PHASE 1 TRIAL OF BRYOSTATIN AND INTERLEUKIN-2

一般的假设是，药理学操纵的 细胞免疫应答可能是成功的抗癌治疗策略。 初步数据表明，苔藓抑素I的治疗组合 （bryo）和白细胞介素-2（IL-2）以适当的时间表和剂量， 其上级优于单独的任何一种药物，并代表有效的治疗。主 一种机制假说认为， 苔藓抑素可增强IL-2的T细胞相关治疗作用。初步 数据表明苔藓抑素调节的剂量反应关系 IL-2相关的治疗作用是双相的， 基本上低于苔藓抑素的最大耐受剂量。申请人 还提出了一个临床Ia/Ib期试验，以确定，在此基础上， 免疫激活的中间标志物，苔藓抑素+IL-2剂量组合 适合第二阶段调查。苔藓抑素正在由CTEP开发， NCI申请人已获得本研究的批准意向书，并且 已收到对议定书草案的评论意见。这些问题将在 研究设计和方法。假设本研究成功完成， 未来的方向将包括（1）苔藓抑素+IL-2在肾移植中的II期试验 细胞癌和黑色素瘤，以及（2）进一步开发药理学 免疫治疗通过添加其他免疫活性剂， 苔藓抑素+IL-2组合。

The general hypothesis is that pharmacological manipulation of the cellular immune response may be a successful anticancer therapeutic strategy. Preliminary data suggest that the therapeutic combination of bryostatin I (bryo) and interleukin-2 (IL-2) in an appropriate schedule and dose may be superior to either agent alone and represent an effective therapy. The primary mechanistic hypothesis is that pharmacological activation of T cells by bryostatin can enhance T cell-related therapeutic effects of IL-2. Preliminary data suggest that the dose response relationship for bryostatin modulation of IL-2-related therapeutic effects is biphasic such that optimal bryostatin doses are substantially less than maximum tolerated bryostatin doses. The applicants also propose a clinical phase Ia/Ib trial to identify, on the basis of intermediate markers of immune activation, a bryostatin+IL-2 dose combination appropriate for phase II investigation. Bryostatin is being developed by CTEP, NCI. The applicants have an approved Letter of Intent for this study, and comments upon a draft protocol have been received. These are discussed under Research Design and Methods. Presuming successful completion of this study, future directions would include (1) phase II trials of bryostatin+IL-2 in renal cell carcinoma and melanoma, and (2) further development of pharmacological immunotherapy through the addition of other immune active agents to the bryostatin+IL-2 combination.