WJCR World Journal of Cancer Research 2164-9049 Scientific Research Publishing 10.12677/WJCR.2024.141008 WJCR-79886 WJCR20240100000_76934602.pdf 医药卫生 PD-1/PD-L1抑制剂在妇科肿瘤中的研究进展 Application of PD-1/PD-L1 Inhibitors in Gynecological Tumors 陈 学维 1 * 刘 云聪 2 * 朱 国庆 4 3 贵州中医药大学第二临床医学院，贵州 贵阳 贵州中医药大学第二附属医院肿瘤科，贵州 贵阳 贵州省人民医院肿瘤科，贵州 贵阳 null 09 01 2024 14 01 48 54 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

现今世界及中国的妇科恶性肿瘤呈逐年渐升趋势，已严重危及妇女们的身体健康。即使现有手术、化疗、放疗、靶向药物、介入等相结合的综合治疗方法可以延缓肿瘤的进展，提高总生存率(OS)，也仍有恶性肿瘤经治疗后，肿瘤进展呈转移性、复发性、耐药性等概率升高的风险。目前，免疫治疗的兴起与发展，在许多实质肿瘤领域中日益成为临床研究中的热点，也在妇科肿瘤方面已步入尝试性临床研究应用，其中程序性死亡受体-1 (PD-1)及其配体(PD-L1)的抗体为例的免疫抑制剂，在卵巢癌(Ovarian Cancer, OC)、宫颈癌(Cervical Cancer, CC)、子宫内膜癌(Endometrial Cancer, EC)等妇科恶性肿瘤的相关临床试验中证实，PD-1/PD-L1抑制剂具有一定的抗肿瘤疗效。本文就PD-1/PD-L1抑制剂在妇科恶性肿瘤中的研究进展作一简要综述。 Nowadays, gynecological malignant tumors in the world and China are on the rise year by year, which has seriously endangered women’s health. Even if the existing comprehensive treatment methods, such as surgery, chemotherapy, radiotherapy, targeted drugs and intervention, can delay the progress of tumor and improve the overall survival rate (OS), there is still the risk that the probability of metastasis, recurrence and drug resistance of malignant tumor will increase after treatment. At present, the rise and development of immunotherapy has increasingly become a hot spot in clinical research in many solid tumor fields, and it has also entered a tentative clinical research application in gynecological tumors. Among them, antibodies against programmed death receptor-1 (PD-1) and its ligand (PD-L1) are immune suppressants, which are used in ovarian cancer (OC), cervical cancer (CC), endometrial cancer (EC) and other gynecological malignant tumors, and it has been confirmed that PD-1/PD-L1 inhibitors have a certain anti-tumor effect. In this paper, the research progress of PD-1/PD-L1 inhibitors in gynecological malignant tumors is briefly re-viewed.

 程序性死亡受体-1 (PD-1)，程序性死亡配体体(PD-L1)，免疫治疗，卵巢癌，宫颈癌，子宫内膜癌，外阴癌, Programmed Death Receptor-1 (PD-1) Programmed Death Ligand (PD-L1) Immunotherapy Ovarian Cancer Cervical Cancer Endometrial Cancer Vulvar Cancer 摘要

现今世界及中国的妇科恶性肿瘤呈逐年渐升趋势，已严重危及妇女们的身体健康。即使现有手术、化疗、放疗、靶向药物、介入等相结合的综合治疗方法可以延缓肿瘤的进展，提高总生存率(OS)，也仍有恶性肿瘤经治疗后，肿瘤进展呈转移性、复发性、耐药性等概率升高的风险。目前，免疫治疗的兴起与发展，在许多实质肿瘤领域中日益成为临床研究中的热点，也在妇科肿瘤方面已步入尝试性临床研究应用，其中程序性死亡受体-1 (PD-1)及其配体(PD-L1)的抗体为例的免疫抑制剂，在卵巢癌(Ovarian Cancer, OC)、宫颈癌(Cervical Cancer, CC)、子宫内膜癌(Endometrial Cancer, EC)等妇科恶性肿瘤的相关临床试验中证实，PD-1/PD-L1抑制剂具有一定的抗肿瘤疗效。本文就PD-1/PD-L1抑制剂在妇科恶性肿瘤中的研究进展作一简要综述。

