Gazit Z, Weiss D W, Shouval D, Yechezkeli M, Schirrmacher V, Notter M, Walter J, Kedar E
Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Cancer Immunol Immunother. 1992;35(2):135-44. doi: 10.1007/BF01741861.
The antitumor effects of chemotherapy, recombinant human interleukin-2 (IL-2), recombinant human interferon alpha A/D (IFN alpha), allogeneic human lymphokine-activated killer (LAK) cells, and antitumor monoclonal antibody (mAb), administered alone and in various combinations, were tested in athymic nude mice carrying human tumor xenografts. Treatment began 6-18 days after i.v. or i.p. inoculation of colorectal carcinoma or melanoma cell lines, when macroscopic growths were evident. Chemotherapy consisted of two or three courses of 5-fluorouracil (5-FU) or dacarbazine. IL-2 and/or IFN alpha were administered three to five times weekly for 1-3 weeks, usually starting 2-5 days after chemotherapy. Human LAK cells were infused once or twice weekly for 2 or 3 weeks concurrently with IL-2. In some experiments, murine anticolorectal carcinoma mAb (SF25) was administered. In both tumor systems, chemotherapy alone or immunotherapy alone (IL-2, IL-2 + LAK cells, IFN alpha, IL-2 + IFN alpha +/- LAK cells) had little or no therapeutic effects. Additive effects were obtained by combining chemotherapy with IL-2 and LAK cells or with IL-2 and IFN alpha. In the majority of the experiments, the most effective combination was chemotherapy + IL-2 + IFN alpha + LAK cells. Treatment with mAb was beneficial in the colorectal carcinoma system when combined with 5-FU + IL-2 or 5-FU + IL-2 + IFN alpha. Homing experiments with radiolabeled human and mouse LAK cells injected i.v. showed increased early accumulation in the liver and lungs, whereas freshly explanted mouse splenocytes localized mostly in the spleen and liver. The tissue distribution pattern of human LAK cells was similar in normal and tumor-bearing mice (with lung metastases). These findings suggest that combination of chemotherapy with cytokines and LAK cells can be partially effective for advanced solid human tumors even in the absence of the host's T-cell immune response. Preliminary experiments showed that tumor-specific, anti-melanoma T-cell clones were effective in local (s.c.) tumor growth inhibition (Winn assay) following coinjection with the autologous tumor cells.
在携带人肿瘤异种移植物的无胸腺裸鼠中，测试了单独及以各种组合方式给予化疗、重组人白细胞介素-2（IL-2）、重组人干扰素αA/D（IFNα）、同种异体人淋巴因子激活的杀伤细胞（LAK）以及抗肿瘤单克隆抗体（mAb）的抗肿瘤效果。在静脉内或腹腔内接种结肠直肠癌或黑色素瘤细胞系6 - 18天后开始治疗，此时肉眼可见肿瘤生长。化疗由两到三个疗程的5-氟尿嘧啶（5-FU）或达卡巴嗪组成。IL-2和/或IFNα每周给药三到五次，持续1 - 3周，通常在化疗后2 - 5天开始。人LAK细胞与IL-2同时每周输注一到两次，持续2或3周。在一些实验中，给予鼠抗结肠直肠癌mAb（SF25）。在这两种肿瘤模型中，单独化疗或单独免疫治疗（IL-2、IL-2 + LAK细胞、IFNα、IL-2 + IFNα ± LAK细胞）几乎没有或没有治疗效果。化疗与IL-2和LAK细胞或与IL-2和IFNα联合使用可获得相加效应。在大多数实验中，最有效的组合是化疗 + IL-2 + IFNα + LAK细胞。当与5-FU + IL-2或5-FU + IL-2 + IFNα联合使用时，mAb治疗在结肠直肠癌模型中是有益的。静脉注射放射性标记的人和小鼠LAK细胞的归巢实验表明，早期在肝脏和肺中的积累增加，而新鲜分离的小鼠脾细胞大多定位于脾脏和肝脏。在正常和荷瘤小鼠（有肺转移）中，人LAK细胞的组织分布模式相似。这些发现表明，即使在宿主T细胞免疫反应缺失的情况下，化疗与细胞因子和LAK细胞联合使用对晚期实体人肿瘤也可能部分有效。初步实验表明，肿瘤特异性抗黑色素瘤T细胞克隆在与自体肿瘤细胞共同注射后，对局部（皮下）肿瘤生长抑制（Winn试验）有效。
