Toward Precision Radiotherapy for Use with Immune Checkpoint Blockers.
Toward Precision Radiotherapy for Use with Immune Checkpoint Blockers.
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与免疫检查点阻断剂一起使用的精准放射治疗。
DOI：
10.1158/1078-0432.ccr-16-0037
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发表时间：
2018-01-15
期刊：
影响因子：
--
通讯作者：
Demaria S
中科院分区：
文献类型：
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作者：
Vanpouille-Box C;Formenti SC;Demaria S
十几年前，在抗 CTLA-4 治疗难治性转移癌小鼠模型中获得了放射治疗 (RT) 增强免疫检查点阻断剂 (ICB) 疗效的第一个证据。当时，ICB 刚刚进入临床测试，这一努力在 2011 年达到顶峰，第一个抗 CTLA-4 抗体用于转移性黑色素瘤患者 (ipilimumab) 获得批准。此后，一些使用易普利姆玛治疗进展的患者仅在对一个病灶接受放射治疗后才表现出全身反应，这在临床上证实了放射线的促免疫原性作用。临床前数据表明，多种免疫调节剂与放疗协同作用，可导致受照射肿瘤的消退，以及较少见的未受照射转移瘤的消退。然而，剂量和分次对放疗免疫刺激潜力的影响尚未得到彻底研究。鉴于越来越多的临床试验测试放疗提高 ICB 疗效的能力，这个问题非常重要。最近的数据表明，树突状细胞向肿瘤病变的募集（从而引发肿瘤特异性 CD8+ T 细胞）高度依赖于 RT 剂量和分级，其机制涉及双链 DNA 在癌细胞细胞质中的积累以及随后的 I 型干扰素释放。细胞对放疗的反应与 I 型干扰素分泌之间的分子联系刚刚被揭示。在这里，我们讨论优化使用放疗的基本原理，以及可以预测放疗联合 ICB 临床反应的候选生物标志物。
The first evidence that radiation therapy (RT) enhances the efficacy of immune checkpoint blockers (ICBs) was obtained a dozen years ago in a mouse model of metastatic carcinoma refractory to anti-CTLA-4 treatment. At the time, ICBs had just entered clinical testing, an endeavor that culminated in 2011 with the approval of the first anti-CTLA-4 antibody for use in metastatic melanoma patients (ipilimumab). Thereafter, some patients progressing on ipilimumab showed systemic responses only upon receiving radiation to one lesion, confirming clinically the pro-immunogenic effects of radiation. Preclinical data demonstrate that multiple immunomodulators synergize with RT to cause the regression of irradiated tumors and, less often, non-irradiated metastases. However, the impact of dose and fractionation on the immunostimulatory potential of RT has not been thoroughly investigated. This issue is extremely relevant given the growing number of clinical trials testing the ability of RT to increase the efficacy of ICBs. Recent data demonstrate that the recruitment of dendritic cells to neoplastic lesions (and hence the priming of tumor-specific CD8+ T cells) is highly dependent on RT dose and fractionation through a mechanism that involves the accumulation of double stranded DNA in the cytoplasm of cancer cells and consequent type I interferon release. The molecular links between the cellular response to RT and type I interferon secretion are just being uncovered. Here, we discuss the rationale for an optimized use of RT, as well as candidate biomarkers that may predict clinical responses to RT combined with ICBs.