Research Progress on Combination of Radiotherapy and Immunotherapy on Advanced Non-small Cell Lung Cancer with Negative Driver Genes
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摘要:
非小细胞肺癌（NSCLC）患者中有很大比例在发现时被诊断为转移性和不可治愈的晚期肺癌，以致于失去了手术的机会，5年生存率较低。免疫治疗时代，众多种类的免疫检查点抑制剂被批准用于驱动基因阴性的晚期NSCLC患者的一/二线治疗，同时与放疗联合作为晚期NSCLC患者的重要治疗策略。放射治疗与免疫治疗相结合的创新策略在临床研究中获得了大量的可行性证据。在分子和细胞水平上观察免疫机制的临床前实验初步揭示了肿瘤、辐射和免疫系统之间的相互作用。本文对放免联合治疗在驱动基因阴性晚期NSCLC治疗中的进展进行简要综述。
Abstract:A large proportion of patients with non-small cell lung cancer (NSCLC) are diagnosed with metastatic and incurable advanced lung cancer at the time of discovery, so these patients are given no surgical opportunity and have a low 5-year survival rate. In the era of immunotherapy, many kinds of immune checkpoint inhibitors (ICIs) have been approved as the first/second-line treatment for patients with advanced NSCLC with negative driving genes and have been combined with radiotherapy as an important treatment strategy for patients with advanced NSCLC. The innovative strategy of combining radiotherapy and immunotherapy has shown feasibility as supported by practical evidence in clinical research. A preclinical experiment of observing the immune mechanism at the molecular and cellular levels preliminarily revealed the interaction among tumor, radiation, and immune system. This paper briefly reviews the progress of combined radiotherapy and immunotherapy in the treatment of advanced NSCLC with negative drvier genes.
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0 引言
肺癌是我国发病率和死亡率居首位的恶性肿瘤，其中非小细胞肺癌（non-small cell lung cancer, NSCLC）约占80%[1]。超过50%的肺癌患者在最初诊断时就被发现伴有远处转移，因此，大多数晚期NSCLC患者在诊断时已经失去了手术机会。以铂类为基础的双药化疗方案是治疗晚期NSCLC的传统标准方案，但其5年生存率仍不如人意，晚期NSCLC的5年生存率不足10%[2]。通过分子靶向治疗，驱动基因阳性的Ⅳ期NSCLC患者的生存率显著提高，据报道，接受酪氨酸激酶抑制剂治疗的患者可稳定1~2年[3]。但未接受靶向治疗的驱动基因阴性的晚期NSCLC患者在常规治疗下预后较差。自从免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）被批准用于一线/二线治疗以来，其单独或联合化疗的应用彻底改变了晚期NSCLC的治疗，使肺癌治疗进入了新时代[4-5]。放射治疗是对抗局部晚期和转移性肿瘤的有力武器，随着ICIs治疗NSCLC的成功，相关临床前和临床研究为放疗联合免疫治疗的创新策略提供了大量的理论和实践证据，本文将综述放疗联合免疫治疗在驱动基因阴性晚期NSCLC治疗中的进展。
1 放免联合治疗的临床前期研究进展
传统上认为NSCLC是非免疫原性肿瘤，但免疫治疗的成功对这一观点提出了挑战。一方面，通过抑制患者PD-1/PD-L1或细胞毒性T淋巴细胞相关抗原-4等免疫检查点的治疗理念取得了开创性进展。另一方面，尽管ICIs治疗NSCLC取得了成功，但放射治疗仍然是治疗局部或转移肿瘤的重要策略[6-7]。
放射治疗对免疫系统是一把双刃剑，抑制肿瘤的同时又刺激肿瘤[8]。肿瘤的发展与免疫抑制性肿瘤微环境有关，放射治疗可通过募集抑制性免疫细胞如肿瘤相关巨噬细胞、免疫抑制调节性T细胞、髓源性抑制细胞等导致抑制性免疫微环境[9-10]。然而，放射治疗在破坏肿瘤细胞DNA链并导致肿瘤细胞死亡的同时以多种方式刺激免疫系统[11-12]。辐射可能暴露先前隐藏的肿瘤相关抗原并诱导免疫刺激分子释放，如损伤相关分子模式、三磷酸腺苷、钙网蛋白和高迁移率族蛋白，促进树突状细胞的成熟和抗肿瘤T细胞的活化[13-14]。
