放疗联合抗PD-1及PD-L1抗体在肿瘤治疗中的进展

doi:10.3760/cma.j.issn.1673-422X.2019.01.011

摘要/Abstract

摘要： 放疗主要以局部治疗肿瘤被广泛应用于临床，它不仅可以通过损伤DNA直接杀伤肿瘤细胞，而且也对机体的免疫系统产生巨大影响。这种治疗方式不仅有抑制作用，更有激活效应。程序性死亡蛋白-1及其配体-1的抗体作为目前最热门的免疫检查点抑制剂，可通过恢复和提高机体T细胞的免疫杀伤功能抑制肿瘤的增长。随着研究的深入，人们发现二者联合应用治疗肿瘤，疗效较单一治疗模式提高。

关键词: 放射疗法, 免疫疗法, PD-1, PD-L1

Abstract: Radiotherapy is widely used in local treatment of tumors. It can not only directly kill tumor cells by damaging DNA, but also have a great impact on the immune system of the body. This effect is not only inhibited, but also more activated. Programmed death1 (PD1) and its ligand 1 (PDL1) antibody, as the most popular immune checkpoint inhibitor, can inhibit tumor growth by restoring and enhancing the immune killing function of T cells. With the deepening of the study, it is found that the combination of the two treatment of tumor, the curative effect is better than the single mode.

Key words: Radiotherapy, Immunotherapy, PD-1, PD-L1

李慧,段永建,葛红. 放疗联合抗PD-1及PD-L1抗体在肿瘤治疗中的进展[J]. 国际肿瘤学杂志, 2019, 46(1): 49-53.

