免疫治疗在晚期或复发性子宫内膜癌中的应用进展

刘逸贤; 陈嵘; 程忠平

doi:10.16766/j.cnki.issn.1674-4152.003217

免疫治疗在晚期或复发性子宫内膜癌中的应用进展

doi: 10.16766/j.cnki.issn.1674-4152.003217

上海市第十人民医院妇产科，上海 200072

基金项目:

上海市卫生健康委先进适宜技术推广项目 2019SY053

详细信息

通讯作者:
程忠平，E-mail: mdcheng18@263.net

中图分类号: R737.3 R730.5
计量
- 文章访问数: 426
- HTML全文浏览量: 217
- PDF下载量: 32
- 被引次数: 0
出版历程
- 收稿日期: 2022-11-08
- 网络出版日期: 2023-11-23

Advances in immunotherapy in advanced or recurrent endometrial carcinoma

Department of Obstetrics and Gynecology, Shanghai Tenth People ' s Hospital, Shanghai 200072, China

摘要

摘要: 子宫内膜癌(EC)是常见的妇科恶性肿瘤之一，由于肥胖和人口老龄化的加剧，其发病率逐渐上升。尽管早期EC通过手术治疗预后一般良好，但仍有部分患者出现或发展为转移性或复发性疾病。近年来，免疫治疗取得了新的进展，在晚期或复发性子宫内膜癌的治疗中具有重要地位，目前其免疫治疗主要包括免疫检查点抑制剂，如程序性细胞死亡蛋白1/程序性细胞死亡配体1抑制剂，细胞毒性T淋巴细胞相关蛋白4抑制剂，其他免疫治疗还包括嵌合抗原受体T细胞免疫疗法，肿瘤疫苗等，联合聚二磷酸腺苷核糖聚合酶抑制剂或靶向药物是研究热点，可以提高客观缓解率，产生附加效应甚至协同效应。免疫检查点抑制剂治疗微卫星不稳定和错配修复缺陷型子宫内膜癌疗效较好，在其他类型肿瘤中仍有待试验。细胞毒性T淋巴细胞相关蛋白4与免疫抑制检查点联合治疗有其独特优势，但是安全性和有效性还需要大量试验验证。联合聚二磷酸腺苷核糖聚合酶(PARP)抑制剂或靶向药物，药物种类和剂量，需要深入挖掘，以在最小副作用的前提下获得最佳疗效。对于癌症疫苗，有研究证实疫苗可以预防EC复发，但其安全性、有效性仍需大量临床试验进行验证。在未来免疫相关生物标志物的研究也将有助于预测EC治疗预后，对免疫治疗的研究具有重要意义。
- 免疫治疗 /
- 晚期或复发性子宫内膜癌 /
- 程序性细胞死亡蛋白1/程序性细胞死亡配体1抑制剂
Abstract: Endometrial cancer (EC) is one of the most common gynecological malignancies, and its incidence is increasing with the increase of obesity and aging population. Although the prognosis of early EC with surgical treatment is generally good, some patients still develop or develop metastatic or recurrent disease. In recent years, immunotherapy has made new progress and plays an important role in the treatment of advanced or recurrent EC. Immunotherapy mainly includes immune checkpoint inhibitors, such as programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Other immunotherapies include chimeric antigen receptor T cell (CAR-T) cell immunotherapy, tumor vaccine, etc. Combined with poly-ADP-ribose polymerase (PARP) inhibitors or targeted drugs is a hotspot, which can improve the objective response rate and produce additional effects or even synergistic effects. Immuno-checkpoint inhibitors are effective in the treatment of microsatellite unstable and mismatch repair defect endometrial carcinoma, but still need to be tested in other tumor types. The combination therapy of CTLA-4 and immunosuppressive checkpoint has its unique advantages, but its safety and efficacy need to be verified in a large number of trials. Combined with PARP inhibitors or targeted drugs, drug types and dosages need to be explored in order to achieve optimal efficacy with minimal side effects. As for cancer vaccine, studies have confirmed that the vaccine can prevent EC recurrence, but its safety and effectiveness still need to be verified. In the future, the study of immune-related biomarkers will also help to predict the prognosis of EC treatment, which is of great significance for the study of immunotherapy.
- Immunotherapy /
- Advanced or recurrent endometrial carcinoma /
- Programmed cell death 1/programmed cell death ligand-1 inhibitors

