免疫检查点抑制剂联合放疗在非小细胞肺癌中的应用

doi:10.3760/cma.j.cn371439-20210126-00134

摘要/Abstract

摘要：

免疫检查点抑制剂(ICI)的出现使非小细胞肺癌(NSCLC)治疗策略发生了巨大的转变。尽管ICI疗效显著,但仍有较多患者无法从单独的免疫治疗中获益。目前研究方向聚焦于多种治疗方案的联合。放疗可以上调免疫原性细胞表面标志物,调节免疫检查点的表达。大量的临床前和临床研究正在探索ICI与放疗联合在不同分期NSCLC中应用的疗效和安全性,同时还包括放疗时序、最佳剂量、剂量分配等。

关键词: 免疫疗法, 放射疗法, 癌, 非小细胞肺

Abstract:

The emergence of immune checkpoint inhibitors (ICIs) has greatly changed the treatment strategy of non-small cell lung cancer (NSCLC). Although ICIs are effective, there are still many patients who cannot benefit from immunotherapy alone. The current research direction focuses on the combination of multiple treatment schemes. Radiotherapy can upregulate immunogenic cell surface markers, and regulate the expressions of immune checkpoints. A large number of preclinical and clinical studies are exploring the efficacy and safety of ICIs combined with radiotherapy in various clinical stages of NSCLC, including radiotherapy timing, optimal dose, dose distribution and so on.

Key words: Immunotherapy, Radiotherapy, Carcinoma, non-small-cell lung

王培伟, 翁一鸣, 崔雪, 彭敏. 免疫检查点抑制剂联合放疗在非小细胞肺癌中的应用[J]. 国际肿瘤学杂志, 2021, 48(11): 678-682.

Wang Peiwei, Weng Yiming, Cui Xue, Peng Min. Application of immune checkpoint inhibitors combined with radiotherapy in non-small cell lung cancer[J]. Journal of International Oncology, 2021, 48(11): 678-682.