 关键词

程序性死亡受体-1 (PD-1)，程序性死亡配体体(PD-L1)，免疫治疗，卵巢癌，宫颈癌，子宫内膜癌，外阴癌

 Application of PD-1/PD-L1 Inhibitors in Gynecological Tumors<sup> </sup>

Xuewei Chen1*, Yuncong Liu2#, Guoqing Zhu3

1The Second Clinical Medical School of Guizhou University of Chinese Medicine, Guiyang Guizhou

2Oncology Department, Guizhou Provincial People’s Hospital, Guiyang Guizhou

3Oncology Department, The Second Affiliated Hospital of Guizhou University of Chinese Medicine, Guiyang Guizhou

Received: Dec. 17th, 2023; accepted: Jan. 17th, 2024; published: Jan. 26th, 2024

 ABSTRACT

Nowadays, gynecological malignant tumors in the world and China are on the rise year by year, which has seriously endangered women’s health. Even if the existing comprehensive treatment methods, such as surgery, chemotherapy, radiotherapy, targeted drugs and intervention, can delay the progress of tumor and improve the overall survival rate (OS), there is still the risk that the probability of metastasis, recurrence and drug resistance of malignant tumor will increase after treatment. At present, the rise and development of immunotherapy has increasingly become a hot spot in clinical research in many solid tumor fields, and it has also entered a tentative clinical research application in gynecological tumors. Among them, antibodies against programmed death receptor-1 (PD-1) and its ligand (PD-L1) are immune suppressants, which are used in ovarian cancer (OC), cervical cancer (CC), endometrial cancer (EC) and other gynecological malignant tumors, and it has been confirmed that PD-1/PD-L1 inhibitors have a certain anti-tumor effect. In this paper, the research progress of PD-1/PD-L1 inhibitors in gynecological malignant tumors is briefly reviewed.

Keywords:Programmed Death Receptor-1 (PD-1), Programmed Death Ligand (PD-L1), Immunotherapy, Ovarian Cancer, Cervical Cancer, Endometrial Cancer, Vulvar Cancer

Copyright © 2024 by author(s) and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

 1. 引言

近年来，全球妇科癌症疾病的发病及其死亡比例仍呈上升的势头。世界卫生机构国际癌症研究机构(IARC)发布了2020年全球最新癌症数据，在全球患病率前十的癌症中，新增女性恶性肿瘤就有BC (226万)、CC (60万)，全球癌症死亡人数前十名就有BC (68万)，CC (34万)，妇科癌症疾病已严重危及着女性们的健康和生活 [ 1 ] 。经过长期的抗肿瘤临床研究治疗的应用，其治疗方式有多元式发展，包括手术、化疗、放疗、靶向药物、介入等相结合的综合治疗，尽可能提高生存率，然而肿瘤病变进展也相当快速及复杂，出现恶性肿瘤后期进展持续性、转移性、复发性、耐药性等概率升高的风险。免疫治疗的兴起与发展，人们发现了新型的治疗方法及药物——免疫抑制剂 [ 2 ] 。目前，免疫治疗在肿瘤领域中日益成为临床研究中的热点，在许多临床实践的科研应用中如荼如火的进行，PD-1/PD-L1抑制免疫疗法已被证实可以有效地在各种类型的肿瘤中产生长效的抗肿瘤免疫反应，其毒性相对较小，如Sánchez-Magraner L等人 [ 3 ] 对188名接受免疫检查点抑制剂治疗的患者进行的多中心盲法分析表明，对患者进行分层的PD-L1表达评分与总生存期的相关性较差；相比之下，PD-1/PD-L1相互作用较高的患者对抗PD-1/PD-L1治疗的反应明显更好。Antony GR [ 4 ] 等人研究PD-L1抑制剂与化疗相结合可以通过抑制上皮–间充质转化来显著减少肿瘤进展，证明PD-L1有助于乳腺癌细胞的转化和进展，其干预是一种很有前途的乳腺癌治疗策略 [ 5 ] 。抗PD-1免疫疗法已广泛应用于某些类型的淋巴瘤患者，经典型霍奇金淋巴瘤(cHL)对免疫治疗高度敏感 [ 6 ] 。Cao Y等人证明 [ 7 ] 了PD-L1与PD-L1结合后在CRC中的作用。综上所述，PD-L1抗体免疫治疗不仅提供了新的理论依据，而且也为患者临床治疗中获益，同样也有PD-1/PD-L1抑制剂药物也在妇科恶性肿瘤领域有了一定研究。本章就PD-1/PD-L1抑制剂在妇科肿瘤中的研究进展作一综述。