参考文献

［1］ Ng J, Dai T. Radiation therapy and the abscopal effect: a concept comes of age［J］. Ann Transl Med, 2016, 4(6): 118. DOI: 10.21037/atm.2016.01.32. ［2］ Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift［J］. J Natl Cancer Inst, 2013, 105(4): 256-265. DOI: 10.1093/jnci/djs629. ［3］ Walle T, Martinez Mong R, Cerwenka A, et al. Radiation effects on antitumor immune responses: current perspectives and challenges［J］. Ther Adv Med Oncol, 2018, 10: 1758834017742575. DOI: 10.1177/1758834017742575. ［4］ Hwang WL, Pike LRG, Royce TJ, et al. Safety of combining radiotherapy with immunecheckpoint inhibition［J］. Nat Rev Clin Oncol, 2018, 15(8): 477-494. DOI: 10.1038/s41571-018-0046-7. ［5］ Bockel S, Durand B, Deutsch E. Combining radiation therapy and cancer immune therapies: from preclinical findings to clinical applications［J］. Cancer Radiother, 2018, 22(6-7): 567-580. DOI: 10.1016/j.canrad.2018.07.136. ［6］ Grass GD, Krishna N, Kim S. The immune mechanisms of abscopal effect in radiation therapy［J］. Curr Probl Cancer, 2016, 40(1): 10-24. DOI: 10.1016/j.currproblcancer.2015.10.003. ［7］ RodríguezRuiz ME, VanpouilleBox C, Melero I, et al. Immunological mechanisms responsible for radiationinduced abscopal effect［J］. Trends Immunol, 2018, 39(8): 644-655. DOI: 10.1016/j.it.2018.06.001. ［8］ Lehrer EJ, McGee HM, Peterson JL, et al. Stereotactic radiosurgery and immune checkpoint inhibitors in the management of brain metastases［J］. Int J Mol Sci, 2018, 19(10), pii: E3054. DOI: 10.3390/ijms19103054. ［9］ Golden EB, Frances D, Pellicciotta I, et al. Radiation fosters dosedependent and chemotherapyinduced immunogenic cell death［J］. Oncoimmunology, 2014, 3: e28518. DOI: 10.4161/onci.28518. ［10］张叔人. 放疗联合免疫治疗肿瘤是今后重要的研究领域［J］. 实用肿瘤杂志, 2015, 30(6): 491-495. DOI: 10.13267/j.cnki.syzlzz.2015.06.023. ［11］ Ahn YO, Kim S, Kim TM, et al. Irradiated and activated autologous PBMCs induce expansion of highly cytotoxic human NK cells in vitro［J］. J Immunother, 2013, 36(7): 373-381. DOI: 10.1097/CJI.0b013e3182a3430f. ［12］ Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift［J］. J Natl Cancer Inst, 2013, 105(4): 256-265. DOI: 10.1093/jnci/djs629. ［13］ Liu Y, Dong Y, Kong L, et al. Abscopal effect of radiotherapy combined with immune checkpoint inhibitors［J］. J Hematol Oncol, 2018, 11(1): 104. DOI: 10.1186/s13045-018-0647-8. ［14］ Ohaegbulam KC, Assal A, LazarMolnar E, et al. Human cancer immunotherapy with antibodies to the PD1 and PDL1 pathway［J］. Trends Mol Med, 2015, 21(1): 24-33. DOI: 10.1016/j.molmed.2014.10.009. ［15］ Dai S, Jia R, Zhang X, et al. The PD-1/PD-L1 pathway and autoimmune diseases［J］. Cell Immunol, 2014, 290(1): 72-79. DOI: 10.1016/j.cellimm.2014.05.006. ［16］ Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure)［J］. Ann Oncol, 2016, 27(8): 1492-1504. DOI: 10.1093/annonc/mdw217. ［17］ John LB, Devaud C, Duong CP, et al. AntiPD1 antibody therapy potently enhances the eradication of established tumors by genemodified T cells［J］. Clin Cancer Res, 2013, 19(20): 5636-5646. DOI: 10.1158/10780432.CCR130458. ［18］ Dovedi SJ, Adlard AL, LipowskaBhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade［J］. Cancer Res, 2014, 74(19): 5458-5468. DOI: 10.1158/0008-5472.CAN-14-1258. ［19］ Park SS, Dong H, Liu X, et al. PD1 restrains radiotherapyinduced abscopal effect［J］. Cancer Immunol Res, 2015, 3(6): 610-619. DOI: 10.1158/2326-6066.CIR-14-0138. ［20］ Deng L, Liang H, Burnette B, et al. Irradiation and antiPDL1 treatment synergistically promote antitumor immunity in mice［J］. J Clin Invest, 2014, 124(2): 687-695. DOI: 10.1172/JCI67313. ［21］秦颂兵. 全人源抗PDL1抗体的筛选及其与放疗联合治疗肿瘤的效果和机制研究［D］. 苏州: 苏州大学, 2015. ［22］ Yuan Z, Fromm A, Ahmed KA, et al. Radiotherapy rescue of a nivolumabrefractory immune response in a patient with PD-L1negative metastatic squamous cell carcinoma of the lung［J］. J Thorac Oncol, 2017, 12(9): e135-e136. DOI: 10.1016/j.jtho.2017.04.029. ［23］ Xie G, Gu D, Zhang L, et al. A rapid and systemic complete response to stereotactic body radiation therapy and pembrolizumab in a patient with metastatic renal cell carcinoma［J］. Cancer Biol Ther, 2017, 18(8): 547-551. DOI: 10.1080/15384047.2017.1345389. ［24］ Kwilas AR, Donahue RN, Bernstein MB, et al. In the field: exploiting the untapped potential of immunogenic modulation by radiation in combination with immunotherapy for the treatment of cancer［J］. Front Oncol, 2012, 2: 104. DOI: 10.3389/fonc.2012.00104. ［25］隋鑫, 赵丹, 林红梅, 等. 放疗联合免疫治疗癌症的研究进展［J］. 中华放射肿瘤学杂志, 2016, 25(10): 1135-1138. DOI: 10.3760/cma.j.issn.1004-4221.2016.10.025. ［26］ Kulzer L, Rubner Y, Deloch L, et al. Norm and hypofractionated radiotherapy is capable of activating human dendritic cells［J］. J Immunotoxicol, 2014, 11(4): 328-336. DOI: 10.3109/1547691X.2014.880533. ［27］ Zeng J, See AP, Phallen J, et al. AntiPD1 blockade and stereotactic radiation produce longterm survival in mice with intracranial gliomas［J］. Int J Radiat Oncol Biol Phys, 2013, 86(2): 343-349. DOI: 10.1016/j.ijrobp.2012.12.025. ［28］ Park B, Yee C, Lee KM. The effect of radiation on the immune response to cancers［J］. Int J Mol Sci, 2014, 15(1): 927-943. DOI: 10.3390/ijms15010927. ［29］张惠博, 龚虹云, 刘华丽, 等. 远隔效应的研究进展与临床意义［J］. 肿瘤学杂志, 2017, 23(4): 321-326. DOI: 10.11735/j.issn.1671-170X.2017.04.B014. ［30］颜次慧, 宋新苗, 任秀宝. 免疫检查点在肿瘤放疗中的应用进展［J］. 中华放射医学与防护杂志, 2016, 36(10): 785-789. DOI: 10.3760/cma.j.issn.0254-5098.2016.10.015. ［31］ Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE001 phase 1 trial［J］. Lancet Oncol, 2017, 18(7): 895-903. DOI: 10.1016/S1470-2045(17)30380-7. ［32］ Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage Ⅲ nonsmallcell lung cancer［J］. N Engl J Med, 2017, 377(20): 1919-1929. DOI: 10.1056/NEJMoa1709937. ［33］ Skrzypski M, Jassem J. Consolidation systemic treatment after radiochemotherapy for unresectable stage Ⅲ nonsmall cell lung cancer［J］. Cancer Treat Rev, 2018, 66: 114-121. DOI: 10.1016/j.ctrv.2018.04.001. ［34］黄乐富, 邸岩, 徐小寒, 等. PD1/PDL1阻断剂免疫治疗不良反应及其处理原则［J］. 中国药物应用与监测, 2017, 14(3): 177-182. DOI: 10.3969/j.issn.1672-8157.2017.03.014. ［35］ Sibaud V, David I, Lamant L, et al. Acute skin reaction suggestive of pembrolizumabinduced radiosensitization［J］. Melanoma Res, 2015, 25(6): 555-558. DOI: 10.1097/CMR.0000000000000191. ［36］ Martin AM, Cagney DN, Catalano PJ, et al. Immunotherapy and symptomatic radiation necrosis in patients with brain metastases treated with stereotactic radiation［J］. JAMA Oncol, 2018, 4(8): 1123-1124. DOI: 10.1001/jamaoncol.2017.3993. ［37］ Tamiya A, Tamiya M, Nakahama K, et al. Correlation of radiation pneumonitis history before nivolumab with onset of interstitial lung disease and progressionfree survival of patients with pre-treated advanced non-small-cell lung cancer［J］. Anticancer Res, 2017, 37(9): 5199-5205. DOI: 10.21873/anticanres.11943.

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