参考文献 39

[1]	Duma N, Santana-Davila R, Molina JR. Non-small cell lung cancer: epidemiology, screening, diagnosis, and treatment[J]. Mayo Clin Proc, 2019, 94(8):1623-1640. DOI: 10.1016/j.mayocp.2019.01.013. doi: 10.1016/j.mayocp.2019.01.013
[2]	Lim SM, Hong MH, Kim HR. Immunotherapy for non-small cell lung cancer: current landscape and future perspectives[J]. Immune Netw, 2020, 20(1):e10. DOI: 10.4110/in.2020.20.e10. doi: 10.4110/in.2020.20.e10
[3]	McLaughlin M, Patin EC, Pedersen M, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy[J]. Nat Rev Cancer, 2020, 20(4):203-217. DOI: 10.1038/s41568-020-0246-1. doi: 10.1038/s41568-020-0246-1 pmid: 32161398
[4]	Sharabi AB, Lim M, DeWeese TL, et al. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy[J]. Lancet Oncol, 2015, 16(13):e498-e509. DOI: 10.1016/S1470-2045(15)00007-8. doi: 10.1016/S1470-2045(15)00007-8
[5]	Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class Ⅰ expression, and induces successful antitumor immunotherapy[J]. J Exp Med, 2006, 203(5):1259-1271. DOI: 10.1084/jem.20052494. doi: 10.1084/jem.20052494
[6]	Gameiro SR, Jammeh ML, Wattenberg MM, et al. Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing[J]. Oncotarget, 2014, 5(2):403-416. DOI: 10.18632/oncotarget.1719. pmid: 24480782
[7]	Xia L, Liu Y, Wang Y. PD-1/PD-L1 blockade therapy in advanced non-small-cell lung cancer: current status and future directions[J]. Oncologist, 2019, 24(Suppl 1):S31-S41. DOI: 10.1634/theoncologist.2019-IO-S1-s05.
[8]	Sato H, Niimi A, Yasuhara T, et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells[J]. Nat Commun, 2017, 8(1):1751. DOI: 10.1038/s41467-017-01883-9. doi: 10.1038/s41467-017-01883-9
[9]	Park JS, Kim IK, Han S, et al. Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment[J]. Cancer Cell, 2016, 30(6):953-967. DOI: 10.1016/j.ccell.2016.10.018. doi: 10.1016/j.ccell.2016.10.018
[10]	Theelen WS, de Jong MC, Baas P. Synergizing systemic responses by combining immunotherapy with radiotherapy in metastatic non-small cell lung cancer: the potential of the abscopal effect[J]. Lung Cancer, 2020, 142:106-113. DOI: 10.1016/j.lungcan.2020.02.015. doi: 10.1016/j.lungcan.2020.02.015
[11]	Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma[J]. N Engl J Med, 2012, 366(10):925-931. DOI: 10.1056/NEJMoa1112824. doi: 10.1056/NEJMoa1112824
[12]	Storozynsky Q, Hitt MM. The impact of radiation-induced DNA damage on cGAS-STING-mediated immune responses to cancer[J]. Int J Mol Sci, 2020, 21(22):8877. DOI: 10.3390/ijms21228877. doi: 10.3390/ijms21228877
[13]	Derer A, Frey B, Fietkau R, et al. Immune-modulating properties of ionizing radiation: rationale for the treatment of cancer by combination radiotherapy and immune checkpoint inhibitors[J]. Cancer Immunol Immunother, 2016, 65(7):779-86. DOI: 10.1007/s00262-015-1771-8. doi: 10.1007/s00262-015-1771-8 pmid: 26590829
[14]	Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer[J]. Nature, 2015, 520(7547):373-377. DOI: 10.1038/nature14292. doi: 10.1038/nature14292
[15]	Zheng X, Fang Z, Liu X, et al. Increased vessel perfusion predicts the efficacy of immune checkpoint blockade[J]. J Clin Invest, 2018, 128(5):2104-2115. DOI: 10.1172/JCI96582. doi: 10.1172/JCI96582
[16]	Martin JD, Seano G, Jain RK. Normalizing function of tumor vessels: progress, opportunities, and challenges[J]. Annu Rev Physiol, 2019, 81:505-534. DOI: 10.1146/annurev-physiol-020518-114700. doi: 10.1146/annurev-physiol-020518-114700 pmid: 30742782
[17]	Lu T, Yang X, Huang Y, et al. Trends in the incidence, treatment, and survival of patients with lung cancer in the last four decades[J]. Cancer Manag Res, 2019, 11:943-953. DOI: 10.2147/CMAR.S187317. doi: 10.2147/CMAR
[18]	Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2017, 28(suppl_4): v1-iv21. DOI: 10.1093/annonc/mdx222.
[19]	Cheema PK, Rothenstein J, Melosky B, et al. Perspectives on treatment advances for stage Ⅲ locally advanced unresectable non-small-cell lung cancer[J]. Curr Oncol, 2019, 26(1):37-42. DOI: 10.3747/co.25.4096. doi: 10.3747/co.25.4096 pmid: 30853796