 2. PD-1/PD-L1抑制剂的机制

PD-L1又叫程序性死亡配体，是PD-1的配体，而PD-1能为CD8+T细胞、活性的CD8+T、B细胞和自然杀伤细胞(NK)单核细胞等免疫细胞跨膜蛋白所表达，其功能是促进T细胞的成熟 [ 8 ] ，而CD8+T细胞在抗肿瘤免疫应答中是起到主要作用的细胞 [ 9 ] 。我们人体内每天都有1014个正常细胞处于分裂状态，而其中又大约有107~109个细胞因各种原因发生变异，人们机体免疫系统具备了免疫监视功能，当人体内存在恶变细胞时，机体免疫系统可开始运作起来，去识别并利用自身免疫机制清除这些“恶变”的细胞，进而抑制癌细胞的正常生长进程，但由于有一定限制，一些恶变细胞组织仍可通过多种机制逃避免疫系统识别和进攻，从而导致了癌细胞在人类机体存活与扩散的现象，这一现象被为称肿瘤免疫逃逸(Tumor immune escape) [ 10 ] 。肿瘤免疫逃避机制又包括由PD-1受体和PD-L1配体结合通路介导的肿瘤免疫逃逸，即阻断PD-1/PD-L1受体–配体结合通路，产生了PD-1/PD-L1抑制剂药物的免疫治疗方法。

 3. PD-1/PD-L1抑制剂在妇科肿瘤中的研究 3.1. 卵巢癌

卵巢癌在全球是最致命的妇科恶性肿瘤 [ 11 ] ，也是女性排名前五的癌症死亡的原因。尽管诊断及治疗方法随着现代医学研究进展而有所前进和提高，但仍出现了复发症状、转移特征方式进展的病情，且预后较差 [ 12 ] [ 13 ] 。因此，探索卵巢癌在免疫治疗中的疗效是必要的。Pfisterer J等人 [ 14 ] 研究出卡铂聚乙二醇化脂质体多柔比星–贝伐单抗是铂类合格复发性卵巢癌的新标准治疗选择，但仍有少部分严重不良事件反应。因此，针对减少铂类耐药复发性卵巢癌化疗后的不良反应，要求更高的安全性和耐受性，不少联合免疫抑制剂治疗的临床试验也有相应进展探索。

在临床试验研究中，Jue Zhu等人 [ 15 ] 对945名患者，分批次为15项试验，以评判PD-1/PD-L1抑制剂治疗晚期OC的疗效，其结果显示总客观缓解率(ORR)为19%，单一PD-1/PD-L1抑制剂疗效有限，其ORR为9%，而联合化疗显示客观缓解率增加36%。表明PD-1/PD-L1抑制剂在铂敏感卵巢恶性肿瘤中的客观缓解率明显优于铂类耐药的OC。Lee Elizabeth K等人 [ 16 ] 帕博利珠单抗(Pembrolizumab)和聚乙二醇化脂质体多柔比星(PLD)联合治疗铂类耐药卵巢癌的II期试验，26名患者每3周静脉内(IV)给予帕博利珠单抗200 mg，每4周给予PLD 40 mg/m2IV，每8周对患者进行一次放射学评估。结果显示12名患者的临床受益率(CBR)为52.2%，有5个部分缓解(PR) 21.7%和1个完全缓解(CR) 4.3%，ORR为26.1%，六名患者的疾病稳定(SD)持续至少24周，临床研究说明联合治疗耐受性良好，毒性反应小，并显示出治疗铂类耐药卵巢癌的临床益处的初步证据，且联合治疗的ORR和中位PFS高于单独使用PLD或单独使用抗PD-1/PD-L1药物。John B Liao等人 [ 17 ] 对29名患者评估了帕博利珠单抗与卡铂在复发性铂耐药卵巢癌中的活性和安全性，所有PD-L1阳性患者均达到PR达42.8%，SD达57.2%；中位PFS为4.63个月，中位OS为11.3个月，研究表明帕博利珠单抗联合卡铂在复发性铂类耐药卵巢癌中具有良好的耐受性和活性。基于以上研究结果回示，虽然单一的PD-1/PD-L1抑制剂在卵巢癌的临床试验效果不佳，但联合化疗显示出最高的ORR，毒副反应小，可以选择免疫治疗继续进一步临床研究应用。

