Targeted therapies to improve tumor immunotherapy
Targeted therapies to improve tumor immunotherapy
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DOI：
10.1158/1078-0432.ccr-07-4804
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发表时间：
2008-07-15
影响因子：
11.5
通讯作者：
Ribas, Antoni
中科院分区：
文献类型：
--
作者：
Begley, Jonathan;Ribas, Antoni
持久的肿瘤消退和转移性实体癌的潜在治愈可以通过多种细胞免疫治疗策略来实现，包括细胞因子治疗、基于树突细胞的疫苗和免疫活化抗体，当用于所谓的免疫敏感性癌症如黑色素瘤和肾细胞癌时。然而，这些免疫治疗策略具有非常低的肿瘤应答率，通常在治疗患者的5%至10%的量级。我们提出，充分刺激的肿瘤抗原特异性T细胞的抗肿瘤活性是有限的局部因素在肿瘤环境和药理学调制这种环境可能会克服肿瘤免疫治疗的阻力。通过了解癌细胞免疫逃逸的机制，有可能设计出能够靶向免疫抑制或抗凋亡分子的新型疗法的合理组合方法，以试图逆转对免疫系统控制的抵抗。我们称这种治疗方式为“免疫增敏”。“免疫增敏药物的理想候选药物将是靶向药物，这些药物可以阻断癌细胞中的关键致癌机制，从而导致癌细胞环境中的促癌细胞增殖，同时不会对关键的淋巴细胞功能产生负面干扰。
Durable tumor regression and potential cures of metastatic solid cancers can be achieved by a variety of cellular immunotherapy strategies, including cytokine therapy, dendritic cell - based vaccines, and immune-activating antibodies, when used in so-called immune-sensitive cancers such as melanoma and renal cell carcinoma. However, these immunotherapy strategies have very low tumor response rates, usually in the order of 5% to 10% of treated patients. We propose that the antitumor activity of adequately stimulated tumor antigen-specific T cells is limited by local factors within the tumor milieu and that pharmacologic modulation of this milieu may overcome tumor resistance to immunotherapy. By understanding the mechanisms of cancer cell immune escape, it may be possible to design rational combinatorial approaches of novel therapies able to target immunosuppressive or antiapoptotic molecules in an attempt to reverse resistance to immune system control. We term this mode of treatment "immunosensitization." Ideal candidates for immunosensitizing drugs would be targeted drugs that block key oncogenic mechanisms in cancer cells resulting in a proapoptolic cancer cell milieu and at the same time do not negatively interfere with critical lymphocyte functions.