HTML全文

参考文献(32)

[1]	SIEGEL R L, MILLER K D, JEMAL A. Cancer statistics, 2019[J]. CA Cancer J Clin, 2019, 69(1): 7-34. doi: 10.3322/caac.21551
[2]	ZHAO D L, ZHANG Z, WANG Z H, et al. Diagnosis and prediction of endometrial carcinoma using machine learning and artificial neural networks based on public databases[J]. Genes (Basel), 2022, 13(6): 935. doi: 10.3390/genes13060935
[3]	DE BOER S M, POWELL M E, MILESHKIN L, et al. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial[J]. Lancet Oncol, 2019, 20(9): 1273-1285. doi: 10.1016/S1470-2045(19)30395-X
[4]	MUTLU L, HAROLD J, TYMON-ROSARIO J, et al. Immune checkpoint inhibitors for recurrent endometrial cancer[J]. Expert Rev Anticancer Ther, 2022, 22(3): 249-258. doi: 10.1080/14737140.2022.2044311
[5]	GOLDBERG K B, BLUMENTHAL G M, MCKEE A E, et al. The FDA Oncology Center of Excellence and precision medicine[J]. Exp Biol Med (Maywood), 2018, 243(3): 308-312. doi: 10.1177/1535370217740861
[6]	DE FELICE F, MARCHETTI C, PALAIA I, et al. Immune check-point in cervical cancer[J]. Crit Rev Oncol Hematol, 2018, 129: 40-43. doi: 10.1016/j.critrevonc.2018.06.006
[7]	GREEN A K, FEINBERG J, MAKKER V. A review of immune checkpoint blockade therapy in endometrial cancer[J]. Am Soc Clin Oncol Educ Book, 2020, 40: 1-7.
[8]	BARBER E L, CHEN S Q, PINEDA M J, et al. Clinical and biological activity of chemoimmunotherapy in advanced endometrial adenocarcinoma: a phase ii trial of the big ten cancer research consortium[J]. Cancer Res Commun, 2022, 2(10): 1293-1303. doi: 10.1158/2767-9764.CRC-22-0147
[9]	KUMAR S, GHOSH S, SHARMA G, et al. Preclinical characterization of dostarlimab, a therapeutic anti-PD-1 antibody with potent activity to enhance immune function in in vitro cellular assays and in vivo animal models[J]. MAbs, 2021, 13(1): 1954136. DOI: 10.1080/19420862.2021.1954136.
[10]	OAKNIN A, TINKER A V, GILBERT L, et al. Clinical activity and safety of the anti-programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial cancer: a nonrandomized phase 1 clinical trial[J]. JAMA Oncol, 2020, 6(11): 1766-1772. doi: 10.1001/jamaoncol.2020.4515
[11]	MATHEWS C, LORUSSO D, COLEMAN R L, et al. An indirect comparison of the efficacy and safety of dostarlimab and doxorubicin for the treatment of advanced and recurrent endometrial cancer[J]. Oncologist, 2022, 27(12): 1058-1066. doi: 10.1093/oncolo/oyac188
[12]	KONSTANTINOPOULOS P A, LUO W X, LIU J F, et al. Phase Ⅱ study of avelumab in patients with mismatch repair deficient and mismatch repair proficient recurrent/persistent endometrial cancer[J]. J Clin Oncol, 2019, 37(30): 2786-2794. doi: 10.1200/JCO.19.01021
[13]	ANTILL Y, KOK P S, ROBLEDO K, et al. Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial[J]. J Immunother Cancer, 2021, 9(6): e002255. DOI: 10.1136/jitc-2020-002255.
[14]	FLEMING G, EMENS L, EDER J, et al. Clinical activity, safety and biomarker results from a phase Ia study of atezolizumab(atezo) in advanced/recurrent endometrial cancer(rEC)[J]. J Clin Oncol, 2017, 35(15_suppl): 5585. doi: 10.1200/JCO.2017.35.15_suppl.5585
[15]	HOSSEINI A, GHARIBI T, MAROFI F, et al. CTLA-4: from mechanism to autoimmune therapy[J]. Int Immunopharmacol, 2020, 80: 106221. DOI: 10.1016/j.intimp.2020.106221.
