免疫检查点抑制剂在妇科恶性肿瘤中的应用

doi:10.12280/gjfckx.20220005

摘要/Abstract

摘要：

子宫内膜癌、宫颈癌和卵巢癌是妇科最常见的三大恶性肿瘤,治疗方式以手术、放化疗为主,然而其复发率和转移率仍较高。免疫检查点抑制剂通过阻断抑制性检查点与其配体结合,激活免疫细胞活性,实现抗肿瘤作用。随着免疫检查点抑制剂在妇科肿瘤中的研究不断深入,发现其客观缓解率多为10%~20%左右,而联合放化疗一定程度上可提高疗效,可能为妇科肿瘤患者提供更大的临床获益。但其不良反应不可忽视,如皮肤瘙痒、黏膜炎、腹泻和结肠炎等。因此,探索预测性生物标志物、筛选出免疫检查点抑制剂治疗的适用人群、早期识别及合理干预不良事件,对免疫检查点抑制剂在妇科恶性肿瘤中的应用至关重要。

关键词: 程序性细胞死亡受体1, CTLA-4抗原, 生殖器肿瘤,女（雌）性, 免疫疗法, 免疫检查点抑制剂

Abstract:

Endometrial cancer, cervical cancer and ovarian cancer are the three most common gynecological malignancies. The treatment methods are mainly surgery, radiotherapy and chemotherapy. However, the recurrence rate and metastasis rate are still high. By blocking the binding of inhibitory checkpoints and their ligands, immune checkpoint inhibitors activate the activity of immune cells and achieve antitumor effects. With the deepening of the research on immune checkpoint inhibitors in gynecological tumors, it is found that the objective response rate is mostly about 10%-20%, and the combination of radiotherapy and chemotherapy can greatly improve the curative effect, which may provide greater clinical benefits for gynecological tumor patients. However, its adverse reactions can not be ignored, such as skin itching, mucositis, diarrhea and colitis. Therefore, exploring predictive biomarkers, screening the applicable population for immune checkpoint inhibitor treatment, early identification and reasonable intervention of adverse events are very important for the application of immune checkpoint inhibitors in gynecological malignant tumors.

Key words: Programmed cell death receptor 1, CTLA-4 antigen, Genital neoplasms, female, Immunotherapy, Immune checkpoint inhibitor

王芳, 杨涛, 吴珍珍, 王惠玲. 免疫检查点抑制剂在妇科恶性肿瘤中的应用[J]. 国际妇产科学杂志, 2022, 49(5): 519-523.

WANG Fang, YANG Tao, WU Zhen-zhen, WANG Hui-ling. Application of Immune Checkpoint Inhibitor in Gynecological Malignant Tumors[J]. Journal of International Obstetrics and Gynecology, 2022, 49(5): 519-523.

