Clinical Trials with IL12

IL12 的临床试验

• 批准号: 6405901
• 负责人: JAMES W MIER
• 金额: $ 15.3万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-18 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6405901
• 关键词: DNA methylation; JAK kinase; T lymphocyte; clinical trials; enzyme activity; enzyme induction /repression; enzyme linked immunosorbent assay; flow cytometry; genetic promoter element; human subject; human therapy evaluation; interferon gamma; interleukin 12; leukocyte activation /transformation; melanoma; metastasis; monophenol monooxygenase; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; oncoproteins; patient oriented research; phosphoproteins; polymerase chain reaction; renal cell carcinoma

Although prolonged IL-12 treatment has been shown to increase the number of peripheral blood CD8' T cells expressing memory phenotypic markers, the antigenic specificity of these cells has not been examined. One of the objectives of this application is to perform serial ELISPOT and tetramer analyses to determine if systemic IL-12 treatment affects the number or phenotype of circulating CD8+ T cells capable of recognizing defined melanoma peptide antigens in vitro. We have shown that the induction of IFNgamma, a critical determinant of IL-12-induced tumor regression, progressively declines with successive IL-12 injections and the extent of this down modulation correlates negatively with clinical outcome. Although this apparent desensitization to IL-12 is most likely an innate physiologic mechanism designed to restrict the duration and severity of TH 1 immune responses, it may also limit the therapeutic utility of IL-12 as an antitumor agent. The elucidation of the molecular mechanism underlying the failure to sustain IL-12-induced IFNgamma production is therefore a priority and one of the objectives of this application. Preliminary data suggest that this failure cannot be attributed to a disappearance of cells expressing IL-12 receptors or a global loss of STATs in PBL. The studies proposed in this application will evaluate events downstream of receptor engagement such as the ability of IL-12 and other cytokines to induce STAT phosphorylation in vitro in PBL obtained at various time points throughout the course of IL-12 treatment. The studies will also assess the effects of IL- 12 treatment on the expression of inhibitors of cytokine signaling (e.g. the Suppressor of Cytokine Signaling or SOCS family members) and on the regulable members of Janus Kinase (JAK) family. Finally, since the limited production of IFNgamma by TH2 and virus-infected T cells has been shown to be secondary to hypermethylation of the IFNgamma promoter, we propose to evaluate the state of methylation of this promoter in PBL obtained serially throughout the course of IL-12 treatment. Collectively, these studies may provide insights into the regulation of IL-12 responses and offer clues as to how the antitumor activity of this important cytokine might be enhanced.

尽管已显示长期IL-12处理可增加表达记忆表型标记的外周血CD8'T细胞的数量，但尚未检查这些细胞的抗原特异性。该应用的目标之一是执行串行ELISPOT和四聚体分析，以确定全身IL-12处理是否影响能够识别体外循环CD8+ T细胞的数量或表型。我们已经表明，IFNGAMMA的诱导是IL-12诱导的肿瘤回归的关键决定因素，随着IL-12注射的连续注射逐渐下降，并且该下降调节的程度与临床结果负相关。尽管这种对IL-12的明显脱敏很可能是一种先天的生理机制，旨在限制TH 1免疫反应的持续时间和严重性，但它也可能限制IL-12作为抗肿瘤剂的治疗效用。因此，阐明无法维持IL-12诱导的IFNGAMMA产生的分子机制是该应用程序的优先事项，也是该目标的目标之一。初步数据表明，这种失败不能归因于表达IL-12受体的细胞消失或PBL中统计数据的全局丢失。本应用中提出的研究将评估受体参与度下游的事件，例如IL-12和其他细胞因子在整个IL-12治疗过程中在各个时间点获得的PBL诱导Stat磷酸化的能力。研究还将评估IL-12处理对细胞因子信号传导抑制剂（例如细胞因子信号传导或SOCS家族成员的抑制剂）以及对Janus激酶（JAK）家族的可调节成员的影响。最后，由于TH2和病毒感染的T细胞对IFNGAMMA的产生有限，已被证明是IFNGAMMA启动子的高甲基化继发的，因此我们建议在整个IL-12治疗过程中评估该启动子在PBL中的甲基化状态。总的来说，这些研究可能会提供有关调节IL-12反应的见解，并提供有关如何增强这种重要细胞因子抗肿瘤活性的线索。