 3.2. 宫颈癌

随着社会生活水平的提高，人们从温饱到富足上升到质的飞跃，关注健康意识越来越重要，特别是女性健康，即使宫颈癌早期诊断筛查的普及开展，宫颈癌的发病率依然呈向上坡线条，由以亚洲人群的发病率一直居高不下 [ 18 ] 。晚期发现的宫颈癌只能用化学疗法或放射疗法治疗，但预后结果不佳，常会发生复发或转移，即使常规化疗后，效果不佳，也可能加速病情进展，那时只能作为姑息性全身治疗。晚期宫颈癌患者的中位生存期仅为16.8个月 [ 19 ] ，为了能提高患者的总体生存率，在顺铂/紫杉醇加贝伐单抗基础上联合Atezolizumab化疗正在研究开展中 [ 20 ] ，以此，PD-L1/PD-1阻断疗法作为晚期宫颈癌的免疫治疗是有巨大潜力探索的。

临床试验研究中，在Ib期KEYNOTE-028中 [ 21 ] ，例24名患者Pembrolizumab治疗，结果显示ORR为17%；6个月PFS为13%，6个月OS为66.7%，表明派姆单抗在PD-L1阳性晚期实体肿瘤队列研究中安全性和有效性可。KEYNOTE-158 [ 22 ] 试验入组98名患者用了Pembrolizumab，在接受过一种或多种化疗方案治疗复发或转移性疾病的患者中，ORR为14.3%。总人群的中位PFS为2.1个月，而在PD-L1阳性肿瘤人群中，ORR为14.3%，总人群的中位OS为9.4个月，PD-L1阳性肿瘤人群的中位OS为11个月，基于研究结论，派姆单抗单药治疗在晚期宫颈癌患者中显示出持久的抗肿瘤活性和可控的安全性，且专家意见一致认可 [ 23 ] ，无论是在转移性还是复发性环境中Pembrolizumab最终可能代表一种治疗具有PD-L1表达的晚期宫颈癌的治疗选择，基于这些研究结果，美国FDA批准了Pembrolizumab应用于化疗时或化疗后发生进展的晚期PD-L1阳性宫颈癌患者。NRG-GY002试验 [ 24 ] 研究中纳入26名持续性或复发性宫颈癌患者运用单药nivolumab，以评估该抑制剂在持续性/复发性宫颈癌中的效果和耐受性，试验结果回示，疾病稳定的中位持续时间为5.7个月，中位PFS和OS的估计值分别为3.5和14.5个月，六个月的估计PFS和OS分别为16%和78.4%，表明单药nivolumab在持续性或复发性宫颈癌患者中的活性有限，但耐受性良好，说明未来评估免疫检查点抑制剂协同组合的试验可能对于提高宫颈癌患者的临床反应率是非常必要的。

 3.3. 子宫内膜癌

子宫内膜癌是常见的女性第二生殖道恶性肿瘤，2020年我国的子宫内膜癌新发病例为82000例，占全球发病率的19.6% [ 1 ] ，也是不可小觑的增长态势，即使子宫内膜癌治疗后的总体预后较好，但晚期复发和一些特殊类型的子宫内膜癌放化疗后，仍预后不佳。根据癌症基因组图谱(TCGA)将子宫内膜癌分为POLE突变型、微卫星不稳定型(MSI)、低拷贝型(CN-low)、高拷贝型(CN-high)，然而Florine等的研究结果显示 [ 25 ] ，POLE突变型与错配修复系统缺陷(dMMR)型两类在子宫内膜癌组织中，PD-1/PD-L1的表达率均较高。有望从PD-1/PD-L1阻断治疗中获得临床收益，这也昭示着基于肿瘤微环境和基因型的免疫治疗时代来临。

临床试验研究方面，Dizon DS、T Danley K等人 [ 26 ] [ 27 ] 分别报告了一例患有侵袭性体细胞MMR缺陷型子宫内膜癌和生殖系BRCA1、Lynch综合征和复发性错配修复缺陷型浆液性子宫内膜癌的患者，在应用派姆单抗治疗后获得了持久缓解；在美国11个中心进行一项晚期复发性子宫内膜癌的2期研究纳入54名患者分析，结果表明 [ 28 ] 乐伐替尼(Lenvatinib)加派姆单抗在晚期复发性子宫内膜癌患者中显示出抗肿瘤活性，但在随着最大耐受剂量的递减队列研究显示 [ 29 ] ，子宫内膜癌ORR：52%，更有力证实对实体肿瘤显示出抗肿瘤的活性及安全性大。查阅有关文献中，也有用免疫抑制剂纳武单抗治疗2例复发难治性子宫内膜癌，结果显示 [ 30 ] 患者在治疗后临床疗效均可，且无不良反应出现；例如15名患者进行子宫内膜癌I期临床研究(NCT01375842) [ 31 ] ，对阿替利珠单抗(atezolizumab)单药治疗复发性子宫内膜癌的安全性和有效性评估得到一定的临床效益，基于以上研究，子宫内膜癌步入免疫治疗时代，为其总生存率的提高带来新的寄托思路，这还得寄于后期的不断探索研究，能为患有恶性肿瘤患者们带来更多益处。

