients with advanced cancer. One of the specific objectives is to clarify the mechanism by which a prior injection of rhIL-12 appears to desensitize patients to the toxic effects of this cytokine. The studies relating to this goal include Scatchard analyses to assess IL-12 receptor expression and measurements of MAPK activity induced in vitro with IL-12 to assess the integrity of signaling pathways downstream of the IL-12 receptor. Several proposed studies deal with various membrane-associated TNF family members such as the fas ligand and CD4O- L which are likely to be expressed on certain T cell populations in response to the administration of rhIL-12. The biological effects of these molecules, either on the cell surface or shed into the plasma, overlap substantially with those of TNF and it is possible that they may play a role in the tumor regression or toxicity induced by rhIL-12 treatment. IL-12 is a potent inducer of IFN-gamma synthesis. One of our proposed studies involves a detailed analysis by RT-PCR of the cytokine genes expressed by TIL isolated from patients receiving rhlL-I 2. Finally, several of our studies are focused on the effects of IL-I 2 administration on activation-induced apoptosis in T cells. This is one of the mechanisms by which the CD4+ T cells population is progressively diminished in patients infected with HIV and may also affect the viability of certain lymphoid cells within tumor infiltrates. IL-I 2 has been reported to inhibit activation- or fas-mediated apoptosis in vitro and one of the goals of this application is to see if this effect is demonstrable in vivo.

本应用程序中提出的研究将探讨几个问题 与使用重组白介素12（RHIL-12）有关 晚期癌症患者。具体目标之一是 阐明先前注射Rhil-12的机制 使患者脱敏该细胞因子的毒性作用。研究 与此目标有关的包括SCATCHARD分析以评估IL-12 受体表达和MAPK活性诱导的体外的测量值 使用IL-12评估下游信号通路的完整性 IL-12受体。一些拟议的研究涉及各种 膜相关的TNF家族成员，例如FAS配体和CD4O- L可能在某些T细胞群体中表达 对rhil-12的给药的反应。生物学作用 这些分子，在细胞表面或脱落到血浆中， 与TNF的基本重叠，他们可能有可能 可能在RHIL-12引起的肿瘤回归或毒性中起作用 治疗。 IL-12是IFN-gamma合成的有效诱导剂。我们的一个 提出的研究涉及细胞因子的RT-PCR进行详细分析 由从接受Rhll-I 2的患者分离的TIL表达的基因。 最后，我们的一些研究集中于IL-I 2的影响 激活诱导的T细胞凋亡。这是一个 CD4+ T细胞种群逐渐逐渐的机制 感染HIV的患者的减少，也可能影响 肿瘤浸润中某些淋巴样细胞的生存能力。 IL-I 2 据报道抑制激活或FAS介导的细胞凋亡 体外和此应用程序的目标之一是查看这种效果是否存在 在体内可证明。

项目成果

Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-gamma induction is associated with clinical response.

• 发表时间: 2000-05
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: J. Gollob;J. Mier;K. Veenstra;D. McDermott;D. Clancy;M. Clancy;M. Atkins