NCI CLINICAL INVESTIGATOR AWARD

淋巴因子白细胞介素2（IL 2）首先被认为是其 诱导抗原激活的T细胞增殖的能力 或丝裂原来表达IL 2受体。 现已在 通过重组DNA技术，IL 2 具有治疗恶性肿瘤的几种潜在用途 包括：诱导非特异性淋巴因子激活 杀伤细胞（LAK）的细胞毒性;刺激分泌的 - 具有抗肿瘤活性的淋巴因子，例如光毒素， 肿瘤坏死因子和巨噬细胞活化因子;和 增强特异性T细胞介导抗肿瘤作用 免疫力 使用现有的检测方法，大多数 人类肿瘤不能引起可证实特异性宿主免疫 应答 因此，LAK反应性的产生出现 代表了利用反 IL-2的肿瘤潜能。 当以高剂量（LAK诱导）给药时，IL 2可以治愈 患有播散性白血病的小鼠。 同样，在初步审判中， 高剂量IL-2治疗晚期难治性 人类恶性肿瘤已经导致几种肿瘤消退， 例 然而，在小鼠和人类中， IL 2的全部治疗潜力可能受到剂量的限制， 依赖性毒性 目前的提案将探讨战略 以减轻毒性和/或增加治疗功效 从而增强总体“治疗指数”（即， IL 2的功效与毒性的比率）。 该提案的具体目标是：1）确定是否 高剂量IL 2的治疗指数可以通过以下方式增加 同时给予体外活化的LAK细胞或LAK 细胞亚群; 2）确定治疗指数是否 高剂量IL 2可以通过同时给予 长期培养的LAK细胞或LAK细胞亚群;和3） 确定高剂量IL 2的治疗指数是否可以 通过体内消除潜在毒性淋巴细胞增加 子集

The lymphokine Interleukin 2 (IL2) was first recognized for its ability to induce the proliferation of T cells activated by antigen or mitogen to express IL2 receptors. Now available in pharmacologic amounts through recombinant DNA technology, IL2 has several potential uses for the treatment of malignancies including: the induction of non-specific lymphokine activated killer (LAK) cytotoxicity; the stimulation of secretion of lymphokines with anti-neoplastic activity, e.g. lymphotoxin, tumor necrosis factor, and macrophage activating factor(s); and the augmentation of specific T cell mediated anti-tumor immunity. Using currently available methods of detection, most human tumors fail to elicit demonstrable specific host immune responses. Therefore, the generation of LAK reactivity appears to represent the most useful approach for exploiting the anti- tumor potential of IL2 at this time. When administered in high (LAK-inducing) doses, IL2 can cure mice with disseminated leukemia. Similarly, in preliminary trials the use of highdose IL2 for the treatment of advanced refractory human malignancy has resulted in tumor regression in several cases. In both mice and humans, however, the expression of the full therapeutic potential of IL2 may be limited by dose- dependent toxicity. The current proposal will explore strategies to attenuate the toxicity and/or increase the therapeutic efficacy of IL2 and thereby enhance the overall "therapeutic index", (i.e. ratio of efficacy to toxicity of IL2). The specific aims of the proposal are: 1) to determine whether the therapeutic index of high-dose IL2 can be increased by concurrent administration of in vitro activated LAK cells or LAK cell subsets; 2) to determine whether the therapeutic index of high-dose IL2 can be increased by concurrent administration of long-term cultured LAK cells or LAK cell subsets; and 3) to determine whether the therapeutic index of high-dose IL2 can be increased by in vivo elimination of potentially toxic lymphoid subsets.