 3.4. 外阴癌

外阴癌(VC)是妇科恶性肿瘤中少见的疾病，只占妇科癌症疾病的4%，每年每100,000名女性中新发外阴癌病例的比率为2.6例，而据统计2011~2017年显示其病5年相对生存期占71.1% [ 32 ] 。VC最常见的病理分型为鳞状细胞癌(VSCC)，约占病例的80%，其次是腺癌、基底细胞癌、恶性黑色素瘤和转移性癌等 [ 33 ] 。Hecking T等人 [ 34 ] 通过免疫组织化学对103名患者的肿瘤相关巨噬细胞进行分析表明PD-1/PD-L1通路诱导耐受的免疫治疗方法有可能改善外阴癌患者的预后。

在临床试验中 [ 35 ] ，CheckMate 358中接受纳武单抗单药治疗的24名复发/转移性宫颈癌、阴道癌或外阴癌患者的队列研究中(宫颈，n = 19；阴道/外阴，n = 5)。研究表明宫颈癌的ORR为26.3%，阴道/外阴癌的ORR为20.0%，纳武单抗单药在复发/转移性宫颈癌和阴道癌或外阴癌患者中的疗效是有希望的，值得进一步研究。在接受铂类联合治疗的晚期或复发性转移性外阴癌患者中，ORR为40%的基础下 [ 36 ] ，Yeku O，Russo AL等人 [ 37 ] 入组为24名患有不可切除、局部晚期或转移性外阴癌的女性进行pembrolizumab联合顺铂致敏放射治疗的单臂II期临床试验，旨在提高外阴癌患者的总体反应率和无复发生存期，并有相关研究表明 [ 38 ] [ 39 ] ，顺铂和放射治疗的组合可以通过PD-1/PD-L1阻断进一步增强每种治疗方式的免疫遗传效应。

 4. 展望与小结

妇科肿瘤的免疫治疗是继手术、放射疗法、化学疗法、内分泌治疗后新的治疗方式，PD-1/PD-L1抑制剂的免疫治疗的主要优势在于，能够通过激活自身免疫系统对正常细胞能够准确识别，杀灭恶性肿瘤细胞，比起抗肿瘤的放化疗法，其副作用要小得多，现今越来越多的PD-1/PD-L1抑制剂在妇科肿瘤领域上不断被探索出，并且不少免疫抑制剂药物被FDA、NCCN指南定为推荐用药。在妇科肿瘤领域中，免疫抑制剂药物更多是集中在晚期复发、转移的肿瘤上应用，期待在未来的妇科肿瘤领域中发挥越来越多的作用，能结合化学疗法、放射疗法、新辅助化疗为抗肿瘤治疗带来更多临床疗效，进而延长肿瘤患者的生存时期和改善生活质量。

 文章引用

陈学维,刘云聪,朱国庆. PD-1/PD-L1抑制剂在妇科肿瘤中的研究进展Application of PD-1/PD-L1 Inhibitors in Gynecological Tumors[J]. 世界肿瘤研究, 2024, 14(01): 48-54. https://doi.org/10.12677/WJCR.2024.141008