已有许多临床前研究证明了放射治疗和ICIs联合使用在小鼠肿瘤模型中治疗的有效性。Deng等[15]研究发现，抗PD-L1治疗能够提高放疗的效率，且放免联合治疗通过抑制髓源性抑制细胞的积聚改变了肿瘤微环境，从而抑制肿瘤的进展。据Gong等[16]报道，在体内和体外研究中，常规分割放疗联合抗PD-L1抗体在NSCLC中表现出协同抗肿瘤免疫的作用。Herter-Sprie等[17]研究发现，放疗联合抗PD-1药物在KRAS基因驱动的基因工程NSCLC小鼠模型中显示了显著和持续的肿瘤消退作用。根据一项回顾性研究[18]，NSCLC放化疗后PD-L1在肿瘤中的表达增加。因此，联合疗法可以通过激活放疗后的免疫系统来杀死肿瘤细胞，并通过阻断肿瘤微环境内的免疫检查点，逆转肿瘤微环境的免疫抑制作用。
2 放疗联合ICIs治疗晚期NSCLC的临床研究进展
大量临床研究表明，放射治疗与ICIs联合应用具有协同抗肿瘤作用。回顾性研究表明[19-20]，放疗有可能在不增加相关常见不良反应的情况下，提高ICIs的有效性。一些临床研究观察到肺癌放免联合治疗患者的生存期增加，与临床前数据一致[21]。目前已有许多研究证实联合治疗是有效和安全的，值得对这些研究进行多方面的讨论和分析，以优化放免联合治疗的更多细节。
2.1 放疗时间的选择
目前，该领域的研究主要集中在放疗和免疫抑制剂联合治疗的给药顺序上，但这种联合治疗的最佳时机和顺序尚未确定。COSINR研究表明[22]，立体定向放射治疗（stereotactic body radiotherapy, SBRT）同步或序贯Navulumab/Ipilimumab治疗Ⅳ期NSCLC患者，同步和序贯治疗的生存结果没有差异。一项Ⅲ期临床研究GEMSTONE-301[23]使用Sugemalimab作为不可切除的Ⅲ期NSCLC患者的巩固治疗，这些患者在序贯放化疗或同步放化疗后没有进展。中期分析显示，无论是同步放化疗还是序贯放化疗，Sugemalimab巩固治疗均能带来PFS获益。
但也有研究发现，放疗和免疫治疗的先后顺序会影响联合治疗的疗效。在PD-1/PD-L1抑制剂使用之前进行放疗比在放疗前给予PD-1/PD-L1抑制剂或PD-1/PD-L1抑制剂和放疗同步治疗更有效[24]。正如PACIFIC试验所示[25-26]，辅助性durvalumab改善了放化疗后的总生存期（overallsurvival, OS）和无进展生存期（progression free survival, PFS），并且在同步放化疗后14天内进行的免疫疗法比14~42天后进行的免疫疗法具有更长的OS获益。另一项回顾性研究发现，在开始SBRT后≥21天接受免疫治疗的患者比在启动SBRT后 < 21天接受免疫治疗的患者OS获益更佳[27]。因此，放射治疗和免疫治疗的联合效果与它们的应用顺序及它们之间的间隔时间有关。目前许多研究表明，放疗后给予免疫治疗可以取得更好的效果。为了确定放疗后给予免疫治疗的最佳时间，仍需要进行大规模的随机临床试验。
2.2 联合治疗的安全性
免疫治疗会导致不良反应，如免疫相关肺炎、皮疹、腹泻和心肌炎等，放射治疗也可引起全身或局部不良反应，如发热、恶心、呕吐、造血功能受损、放射性肺炎和食管炎等。就迄今为止发表的临床试验和回顾性研究表明，放疗和免疫治疗联合治疗一般不会导致附加不良反应的增加[28-29]。
对188例接受ICIs治疗的晚期NSCLC患者的调查，Voong等[30]发现在胸部放疗前接受ICIs的患者没有发生免疫相关性肺炎。对KEYNOTE-001研究结果的二次分析发现[31]，放疗后接受Pembrolizumab治疗的患者比未接受Pembrolizumab治疗的患者获得更长的PFS和OS，肺毒性（≥3级）在所有患者中并没有显著升高，并且≥3级不良反应两组间没有显著差异。一项多中心回顾性研究纳入了117例因肺部病变接受过SBRT的患者[32]，发现SBRT联合ICIs治疗组与SBRT组相比，放射性肺炎的发生率相似，总体是安全的。
此外，一些研究者评价了放疗联合ICIs治疗颅内转移瘤的安全性。Hubbeling等[33]回顾性研究发现，接受立体定向放射外科（stereotatic radiosurgery, SRS）联合ICIs治疗的患者，未增加放射相关不良反应。根据玛嘉烈癌症中心发表的Navulamab联合SRS治疗NSCLC脑转移的Ⅱ期临床研究数据[34]，颅内中位PFS时间为5个月，颅外中位PFS和OS分别为2.9个月和14个月，并且患者的认知功能和生活质量评分在2~3个月内有显著改善，研究期间，有2例（9%）患者出现3级及以上不良反应。研究结果显示了联合治疗肺癌脑转移的安全性和有效性。另一项涉及立体定向放射手术的临床研究（Ⅰ/Ⅱ期）中，纳入了正在接受抗PD-1和立体定向放射手术治疗的黑色素瘤和NSCLC合并脑转移瘤患者[35]，研究尚未发现≥3级中枢神经系统不良事件，初步证实Pambolizumab联合SRS治疗脑内转移瘤是有效且安全的。
2.3 放疗方式和放疗剂量的选择
