文章：

免疫治疗与靶向治疗在癌症治疗中的结合

Combining immunotherapy and targeted therapies in cancer treatment

原文发布日期：2012-03-22

DOI: 10.1038/nrc3237

类型: Review Article

开放获取: 否

要点：

1. The so-called targeted therapies and cancer immunotherapies are two novel treatment modalities that have recently begun to enter the oncology clinic. Targeted therapies and immunotherapy offer a number of possible synergies in treatment when used together; however, these combinations have not been well studied.
2. Many targeted therapies against tumours affect pathways that are also crucial for immune development and function, which suggests the possibility that targeted therapies may help to optimize anti-tumour immune responses from immunotherapies. Similarly, immunotherapies may serve to consolidate impressive clinical responses from targeted therapies into long-lasting clinical remissions.
3. Targeted therapies promote effective dendritic cell (DC) maturation, T cell priming, activation and differentiation into long-lived memory T cells, which suggests possible combinations of cancer vaccines along with targeted therapies to bolster vaccine responses, as well as effector T cell function.
4. Targeted therapies may sensitize tumour cells to immune-mediated killing by increasing the expression of death receptors or 'distress' ligands while simultaneously diminishing the expression of pro-survival signals, which increases the efficiency of immune-mediated tumour clearance once immune cells are activated in vivo.
5. Targeted therapies might diminish tumour-mediated immunosuppression by abrogating the production of tumorigenic inflammation and by inhibiting immunosuppressive cell types. Impairing immunosuppression improves effector T cell function and increases immune destruction of tumour targets, suggesting possible synergy with immunotherapies that are designed to generate anti-tumour T cells or to bolster their effector function.
6. Important considerations regarding optimizing dose, sequence and timing of targeted therapies will be required when rationally designing future clinical trials in order to maximize anti-tumour efficacy while minimizing any immunosuppressive side effects.

要点翻译：

1. 所谓靶向治疗与癌症免疫治疗是两种新型治疗模式，近期已开始应用于肿瘤临床。靶向治疗与免疫治疗联合使用可能产生多重协同效应，然而这些联合方案尚未得到充分研究。
2. 许多抗肿瘤靶向药物作用的信号通路同样对免疫发育及功能至关重要，这表明靶向治疗可能有助于优化免疫疗法激发的抗肿瘤免疫应答。同样，免疫治疗或许能够将靶向治疗取得的显著临床疗效转化为长期持续的临床缓解。
3. 靶向治疗能促进树突状细胞有效成熟、T细胞启动、活化并分化为长效记忆T细胞，这提示癌症疫苗与靶向疗法联合可能增强疫苗应答及效应T细胞功能。
4. 靶向治疗可通过增加死亡受体或“应激”配体的表达，同时削弱促生存信号的表达，使肿瘤细胞对免疫介导的杀伤作用更敏感。一旦体内免疫细胞被激活，这种机制将提升免疫介导的肿瘤清除效率。
5. 靶向治疗可通过阻断致瘤性炎症因子的产生及抑制免疫抑制性细胞类型，从而减轻肿瘤介导的免疫抑制。削弱免疫抑制能改善效应T细胞功能，增强对肿瘤靶标的免疫破坏，这表明其与旨在产生抗肿瘤T细胞或增强其效应功能的免疫疗法存在潜在协同作用。
6. 在合理设计未来临床试验时，需重点考量靶向治疗的剂量、序贯与时机优化，以期在最大化抗肿瘤疗效的同时，尽可能降低免疫抑制相关副作用。

英文摘要：

During the past two decades, the paradigm for cancer treatment has evolved from relatively nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain the backbone of current treatment, but they are limited by a narrow therapeutic index, significant toxicities and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are crucial for tumour growth and maintenance; whereas, immunotherapy endeavours to stimulate a host immune response that effectuates long-lived tumour destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes.

摘要翻译： 

在过去二十年中，癌症治疗的模式已从相对非特异性的细胞毒药物转变为基于机制的特异性疗法。最初，癌症化疗药物是通过筛选能够杀死快速分裂细胞的化合物发现的。这些药物仍是目前治疗的基础，但它们的治疗窗窄、毒性显著，且常出现获得性耐药。近年来，随着对癌症发病机制的深入理解，出现了新的治疗选择，包括靶向药物和癌症免疫治疗。靶向治疗旨在抑制对肿瘤生长和维持至关重要的分子通路；而免疫治疗则致力于激发宿主的免疫反应，实现持久的肿瘤破坏。靶向疗法和细胞毒药物也能调节免疫反应，这提示这些治疗策略可能与免疫治疗有效结合，以改善临床结局。

原文链接：

Combining immunotherapy and targeted therapies in cancer treatment