Kedar E, Ben-Aziz R, Shiloni E
Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Isr J Med Sci. 1988 Sep-Oct;24(9-10):494-504.
Adoptive immunotherapy with LAK-cells in conjunction with high-dose IL-2 has recently been introduced in the treatment of patients with advanced cancer. This therapeutic modality has thus far proved to be of limited efficacy, severe toxicity and entails complicated logistics. Our present study is aimed at establishing a model system to test for increasing efficacy and reducing toxicity by using AIT cojointly with chemotherapy. Mice implanted i.v. or i.p. with weakly immunogenic tumors (M109 lung carcinoma, MCA-105 sarcoma) were treated 7 to 20 days after tumor inoculation with or without CTX, with and without recombinant human IL-2, and with and without syngeneic/allogeneic LAK-cells. Whereas IL-2 or IL-2 + LAK-cells without CTX was largely ineffective, and CTX alone cured 0 to 20% of the animals with an i.p. tumor and only slightly reduced pulmonary tumor mass, the combination of CTX + IL-2 cured 50 to 80% of the mice bearing i.p. tumors and reduced pulmonary tumor growth by greater than or equal to 80%. The combination of CTX + IL-2 + LAK-cells proved no more beneficial than CTX + IL-2 without LAK-cells. Also relevant were the observations that murine LAK-cells are transiently sensitive to moderate doses of CTX (greater than or equal to 100 mg/kg body weight) and X-irradiation (greater than equal to 400 rad), and that administration of IL-2 by the i.v. or i.p. route variously affects LAK-cell activation in different tissues and eradication of growths localized at different sites. With the regimens used, no signs of toxicity were detected. It is proposed that instillation of IL-2 (and perhaps of additional immunostimulating cytokines as well) as an adjunct to chemotherapy (or chemoradiotherapy), each given at a subtoxic dose, is both safe and effective in the treatment of metastatic advanced tumors, and that the additional administration of LAK-cells may not be required.
最近，大剂量白细胞介素-2联合LAK细胞的过继性免疫疗法已被用于晚期癌症患者的治疗。迄今为止，这种治疗方式已被证明疗效有限、毒性严重且后勤保障复杂。我们目前的研究旨在建立一个模型系统，通过将过继性免疫疗法（AIT）与化疗联合使用来提高疗效并降低毒性。给静脉内或腹腔内植入弱免疫原性肿瘤（M109肺癌、MCA-105肉瘤）的小鼠在接种肿瘤7至20天后，分别给予或不给予环磷酰胺（CTX）、给予或不给予重组人白细胞介素-2、给予或不给予同基因/异基因LAK细胞进行治疗。单独使用白细胞介素-2或白细胞介素-2 + LAK细胞而不使用CTX基本无效，单独使用CTX可治愈0至20%的腹腔内肿瘤动物且仅略微减少肺部肿瘤肿块，而CTX +白细胞介素-2的联合治疗可治愈50至80%的腹腔内肿瘤小鼠并使肺部肿瘤生长减少大于或等于80%。CTX +白细胞介素-2 + LAK细胞的联合治疗并未证明比不使用LAK细胞的CTX +白细胞介素-2更有益。同样相关的观察结果是，小鼠LAK细胞对中等剂量的CTX（大于或等于100 mg/kg体重）和X射线照射（大于或等于400拉德）具有短暂敏感性，并且通过静脉内或腹腔内途径给予白细胞介素-2会以不同方式影响不同组织中的LAK细胞活化以及位于不同部位的肿瘤生长的消除。在所使用的方案中，未检测到毒性迹象。有人提出，以亚毒性剂量给予白细胞介素-2（可能还有其他免疫刺激细胞因子）作为化疗（或放化疗）的辅助手段，在治疗转移性晚期肿瘤时既安全又有效，并且可能不需要额外给予LAK细胞。