理想的放疗剂量应能诱导肿瘤细胞凋亡，同时激活抗肿瘤反应，从而产生长时间的反应。低剂量放射治疗激活人STING通路，并促进免疫细胞的募集[36]。每次8~10 Gy的辐射剂量现在被普遍认为是引起有效抗肿瘤反应的最佳剂量。一项小鼠实验比较了加速超分割放射治疗（accelerated hyperfractionated radiation therapy, AHFRT）、常规分割放射治疗（conventional fractionated radiation therapy, CFRT）和应用大分割放射治疗的立体定向消融放射治疗（stereotactic ablativeradiotherapy, SABR）对免疫系统的影响[37]，与CFRT相比，消融大分割放疗对免疫系统有更大的刺激作用，随着肿瘤淋巴细胞浸润强度的增加，肿瘤的抑制性髓系细胞募集减少，进一步实验发现，PD-L1抗体联合AHFRT治疗明显减少了肿瘤生长及延长了小鼠存活率。
有研究者提出SBRT比常规分割放疗更能有效激活机体抗肿瘤免疫，是NSCLC免疫治疗时代联合ICIs的最佳“伴侣”[38]。据了解，放疗虽然可以激活免疫系统，但也可能导致淋巴细胞减少，从而对ICIs的有效性产生不利影响。多疗程放疗、多个照射部位、高剂量放疗会增加放疗相关淋巴细胞减少症的风险，而SBRT/SRS则降低了这一风险[39]。SBRT和粒子束放射治疗也可以有效激活免疫系统，同时最大限度地减少正常组织体积的照射，因此，SBRT或SRS与PD-1/PD-L1抑制剂联合使用时，是一种较好的放射治疗选择。对于晚期NSCLC患者，SBRT或SRS联合PD-1/PD-L1抑制剂可能比常规放疗联合PD-1/PD-L1抑制剂获益更多。一项Ⅱ期随机临床试验现[40]，与SBRT相关的长期OS的获益仅见于缺乏PD-L1表达的患者。Welsh等进行的Ⅰ/Ⅱ期随机对照研究证实单病灶SBRT（50 Gy/4 F）联合Pembrolizumab治疗转移性NSCLC的客观缓解率（objective responserate, ORR）明显优于常规分割放疗（45 Gy/15 F）联合Pembrolizumab，PD-L1低表达组PFS明显延长。这表明放疗，尤其是SBRT可通过改变PD-L1的表达来提高ICIs的疗效[41]。
2.4 远隔效应
远隔效应是指放射治疗野外的肿瘤、病灶或转移区的放疗诱导消退。然而，当放疗作为唯一的治疗方式时，远隔效应很快被肿瘤抑制性微环境内外的自身/肿瘤免疫应答的调节信号通路所抑制[42]。因此，单纯放疗的远隔离疗效比较少见。随着免疫检查点抑制剂的出现和应用，抑制性肿瘤定向免疫反应被解除，放射治疗与免疫治疗相结合以诱导远隔效应成为一个新的研究热点。目前研究结果表明，SABR联合ICIs治疗的患者远隔反应率较高。
多项研究发现，远处转移的NSCLC患者在接受SABR联合免疫治疗后可能会产生远隔效应。1例多线治疗失败的晚期肺腺癌患者在nivolumab治疗后出现肝转移和骨转移进展，随后进行了SABR治疗，完全治疗了肝转移，而且PET-CT检查提示患者胸部病变的代谢明显减少，考虑发生了远隔效应[43]。一项研究发现[44]，对39例复发难治性远处转移的NSCLC患者应用lpilimumab并进行放疗（6 Gy/5 F），并在治疗前后88 d进行PET-CT检查评价其疗效，21例患者完成4个周期的免疫治疗后，7例（33%）患者出现远隔效应，且远隔效应患者在联合治疗3周后外周血T细胞明显增多。Theelen等[45]研究发现在SBRT与ICIs联合治疗晚期NSCLC疗效显著的前提下，联合治疗组的远隔效应发生率高达41.7%（Pembrolizumab组19.7%, P=0.0039）。
3 结论与展望
在大量临床前或临床研究的基础上，放疗与ICIs联合治疗有望成为未来治疗驱动基因阴性晚期NSCLC的有效策略。目前，正在进行不同治疗方案的临床研究，如不同的免疫治疗、不同的剂量选择以及各种联合治疗方案。由于ICIs和SBRT具有良好的耐受性，在晚期驱动基因阴性的NSCLC患者可能制定联合策略。与常规巩固治疗相比，放免联合治疗提高了晚期NSCLC患者的生存率。多部位同时给予SBRT与ICIs联合使用可能更有利于增强转移性NSCLC患者的疗效，但免疫调节所需的辐射量未明确。目前仍需大量研究去发现激活免疫反应所需的最佳放疗剂量以及放疗和免疫治疗的先后顺序。
Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：李朋：文章撰写吴晓婷：文章修改宫晓梅：文章审阅 -
[1] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. doi: 10.3322/caac.21660
[2] Siegel RL, Miller KD, Fuchs HE, et al. Cancer Statistics, 2021[J]. CA Cancer J Clin, 2021, 71(1): 7-33. doi: 10.3322/caac.21654
[3] Greenhalgh J, Boland A, Bates V, et al. First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer[J]. Cochrane Database Syst Rev, 2021, 3(3): CD010383.
[4] Youn B, Trikalinos NA, Mor V, et al. Real-world use and survival outcomes of immune checkpoint inhibitors in older adults with non-small cell lung cancer[J]. Cancer, 2020, 126(5): 978-985. doi: 10.1002/cncr.32624