参考文献 32

[1]	International Agency for Research on Cancer. Global Cancer Observatory: Cancer Tomorrow[EB/OL]. (2019-08-10). https://gco.iarc.fr/tomorrow/home.
[2]	Linsley PS, Bradshaw J, Greene J, et al. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement[J]. Immunity, 1996, 4(6):535-543. doi: 10.1016/s1074-7613(00)80480-x. doi: 10.1016/s1074-7613(00)80480-x pmid: 8673700
[3]	Hodi FS, O′Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma[J]. N Engl J Med, 2010, 363(8):711-723. doi: 10.1056/NEJMoa1003466. doi: 10.1056/NEJMoa1003466
[4]	Page DB, Postow MA, Callahan MK, et al. Immune modulation in cancer with antibodies[J]. Annu Rev Med, 2014, 65:185-202. doi: 10.1146/annurev-med-092012-112807. doi: 10.1146/annurev-med-092012-112807 pmid: 24188664
[5]	Kasten BB, Ferrone S, Zinn KR, et al. B7-H3-targeted Radioimmunotherapy of Human Cancer[J]. Curr Med Chem, 2020, 27(24):4016-4038. doi: 10.2174/0929867326666190228120908. doi: 10.2174/0929867326666190228120908 pmid: 30836909
[6]	Nocentini G, Cari L, Ronchetti S, et al. Modulation of tumor immunity: a patent evaluation of WO2015026684A1[J]. Expert Opin Ther Pat, 2016, 26(3):417-425. doi: 10.1517/13543776.2016.1118061. doi: 10.1517/13543776.2016.1118061 pmid: 26560753
[7]	Herzog TJ, Arguello D, Reddy SK, et al. PD-1, PD-L1 expression in 1599 gynecological cancers: Implications for immunotherapy[J]. Gynecol Oncol, 2015, 137(Suppl 1):204-205. doi: 10.1016/j.ygyno.2015.01.514. doi: 10.1016/j.ygyno.2015.01.514
[8]	Frenel JS, Le Tourneau C, O′Neil B, et al. Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1-Positive Cervical Cancer: Results From the Phase Ib KEYNOTE-028 Trial[J]. J Clin Oncol, 2017, 35(36):4035-4041. doi: 10.1200/JCO.2017.74.5471. doi: 10.1200/JCO.2017.74.5471
[9]	Chung HC, Schellens JHM, Delord JP, et al. Pembrolizumab treatment of advanced cervical cancer: Updated results from the phase 2 KEYNOTE-158 study[J]. J Clin Oncol, 2018, 36 (suppl 15):5522. doi: 10.1200/JCO.2018.36.15_suppl.5522. doi: 10.1200/JCO.2018.36.15_suppl.5522
[10]	Santin AD, Deng W, Frumovitz M, et al. Phase II evaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002)[J]. Gynecol Oncol, 2020, 157(1):161-166. doi: 10.1016/j.ygyno.2019.12.034. doi: S0090-8258(19)31864-5 pmid: 31924334
[11]	Tamura K, Hasegawa K, Katsumata N, et al. Efficacy and safety of nivolumab in Japanese patients with uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma: Multicenter, open-label phase 2 trial[J]. Cancer Sci, 2019, 110(9):2894-2904. doi: 10.1111/cas.14148. doi: 10.1111/cas.14148
[12]	Tewari KS, Monk BJ, Vergote I, et al. Survival with Cemiplimab in Recurrent Cervical Cancer[J]. N Engl J Med, 2022, 386(6):544-555. doi: 10.1056/NEJMoa2112187. doi: 10.1056/NEJMoa2112187
[13]	Mayadev JS, Enserro D, Lin YG, et al. Sequential Ipilimumab After Chemoradiotherapy in Curative-Intent Treatment of Patients With Node-Positive Cervical Cancer[J]. JAMA Oncol, 2020, 6(1):92-99. doi: 10.1001/jamaoncol.2019.3857. doi: 10.1001/jamaoncol.2019.3857
[14]	Liu Y, Wu L, Tong R, et al. PD-1/PD-L1 Inhibitors in Cervical Cancer[J]. Front Pharmacol, 2019, 10:65. doi: 10.3389/fphar.2019.00065. doi: 10.3389/fphar.2019.00065 pmid: 30774597
[15]	Ott PA, Bang YJ, Berton-Rigaud D, et al. Safety and Antitumor Activity of Pembrolizumab in Advanced Programmed Death Ligand 1-Positive Endometrial Cancer: Results From the KEYNOTE-028 Study[J]. J Clin Oncol, 2017, 35(22):2535-2541. doi: 10.1200/JCO.2017.72.5952. doi: 10.1200/JCO.2017.72.5952 pmid: 28489510
[16]	Fader AN, Diaz LA, Armstrong DK, et al. Preliminary results of a phase II study: PD-1 blockade in mismatch repair-deficient, recurrent or persistent endometrial cancer[J]. Gynecol Oncol, 2016, 141(1):206-207. doi: 10.1016/j.ygyno.2016.04.532. doi: 10.1016/j.ygyno.2016.04.532