[20]	Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 blockade in resectable lung cancer[J]. N Engl J Med, 2018, 378(21):1976-1986. DOI: 10.1056/NEJMoa1716078. doi: 10.1056/NEJMoa1716078
[21]	Cascone T, William WN Jr, Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial[J]. Nat Med, 2021, 27(3):504-514. DOI: 10.1038/s41591-020-01224-2. doi: 10.1038/s41591-020-01224-2 pmid: 33603241
[22]	Vanpouille-Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity[J]. Nat Commun, 2017, 8:15618. DOI: 10.1038/ncomms15618. doi: 10.1038/ncomms15618 pmid: 28598415
[23]	Altorki N, Borczuk A, Saxena A, et al. P2.04-92 neoadjuvant durvalumab with or without sub-ablative stereotactic radiotherapy (SBRT) in patients with resectable NSCLC (NCT02904954)[J]. J Thorac Oncol, 2019, 14:S746. doi: 10.1016/j.jtho.2019.08.1597
[24]	Lu T, Yang X, Huang Y, et al. Trends in the incidence, treatment, and survival of patients with lung cancer in the last four decades[J]. Cancer Manag Res, 2019, 11:943-953. DOI: 10.2147/CMAR.S187317. doi: 10.2147/CMAR
[25]	Hanna N, Neubauer M, Yiannoutsos C, et al. Phase Ⅲ study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage Ⅲ non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology[J]. J Clin Oncol, 2008, 26(35):5755-5760. DOI: 10.1200/JCO.2008.17.7840. doi: 10.1200/JCO.2008.17.7840
[26]	Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage ⅢA or ⅢB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study[J]. Lancet Oncol, 2015, 16(2):187-199. DOI: 10.1016/S1470-2045(14)71207-0. doi: 10.1016/S1470-2045(14)71207-0
[27]	Antonia SJ, Villegas A, Daniel D, et al. PACIFIC investigators. 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. doi: 10.1056/NEJMoa1709937
[28]	Spaas M, Lievens Y. Is the combination of immunotherapy and radiotherapy in non-small cell lung cancer a feasible and effective approach?[J]. Front Med (Lausanne), 2019, 6:244. DOI: 10.3389/fmed.2019.00244.
[29]	Wao H, Mhaskar R, Kumar A, et al. Survival of patients with non-small cell lung cancer without treatment: a systematic review and meta-analysis[J]. Syst Rev, 2013, 2:10. DOI: 10.1186/2046-4053-2-10. doi: 10.1186/2046-4053-2-10
[30]	Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer[J]. N Engl J Med, 2016, 375(19):1823-1833. DOI: 10.1056/NEJMoa1606774. doi: 10.1056/NEJMoa1606774
[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. doi: S1470-2045(17)30380-7 pmid: 28551359
[32]	Theelen WSME, Peulen HMU, Lalezari F, et al. Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial[J]. JAMA Oncol, 2019, 5(9):1276-1282. DOI: 10.1001/jamaoncol.2019.1478. doi: 10.1001/jamaoncol.2019.1478
[33]	Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial[J]. Lancet, 2016, 387(10027):1540-1550. DOI: 10.1016/S0140-6736(15)01281-7. doi: S0140-6736(15)01281-7 pmid: 26712084
[34]	Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade[J]. N Engl J Med, 2018, 378(2):158-168. DOI: 10.1056/NEJMra1703481. doi: 10.1056/NEJMra1703481
[35]	Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline[J]. J Clin Oncol, 2018, 36(17):1714-1768. DOI: 10.1200/JCO.2017.77.6385. doi: 10.1200/JCO.2017.77.6385 pmid: 29442540
[36]	Hwang WL, Pike L, 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. doi: 10.1038/s41571-018-0046-7
[37]	Hwang WL, Niemierko A, Hwang KL, et al. Clinical outcomes in patients with metastatic lung cancer treated with PD-1/PD-L1 inhibitors and thoracic radiotherapy[J]. JAMA Oncol, 2018, 4(2):253-255. DOI: 10.1001/jamaoncol.2017.3808. doi: 10.1001/jamaoncol.2017.3808
[38]	Faivre-Finn C, Vicente D, Kurata T, et al. Four-year survival with durvalumab after chemoradiotherapy in stage Ⅲ NSCLC—an update from the PACIFIC trial[J]. J Thorac Oncol, 2021, 16(5):860-867. DOI: 10.1016/j.jtho.2020.12.015. doi: 10.1016/j.jtho.2020.12.015 pmid: 33476803
[39]	Bauml JM, Mick R, Ciunci C, et al. Pembrolizumab after completion of locally ablative therapy for oligometastatic non-small cell lung cancer: a phase 2 trial[J]. JAMA Oncol, 2019, 5(9):1283-1290. DOI: 10.1001/jamaoncol.2019.1449. doi: 10.1001/jamaoncol.2019.1449