[5] Waterhouse D, Lam J, Betts KA, et al. Real-world outcomes of immunotherapy-based regimens in first-line advanced non-small cell lung cancer[J]. Lung Cancer, 2021, 156: 41-49. doi: 10.1016/j.lungcan.2021.04.007
[6] Formenti SC, Rudqvist NP, Golden E, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade[J]. Nat Med, 2018, 24(12): 1845-1851. doi: 10.1038/s41591-018-0232-2
[7] Vrankar M, Stanic K, Jelercic S, et al. Clinical outcomes in stage Ⅲ non-small cell lung cancer patients treated with durvalumab after sequential or concurrent platinum-based chemoradiotherapy- single institute experience[J]. Radiol Oncol, 2021, 55(4): 482-490. doi: 10.2478/raon-2021-0044
[8] Suwa T, Kobayashi M, Nam JM, et al. Tumor microenvironment and radioresistance[J]. Exp Mol Med, 2021, 53(6): 1029-1035. doi: 10.1038/s12276-021-00640-9
[9] Mantovani A, Marchesi F, Malesci A, et al. Tumour-associated macrophages as treatment targets in oncology[J]. Nat Rev Clin Oncol, 2017, 14(7): 399-416. doi: 10.1038/nrclinonc.2016.217
[10] Barker HE, Paget JT, Khan AA, et al. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence[J]. Nat Rev Cancer, 2015, 15(7): 409-425. doi: 10.1038/nrc3958
[11] Harding SM, Benci JL, Irianto J, et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei[J]. Nature, 2017, 548(7668): 466-470. doi: 10.1038/nature23470
[12] Jarosz-Biej M, Smolarczyk R, Cichon T, et al. Tumor Microenvironment as A "Game Changer" in Cancer Radiotherapy[J]. Int J Mol Sci, 2019, 20(13): 3212. doi: 10.3390/ijms20133212
[13] Krysko DV, Garg AD, Kaczmarek A, et al. Immunogenic cell death and DAMPs in cancer therapy[J]. Nat Rev Cancer, 2012, 12(12): 860-875. doi: 10.1038/nrc3380
[14] Rodriguez-Ruiz ME, Vitale I, Harrington KJ, et al. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment[J]. Nat Immunol, 2020, 21(2): 120-134. doi: 10.1038/s41590-019-0561-4
[15] Deng LF, 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
[16] Gong XM, Li XF, Jiang T, et al. Combined Radiotherapy and Anti-PD-L1 Antibody Synergistically Enhances Antitumor Effect in Non-Small Cell Lung Cancer[J]. J Thorac Oncol, 2017, 12(7): 1085-1097. doi: 10.1016/j.jtho.2017.04.014
[17] Herter-Sprie GS, Koyama S, Korideck H, et al. Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer[J]. JCI Insight, 2016, 1(9): e87415.