 参考文献 References 王劲松, 魏家燕, 彭敏. 2023年美国癌症统计报告和全球最新癌症统计数据解读及启示[J]. 实用肿瘤杂志, 2023, 38(6): 523-527.
https://doi.org/10.13267/j.cnki.syzlzz.2023.083 Ventriglia, J., Paciolla, I., Pisano, C., Cecere, S.C., Di Napoli, M., Tambaro, R., et al. (2017) Immunotherapy in Ovarian, Endometrial and Cervical Cancer: State of the Art and Future Perspectives. Cancer Treatment Reviews, 59, 109-116.
https://doi.org/10.1016/j.ctrv.2017.07.008 Sánchez-Magraner, L., Gumuzio, J., Miles, J., Quimi, N., Martínez Del Prado, P., Abad-Villar, M.T., et al. (2023) Functional Engagement of the PD-1/PD-L1 Complex But Not PD-L1 Expression Is Highly Predictive of Patient Response to Immunotherapy in Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 41, 2561-2570.
https://doi.org/10.1200/JCO.22.01748 Antony, G.R., Littleflower, A.B., Parambil, S.T. and Subhadradevi, L. (2023) PD-1/PD-L1 Blockade Inhibits Epithelial-Mesenchymal Transition and Improves Chemotherapeutic Response in Breast Cancer. Medical Oncology, 40, Article No. 108.
https://doi.org/10.1007/s12032-023-01965-3 Yang, L., Zhao, Q., Chen, T., Liu, W., Qiu, X., Chen, J., et al. (2023) An HPK1 Inhibitor Enhanced the Tumour Response to An-ti-PD-1 Immunotherapy in Non-Hodgkin’s Lymphoma. Clinical and Experimental Medicine, 23, 3767-3780.
https://doi.org/10.1007/s10238-023-01068-3 Cao, Y., Liang, W., Fang, L., Liu, M.K., Zuo, J., Peng, Y.L., et al. (2022) PD-L1/PD-L1 Signalling Promotes Colorectal Cancer Cell Migration Ability through RAS/MEK/ERK. Clini-cal and Experimental Pharmacology and Physiology, 49, 1281-1293.
https://doi.org/10.1111/1440-1681.13717 Trefny, M.P., Kaiser, M., Stanczak, M.A., Herzig, P., Savic, S., Wiese, M., et al. (2020) PD-1+ Natural Killer Cells in Human Non-Small Cell Lung Cancer Can Be Activated by PD-1/PD-L1 Blockade. Cancer Immunology, Immunotherapy, 69, 1505-1517.
https://doi.org/10.1007/s00262-020-02558-z Gurung, P., et al. (2023) Chlorin e6-Associated Photodynamic Therapy Enhances Abscopal Antitumor Effects via Inhibition of PD-1/PD-L1 Immune Checkpoint. Scientific Reports, 13, Article No. 4647.
https://doi.org/10.1038/s41598-023-30256-0 Gurung, P., Lim, J., Shrestha, R. and Kim, Y.W. (2023) Author Correction: Chlorin e6-Associated Photodynamic Therapy Enhances Abscopal Antitumor Effects via Inhibition of PD-1/PD-L1 Immune Checkpoint. Scientific Reports, 13, Article No. 8906.
https://doi.org/10.1038/s41598-023-35267-5 糜亚琴, 蒋敬庭, 吴昌平. PD-L1/PD-1在卵巢癌中的表达机制及免疫治疗研究进展[J]. 临床肿瘤学杂志, 2017, 22(2): 180-183. Li, X., Zhang, Y., Wang, X., Lin, F., Cheng, X., Wang, Z., et al. (2022) Long Non-Coding RNA CTSLP8 Mediates Ovarian Cancer Progression and Chem-otherapy Resistance by Modulating Cellular Glycolysis and Regulating c-Myc Expression through PKM2. Cell Biology and Toxicology, 38, 1027-1045.
https://doi.org/10.1007/s10565-021-09650-9 Liu, C., Li, Y., Zhu, Y. and Lu, M. (2022) The Value of IOTA Simple Rules Combined with CEUS Scoring System in the Diagnosis of Benign and Ma-lignant Ovarian Masses and Its Correlation with MVD and VEGF: A Preliminary Study. Journal of Ultrasound in Med-icine, 41, 2983-2992.
https://doi.org/10.1002/jum.15999 Matsuura, H., Miyamoto, M., Hada, T., Ishibashi, H., Iwahashi, H., Kakimoto, S., et al. (2022) The Worsening Impact of Programmed Cell Death Ligand 1 in Ovarian Clear Cell Carcinomas. Archives of Gynecology and Obstetrics, 306, 2133-2142.
https://doi.org/10.1007/s00404-022-06582-5 Pfisterer, J., Shannon, C.M., Baumann, K., Rau, J., Harter, P., Joly, F., et al. (2020) Bevacizumab and Platinum-Based Combinations for Recurrent Ovarian Cancer: A Randomised, Open-Label, Phase 3 Trial. The Lancet Oncology, 21, 699-709.
