Ovarian Cancer Research Center, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
J Transl Med. 2011 May 25;9:77. doi: 10.1186/1479-5876-9-77.
Time-dependent chemotherapeutic agents can selectively target tumor cells in susceptible phases of the cell cycle however a fraction of tumor cells in non-vulnerable cell cycle phases remain drug-resistant. Immunotherapy represents a promising approach to overcome the limitation of phase-specific drugs and improve their clinical efficacy. Here, we investigated the potential use of anticancer chemotherapeutic drugs in combination with IL-18, a cytokine with strong immunostimulatory properties.
Four chemotherapeutic drugs commonly used in ovarian cancer were first tested for the ability to increase the immunogenicity and killing of the murine ovarian cancer cell line ID8 in vitro. Chemotherapeutric agents with measured time-dependent immune-enhancing effects were then tested for antitumor effectiveness in vivo in combination with IL-18 immunotherapy using the ID8-Vegf ovarian cancer model.
Paclitaxel or topotecan exposure alone mediated incomplete, time-dependent killing against the murine ovarian cancer cell line ID8 in vitro, whereas carboplatin or gemcitabine mediated comprehensive, dose-dependent killing. In the plateau phase of the time-dependent killing by topotecan or paclitaxel, drug-resistant ID8 cells were more immunogenic with elevated expression of MHC-I and Fas, and increased sensitivity to CTL and Fas agonistic antibody in vitro. Moreover, the antitumor effectiveness of time-dependent agents in vivo was significantly improved with the addition of IL-18 through a T cell-dependent mechanism, while the effectiveness of drugs without significant phase specificity were not.
Tumor immunotherapy with IL-18 can significantly augment the killing fraction of phase-specific chemotherapeutic drugs and provide survival benefit. The safety profile of IL-18 and its positive interactions with select anticancer chemotherapeutic agents strongly supports the clinical investigation of this combinatorial approach.
时相依赖化疗药物可以选择性地靶向细胞周期中敏感阶段的肿瘤细胞，但处于非易损细胞周期阶段的肿瘤细胞仍具有耐药性。免疫疗法代表了一种克服相特异性药物局限性并提高其临床疗效的有前途的方法。在这里，我们研究了将抗癌化疗药物与具有强大免疫刺激特性的细胞因子 IL-18 联合使用的潜力。
首先测试了四种常用于卵巢癌的化疗药物在体外增加小鼠卵巢癌细胞系 ID8 的免疫原性和杀伤能力。然后，测试了具有测量的时相依赖性免疫增强作用的化疗药物与 IL-18 免疫疗法联合使用在 ID8-Vegf 卵巢癌模型中的抗肿瘤有效性。
紫杉醇或拓扑替康单独暴露在体外对小鼠卵巢癌细胞系 ID8 产生不完全的、时相依赖性杀伤，而卡铂或吉西他滨则产生全面的、剂量依赖性杀伤。在拓扑替康或紫杉醇时相依赖性杀伤的平台期，耐药性 ID8 细胞具有更高的免疫原性，MHC-I 和 Fas 表达上调，体外对 CTL 和 Fas 激动性抗体的敏感性增加。此外，通过 T 细胞依赖性机制，IL-18 的添加显著提高了时相依赖性药物在体内的抗肿瘤效果，而没有显著相特异性的药物则没有。
IL-18 肿瘤免疫疗法可以显著增加相特异性化疗药物的杀伤分数，并提供生存获益。IL-18 的安全性特征及其与选定抗癌化疗药物的积极相互作用强烈支持该联合治疗方法的临床研究。