[18] Yoneda K, Kuwata T, Kanayama M, et al. Alteration in tumoural PD-L1 expression and stromal CD8-positive tumour-infiltrating lymphocytes after concurrent chemo-radiotherapy for non-small cell lung cancer[J]. Br J Cancer, 2019, 121(6): 490-496. doi: 10.1038/s41416-019-0541-3
[19] Tian S, Switchenko JM, Buchwald ZS, et al. Lung Stereotactic Body Radiation Therapy and Concurrent Immunotherapy: A Multicenter Safety and Toxicity Analysis[J]. Int J Radiat Oncol Biol Phys, 2020, 108(1): 304-313. doi: 10.1016/j.ijrobp.2019.12.030
[20] Singh C, Qian JM, Yu JB, et al. Local tumor response and survival outcomes after combined stereotactic radiosurgery and immunotherapy in non-small cell lung cancer with brain metastases[J]. J Neurosurg, 2019, 132(2): 512-517.
[21] Fiorica F, Belluomini L, Stefanelli A, et al. Immune Checkpoint Inhibitor Nivolumab and Radiotherapy in Pretreated Lung Cancer Patients Efficacy and Safety of Combination[J]. Am J Clin Oncol, 2018, 41(11): 1101-1105. doi: 10.1097/COC.0000000000000428
[22] Bestvina CM, Pointer KB, Karrison T, et al. A Phase 1 Trial of Concurrent or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage Ⅳ NSCLC Study[J]. J Thorac Oncol, 2022, 17(1): 130-140. doi: 10.1016/j.jtho.2021.08.019
[23] Zhou Q, Chen M, Jiang O, et al. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage Ⅲ non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial[J]. Lancet Oncol, 2022, 23(2): 209-219. doi: 10.1016/S1470-2045(21)00630-6
[24] Geng Y, Zhang Q, Feng S, et al. Safety and Efficacy of PD-1/PD-L1 inhibitors combined with radiotherapy in patients with non-small-cell lung cancer: a systematic review and meta-analysis[J]. Cancer Med, 2021, 10(4): 1222-1239. doi: 10.1002/cam4.3718
[25] Bang A, Schoenfeld JD, Sun AY. PACIFIC: shifting tides in the treatment of locally advanced non-small cell lung cancer[J]. Transl Lung Cancer Res, 2019, 8(Suppl 2): S139-S146.
[26] Gray JE, Villegas A, Daniel D, et al. Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage Ⅲ NSCLC-Update from PACIFIC[J]. J Thorac Oncol, 2020, 15(2): 288-293. doi: 10.1016/j.jtho.2019.10.002
[27] Wegner RE, Abel S, Hasan S, et al. Time from stereotactic body radiotherapy to immunotherapy as a predictor for outcome in metastatic non small cell lung cancer[J]. J Clin Oncol, 2019, 37(15-suppl): 9024.