https://doi.org/10.1016/S1470-2045(20)30142-X Zhu, J., Yan, L. and Wang, Q. (2021) Efficacy of PD-1/PD-L1 Inhibitors in Ovarian Cancer: A Single-Arm Meta-Analysis. Journal of Ovarian Research, 14, Article No. 112.
https://doi.org/10.1186/s13048-021-00862-5 Lee, E.K., Xiong, N., Cheng, S.C., Barry, W.T., Penson, R.T., Konstantinopoulos, P.A., et al. (2020) Combined Pembrolizumab and Pegylated Liposomal Doxorubicin in Plati-num Resistant Ovarian Cancer: A Phase 2 Clinical Trial. Gynecologic Oncology, 159, 72-78.
https://doi.org/10.1016/j.ygyno.2020.07.028 Liao, J.B., Gwin, W.R., Urban, R.R., Hitchcock-Bernhardt, K.M., Coveler, A.L., Higgins, D.M., et al. (2021) Pembrolizumab with Low-Dose Carboplatin for Recurrent Plati-num-Resistant Ovarian, Fallopian Tube, and Primary Peritoneal Cancer: Survival and Immune Correlates. The Journal for ImmunoTherapy of Cancer, 9, e003122.
https://doi.org/10.1136/jitc-2021-003122 Zhao, F., Fang, T., Liu, H. and Wang, S. (2023) Long Non-Coding RNA MALAT1 Promotes Cell Proliferation, Migration and Invasion in Cervical Cancer by Targeting miR-625-5p and AKT2. Panminerva Medica, 65, 266-267.
https://doi.org/10.23736/S0031-0808.19.03845-X Kagabu, M., Nagasawa, T., Sato, C., Fukagawa, Y., Ka-wamura, H., Tomabechi, H., et al. (2020) Immunotherapy for Uterine Cervical Cancer Using Checkpoint Inhibitors: Fu-ture Directions. International Journal of Molecular Sciences, 21, Article No. 2335.
https://doi.org/10.3390/ijms21072335 Grau, J.F., Farinas-Madrid, L. and Oaknin, A. (2020) A Randomized Phase III Trial of Platinum Chemotherapy plus Paclitaxel with Bevacizumab and Atezolizumab versus Platinum Chemo-therapy plus Paclitaxel and Bevacizumab in Metastatic (Stage IVB), Persistent, or Recurrent Carcinoma of the Cervix: The BEATcc Study (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030). International Journal of Gynecological Cancer, 30, 139-143.
https://doi.org/10.1136/ijgc-2019-000880 Frenel, J.S., Le Tourneau, C., O’Neil, B., Ott, P.A., Piha-Paul, S.A., Gomez-Roca, C., et al. (2017) Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1-Positive Cervical Cancer: Results from the Phase Ib KEYNOTE-028 Trial. Journal of Clinical Oncology, 35, 4035-4041.
https://doi.org/10.1200/JCO.2017.74.5471 Chung, H.C., Ros, W., Delord, J.P., Perets, R., Ital-iano, A., Shapira-Frommer, R., et al. (2019) Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cer-vical Cancer: Results from the Phase II KEYNOTE-158 Study. Journal of Clinical Oncology, 37, 1470-1478.
https://doi.org/10.1200/JCO.18.01265 De Felice, F., Giudice, E., Bolomini, G., Distefano, M.G., Scambia, G., Fagotti, A. and Marchetti, C. (2021) Pembrolizumab for Advanced Cervical Cancer: Safety and Efficacy. Expert Review of Anticancer Therapy, 21, 221-228.
https://doi.org/10.1080/14737140.2021.1850279 Santin, A.D., Deng, W., Frumovitz, M., Buza, N., Bellone, S., Huh, W., et al. (2020) Phase II Evaluation of Nivolumab in the Treatment of Persistent or Recurrent Cervical Cancer (NCT02257528/NRG-GY002). Gynecologic Oncology, 157, 161-166.
https://doi.org/10.1016/j.ygyno.2019.12.034 Eggink, F.A., Van Gool, I.C., Leary, A., Pollock, P.M., Crosbie, E.J., Mileshkin, L., et al. (2017) Immunological Profiling of Molecularly Classified High-Risk Endometrial Cancers Identifies POLE-Mutant and Microsatellite Unstable Carcinomas as Candidates for Checkpoint Inhibition. Oncoim-munology, 6, e1264565.
https://doi.org/10.1080/2162402X.2016.1264565 Dizon, D.S., Dias-Santagata, D., Bregar, A., Sullivan, L., Filipi, J., Di Tavi, E., et al. (2018) Complete Remission Following Pembrolizumab in a Woman with Mismatch Re-pair-Deficient Endometrial Cancer and a Germline BRCA1 Mutation. Oncologist, 23, 650-653.
