Cancer immunotherapy by interleukin-21: Potential treatment strategies evaluated in a mathematical model
Cancer immunotherapy by interleukin-21: Potential treatment strategies evaluated in a mathematical model
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DOI：
10.1158/0008-5472.can-06-0241
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发表时间：
2006-07-15
期刊：
影响因子：
11.2
通讯作者：
Agur, Zvia
中科院分区：
文献类型：
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作者：
Cappuccio, Antonio;Elishmereni, Moran;Agur, Zvia
新发现的白细胞介素(IL)-21在小鼠从先天免疫到适应性免疫的转变中起核心作用，并显示出实质性的肿瘤消退。IL-21目前已被开发为一种癌症免疫治疗药物，但有效治疗的条件以及细胞因子的免疫刺激和免疫抑制作用的冲突尚未确定。我们通过自然杀伤（NK）细胞介导和CD8(+) t细胞介导的肿瘤细胞裂解的数学模型研究了IL-21对肿瘤根除的影响。通过细胞因子基因治疗（CGT）、基于流体动力学的基因传递（HGD）或标准间隔给药（SID）对荷瘤小鼠进行IL-21治疗的结果估计模型参数。我们的模型准确地检索了非免疫原性B16黑色素瘤和免疫原性MethA和MCA205纤维肉瘤的实验生长动态，显示nk细胞/CD8(+) t细胞平衡对肿瘤免疫原性的强烈依赖。此外，在黑色素瘤中，模拟cgt样给药方案，根据肿瘤质量的变化动态确定，导致有效的疾病消除。相比之下，在纤维肉瘤中，这种策略并不优于固定剂量方案、HGD或SID。我们的模型支持临床使用IL-21作为细胞免疫对抗癌症的有效刺激物，并建议根据肿瘤的免疫原性选择免疫治疗策略。非免疫原性肿瘤，但不是高度免疫原性肿瘤。应由IL-21剂量控制，这取决于给药时的肿瘤质量。这种方法模仿、放大自然的抗癌免疫反应，而不是以不平衡的方式加速其中一个反应臂。
The newly characterized interleukin (IL)-21 plays a central role in the transition from innate immunity to adaptive immunity and shows substantial tumor regression in mice. IL-21 is now developed as a cancer immunotherapeutic drug, but conditions for efficacious therapy, and the conflicting immunostimulatory and immunoinhibitory influence of the cytokine, are yet to be defined. We studied the effects of IL-21 on tumor eradication in a mathematical model focusing on natural killer (NK) cell-mediated and CD8(+) T-cell-mediated lysis of tumor cells. Model parameters were estimated using results in tumor-bearing mice treated with IL-21 via cytokine gene therapy (CGT), hydrodynamics-based gene delivery (HGD), or standard interval dosing (SID). Our model accurately retrieved experimental growth dynamics in the nonimmunogenic B16 melanoma and the immunogenic MethA and MCA205 fibrosarcomas, showing a strong dependence of the NK-cell/CD8(+) T-cell balance on tumor immunogenicity. Moreover, in melanoma, simulations of CGT-like dosing regimens, dynamically determined according to tumor mass changes, resulted in efficient disease elimination. In contrast, in fibrosarcoma, such a strategy was not superior to that of fixed dosing regimens, HGD or SID. Our model supports clinical use of IL-21 as a potent stimulator of cellular immunity against cancer, and suggests selecting the immunotherapy strategy according to tumor immunogenicity. Nonimmunogenic tumors, but not highly immunogenic tumors. should be controlled by IL-21 dosing, which depends on tumor mass at the time of administration. This method imitates, vet amplifies, the natural anticancer immune response rather than accelerates only one of the response arms in an unbalanced manner.