[17]	Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma[J]. Nature, 2013, 497(7447):67-73. doi: 10.1038/nature12113. doi: 10.1038/nature12113
[18]	Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade[J]. Science, 2017, 357(6349):409-413. doi: 10.1126/science.aan6733. doi: 10.1126/science.aan6733 pmid: 28596308
[19]	Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study[J]. J Clin Oncol, 2020, 38(1):1-10. doi: 10.1200/JCO.19.02105. doi: 10.1200/JCO.19.02105 pmid: 31682550
[20]	Bellone S, Roque DM, Siegel ER, et al. A phase II evaluation of pembrolizumab in recurrent microsatellite instability-high (MSI-H) endometrial cancer patients with Lynch-like versus MLH-1 methylated characteristics (NCT02899793)[J]. Ann Oncol, 2021, 32(8):1045-1046. doi: 10.1016/j.annonc.2021.04.013. doi: 10.1016/j.annonc.2021.04.013 pmid: 33932502
[21]	Makker V, Rasco D, Vogelzang NJ, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial[J]. Lancet Oncol, 2019, 20(5):711-718. doi: 10.1016/S1470-2045(19)30020-8. doi: S1470-2045(19)30020-8 pmid: 30922731
[22]	Varga A, Piha-Paul S, Ott PA, et al. Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028[J]. Gynecol Oncol, 2019, 152(2):243-250. doi: 10.1016/j.ygyno.2018.11.017. doi: S0090-8258(18)31418-5 pmid: 30522700
[23]	Liu JF, Gordon M, Veneris J, et al. Safety, clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers[J]. Gynecol Oncol, 2019, 154(2):314-322. doi: 10.1016/j.ygyno.2019.05.021. doi: S0090-8258(19)31265-X pmid: 31204078
[24]	Disis ML, Taylor MH, Kelly K, et al. Efficacy and Safety of Avelumab for Patients With Recurrent or Refractory Ovarian Cancer: Phase 1b Results From the JAVELIN Solid Tumor Trial[J]. JAMA Oncol, 2019, 5(3):393-401. doi: 10.1001/jamaoncol.2018.6258. doi: 10.1001/jamaoncol.2018.6258 pmid: 30676622
[25]	Varga A, Pihapaul SA, Ott PA, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer: Interim results from a phase Ib study[J]. J Clin Oncol, 2015, 33(suppl 15):5510. doi: 10.1200/jco.2015.33.15_suppl.5510. doi: 10.1200/jco.2015.33.15_suppl.5510
[26]	Matulonis UA, Shapira-Frommer R, Santin AD, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study[J]. Ann Oncol, 2019, 30(7):1080-1087. doi: 10.1093/annonc/mdz135. doi: S0923-7534(19)31241-4 pmid: 31987374
[27]	Pujade-Lauraine E, Fujiwara K, Ledermann JA, et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study[J]. Lancet Oncol, 2021, 22(7):1034-1046. doi: 10.1016/S1470-2045(21)00216-3. doi: 10.1016/S1470-2045(21)00216-3
[28]	Xia LF, Peng J, Lou G, et al. Antitumor activity and safety of camrelizumab plus famitinib in patients with platinum-resistant recurrent ovarian cancer: results from an open-label, multicenter phase 2 basket study[J]. J Immunother Cancer, 2022, 10(1):e003831. doi: 10.1136/jitc-2021-003831. doi: 10.1136/jitc-2021-003831
[29]	Lan C, Shen J, Wang Y, et al. Camrelizumab Plus Apatinib in Patients With Advanced Cervical Cancer (CLAP): A Multicenter, Open-Label, Single-Arm, Phase II Trial[J]. J Clin Oncol, 2020, 38(34):4095-4106. doi: 10.1200/JCO.20.01920. doi: 10.1200/JCO.20.01920 pmid: 33052760
[30]	Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer[J]. N Engl J Med, 2021, 385(20):1856-1867. doi: 10.1056/NEJMoa2112435. doi: 10.1056/NEJMoa2112435
[31]	Kumar V, Chaudhary N, Garg M, et al. Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy[J]. Front Pharmacol, 2017, 8:49. doi: 10.3389/fphar.2017.00049. doi: 10.3389/fphar.2017.00049 pmid: 28228726
[32]	Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency[J]. N Engl J Med, 2015, 372(26):2509-2520. doi: 10.1056/NEJMoa1500596. doi: 10.1056/NEJMoa1500596