[28] 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
[29] Naidoo J, Wang X, Woo KM, et al. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy[J]. J Clin Oncol, 2017, 35(7): 709-717. doi: 10.1200/JCO.2016.68.2005
[30] Voong KR, Hazell SZ, Fu W, et al. Relationship Between Prior Radiotherapy and Checkpoint-Inhibitor Pneumonitis in Patients With Advanced Non-Small-Cell Lung Cancer[J]. Clin Lung Cancer, 2019, 20(4): e470-e479. doi: 10.1016/j.cllc.2019.02.018
[31] Garon EB, Hellmann MD, Rizvi NA, et al. Five-Year Overall Survival for Patients With Advanced Non-Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase ⅠKEYNOTE-001 Study[J]. J Clin Oncol, 2019, 37(28): 2518-2527. doi: 10.1200/JCO.19.00934
[32] Tian S, Switchenko JM, Buchwald ZS, et al. Lung Stereotactic Body Radiation Therapy and Concurrent Immunotherapy: A Multicenter Safety and Toxicity Analysis[J]. Int J Radiat Oncol Biol Phys, 2020, 108(1): 304-313. doi: 10.1016/j.ijrobp.2019.12.030
[33] Hubbeling HG, Schapira EF, Horick NK, et al. Safety of Combined PD-1 Pathway Inhibition and Intracranial Radiation Therapy in Non-Small Cell Lung Cancer[J]. J Thorac Oncol, 2018, 13(4): 550-558. doi: 10.1016/j.jtho.2018.01.012
[34] Wong P, Florescu M, Plourde ME, et al. A phase Ⅱ trial combining nivolumab and stereotactic brain radiosurgery for treatment of brain metastases in patients with NSCLC[J]. J Clin Oncol, 2021, 39(15_suppl): 2023. doi: 10.1200/JCO.2021.39.15_suppl.2023
[35] Khan MK, Nasti T, Kleber T, et al. Phase 1, 2 trial of concurrent anti-PD1 and stereotactic radiosurgery for melanoma and non-small cell lung cancer brain metastases (NCT02858869)[J]. J Clin Oncol, 2021, 39(15).
[36] 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
[37] Wani SQ, Dar IA, Khan T, et al. Radiation Therapy and its Effects Beyond the Primary Target: An Abscopal Effect[J]. Cureus, 2019, 11(2): e4100.
[38] Chen Y, Gao M, Huang Z, et al. SBRT combined with PD-1/PD-L1 inhibitors in NSCLC treatment: a focus on the mechanisms, advances, and future challenges[J]. J Hematol Oncol, 2020, 13(1): 105. doi: 10.1186/s13045-020-00940-z
[39] Cho Y, Park S, Byun HK, et al. Impact of Treatment-Related Lymphopenia on Immunotherapy for Advanced Non-Small Cell Lung Cancer[J]. Int J Radiat Oncol Biol Phys, 2019, 105(5): 1065-1073. doi: 10.1016/j.ijrobp.2019.08.047
[40] 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
[41] Welsh J, Menon H, Chen D, et al. Pembrolizumab with or without radiation therapy for metastatic non-small cell lung cancer: a randomized phase Ⅰ/Ⅱ trial[J]. J Immunother Cancer, 2020, 8(2): e001001. doi: 10.1136/jitc-2020-001001
[42] Reck M, Ciuleanu TE, Dols MC, et al. Nivolumab (NIVO) plus ipilimumab (IPI)+2 cycles of platinum-doublet chemotherapy (chemo) vs. 4 cycles chemo as first-line (1L) treatment (tx) for stage Ⅳ/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA[J]. Oncol Res Treat, 2020, 43(Suppl 4): 140.
[43] Schoenhals JE, Seyedin SN, Tang C, et al. Preclinical Rationale and Clinical Considerations for Radiotherapy Plus Immunotherapy: Going Beyond Local Control[J]. Cancer J, 2016, 22(2): 130-137. doi: 10.1097/PPO.0000000000000181
[44] Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer[J]. Cancer Immunol Res, 2013, 1(6): 365-372. doi: 10.1158/2326-6066.CIR-13-0115
[45] Theelen W, Chen D, Verma V, et al. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials[J]. Lancet Respir Med, 2021, 9(5): 467-475. doi: 10.1016/S2213-2600(20)30391-X
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