NCI CLINICAL INVESTIGATOR AWARD

淋巴因子白细胞介素2(IL2)首次被发现是因为它的 诱导抗原激活的T细胞增殖的能力 或有丝分裂原表达IL2受体。现已在 重组DNA技术的药理剂量，IL2 在治疗恶性肿瘤方面有几个潜在的用途 包括：诱导非特异性淋巴因子激活 杀伤(LAK)细胞毒性；刺激分泌 具有抗肿瘤活性的淋巴因子，如淋巴毒素， 肿瘤坏死因子和巨噬细胞激活因子(S)；以及 特异性T细胞介导的抗肿瘤效应的增强 豁免权。使用目前可用的检测方法，大多数 人类肿瘤未能激发明显的特异性宿主免疫 回应。因此，LAK反应性的产生就出现了 来代表最有用的方法来利用反 此时IL-2的肿瘤潜能。 当给予高剂量(LAK诱导)时，IL2可以治愈 患有播散性白血病的小鼠。同样，在初步试验中 大剂量白介素2治疗晚期难治性白血病 人类的恶性肿瘤在几个方面导致了肿瘤的退化 案子。然而，无论是在小鼠还是在人类身上， IL2的全部治疗潜力可能会受到剂量的限制- 依赖毒性。目前的提案将探索战略 减轻毒性和/或提高治疗效果 从而提高整体的“治疗指数”(即 白介素2的有效毒性比)。 该提案的具体目的是：1)确定是否 大剂量白介素2治疗指数可通过 体外激活的LAK细胞或LAK的同时给药 细胞亚群；2)确定治疗指数是否 大剂量IL2可通过同时给药而增加 长期培养的LAK细胞或LAK细胞亚群； 确定大剂量白介素2的治疗指数能否 通过体内消除潜在的有毒淋巴而增加 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.