https://doi.org/10.1634/theoncologist.2017-0526 Danley, K., Schmitz, K., Ghai, R., Sclamberg, J.S., Bucking-ham, L.E., Burgess, K., et al. (2021) A Durable Response to Pembrolizumab in a Patient with Uterine Serous Carcinoma and Lynch Syndrome due to the MSH6 Germline Mutation. Oncologist, 26, 811-817.
https://doi.org/10.1002/onco.13832 Makker, V., Rasco, D., Vogelzang, N.J., Brose, M.S., Cohn, A.L., Mier, J., et al. (2019) Lenvatinib plus Pembrolizumab in Patients with Advanced Endometrial Cancer: An Interim Analysis of a Multicentre, Open-Label, Single-Arm, Phase 2 Trial. The Lancet Oncology, 20, 711-718.
https://doi.org/10.1016/S1470-2045(19)30020-8 Taylor, M.H., Lee, C.H., Makker, V., Rasco, D., Dutcus, C.E., Wu, J., et al. (2020) Phase IB/II Trial of Lenvatinib plus Pembrolizumab in Patients with Advanced Renal Cell Car-cinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors. Journal of Clinical Oncology, 38, 1154-1163.
https://doi.org/10.1200/JCO.19.01598 刘鸥萱, 胡悦欣, 林蓓. PD-1/PD-L1抑制剂治疗晚期或复发性子宫内膜癌的临床研究进展[J]. 现代肿瘤医学, 2021, 29(8): 1449-1456. Liu, J.F., Gordon, M., Veneris, J., Braiteh, F., Balmanoukian, A., Eder, J.P., et al. (2019) Safety, Clinical Activity and Biomarker Assessments of Atezolizumab from a Phase I Study in Advanced/Recurrent Ovarian and Uterine Cancers. Gynecologic Oncology, 154, 314-322.
https://doi.org/10.1016/j.ygyno.2019.05.021 Huepenbecker, S.P., Fu, S., Sun, C.C., Zhao, H., Primm, K.M., Giordano, S.H., et al. (2022) Medicaid Expansion and 2-Year Survival in Women with Gynecologic Cancer: A Differ-ence-in-Difference Analysis. American Journal of Obstetrics & Gynecology, 227, 482.e1-482.e15.
https://doi.org/10.1016/j.ajog.2022.04.045 Borella, F., Preti, M., Bertero, L., Collemi, G., Castellano, I., Cas-soni, P., et al. (2020) Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Re-view. International Journal of Molecular Sciences, 22, Article No. 190.
https://doi.org/10.3390/ijms22010190 Hecking, T., et al. (2017) Tumoral PD-L1 Expression Defines a Sub-group of Poor-Prognosis Vulvar Carcinomas with Non-Viral Etiology. Oncotarget, 8, 92890-92903.
https://doi.org/10.18632/oncotarget.21641 Naumann, R.W., Hollebecque, A., Meyer, T., Devlin, M.J., Oaknin, A., Kerger, J., et al. (2019) Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results from the Phase I/II CheckMate 358 Trial. Journal of Clinical Oncology, 37, 2825-2834.
https://doi.org/10.1200/JCO.19.00739 Cormio, G., Loizzi, V., Gissi, F., Serrati, G., Panzarino, M., Carriero, C., et al. (2009) Cisplatin and Vinorelbine Chemotherapy in Recurrent Vulvar Carcinoma. Oncology, 77, 281-284.
https://doi.org/10.1159/000259259 Yeku, O., Russo, A.L., Lee, H. and Spriggs, D. (2020) A Phase 2 Study of Combined Chemo-Immunotherapy with Cisplatin-Pembrolizumab and Radiation for Unresectable Vulvar Squamous Cell Carcinoma. Journal of Translational Medicine, 18, Article No. 350.
https://doi.org/10.1186/s12967-020-02523-5 Shapira-Frommer, R., Mileshkin, L., Manzyuk, L., Penel, N., Burge, M., Piha-Paul, S.A., et al. (2022) Efficacy and Safety of Pembrolizumab for Patients with Previously Treated Advanced Vulvar Squamous Cell Carcinoma: Results from the Phase 2 KEYNOTE-158 Study. Gynecologic Oncology, 166, 211-218.
https://doi.org/10.1016/j.ygyno.2022.01.029 Bogani, G., Palaia, I., Perniola, G., Tomao, F., Giancotti, A., Di Mascio, D., et al. (2023) An Update on Current Pharmacotherapy for Vulvar Cancer. Expert Opinion on Pharmacother-apy, 24, 95-103.
https://doi.org/10.1080/14656566.2022.2117608
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