[16]	OH M S, CHEN Y K. Deep and durable response with combination CTLA-4 and PD-1 blockade in Mismatch Repair (MMR)-proficient endometrial cancer[J]. J Immunother, 2019, 42(2): 51-54. doi: 10.1097/CJI.0000000000000244
[17]	RUBINSTEIN M M, CAIRD I, ZHOU Q, et al. A phase Ⅱ trial of durvalumab with or without tremelimumab in patients with persistent or recurrent endometrial carcinoma and endometrial carcinosarcoma[J]. J Clin Oncol, 2019, 37: 5582. doi: 10.1200/JCO.2019.37.15_suppl.5582
[18]	MAHMOOD S S, CHEN C L, SHAPNIK N, et al. Myocarditis with tremelimumab plus durvalumab combination therapy for endometrial cancer: a case report[J]. Gynecol Oncol Rep, 2018, 25: 74-77. doi: 10.1016/j.gore.2018.05.014
[19]	MILIOTOU A N, PAPADOPOULOU L C. CAR T-cell therapy: a new era in cancer immunotherapy[J]. Curr Pharm Biotechnol, 2018, 19(1): 5-18. doi: 10.2174/1389201019666180418095526
[20]	SCHEPISI G, CASADEI C, TOMA I, et al. Immunotherapy and its development for gynecological (ovarian, endometrial and cervical) tumors: from immune checkpoint inhibitors to Chimeric Antigen Receptor (CAR)-T cell therapy[J]. Cancers (Basel), 2021, 13(4): 804. doi: 10.3390/cancers13040804
[21]	CÉSAIRE M, THARIAT J, CANDÉIAS S M, et al. Combining PARP inhibition, radiation, and immunotherapy: a possible strategy to improve the treatment of cancer?[J]. Int J Mol Sci, 2018, 19(12): 3793. doi: 10.3390/ijms19123793
[22]	DING L Y, KIM H J, WANG Q W, et al. PARP inhibition elicits STING-dependent antitumor immunity in brca1-deficient ovarian cancer[J]. Cell Rep, 2018, 25(11): 2972-2980. doi: 10.1016/j.celrep.2018.11.054
[23]	NATARAJAN U, VENKATESAN T, DHANDAYUTHAPANI S, et al. Differential mechanisms involved in RG-7388 and Nutlin-3 induced cell death in SJSA-1 osteosarcoma cells[J]. Cell Signal, 2020, 11(75): 109742. DOI: 10.1016/j.cellsig.2020.109742.
[24]	SHEN K, YANG L, LI F Y, et al. Research progress of PARP inhibitor monotherapy and combination therapy for endometrial cancer[J]. Curr Drug Targets, 2022, 23(2): 145-155. doi: 10.2174/1389450122666210617111304
[25]	POST C C B, WESTERMANN A M, BOERE I A, et al. Efficacy and safety of durvalumab with olaparib in metastatic or recurrent endometrial cancer (phase Ⅱ DOMEC trial)[J]. Gynecol Oncol, 2022, 165(2): 223-229. doi: 10.1016/j.ygyno.2022.02.025
[26]	KONSTANTINOPOULOS P A, GOCKLEY A A, XIONG N, et al. Evaluation of treatment with talazoparib and avelumab in patients with recurrent mismatch repair proficient endometrial cancer[J]. JAMA Oncol, 2022, 8(9): 1317-1322. doi: 10.1001/jamaoncol.2022.2181
[27]	MIMCHELL T C, HAMID O, SMITH D C, et al. Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase Ⅰ results from a multicenter, open-label phase Ⅰ/Ⅱ trial (ECHO-202/KEYNOTE-037)[J]. J Clin Oncol, 2018, 36(32): 3223-3230. doi: 10.1200/JCO.2018.78.9602
[28]	MAKKER V, RASCO D, VOGELZANG N J, 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
[29]	ZIMMER A S, NICHOLS E, CIMINO-MATHEWS A, et al. A phase I study of the PD-L1 inhibitor, durvalumab, in combination with a PARP inhibitor, olaparib, and a VEGFR1-3 inhibitor, cediranib, in recurrent women ' s cancers with biomarker analyses[J]. J Immunother Cancer, 2019, 7(1): 197. doi: 10.1186/s40425-019-0680-3
[30]	KOOSHKAKI O, DERAKHSHANI A, SAFARPOUR H, et al. The latest findings of PD-1/PD-L1 inhibitor application in gynecologic cancers[J]. Int J Mol Sci, 2020, 21(14): 5034. doi: 10.3390/ijms21145034
[31]	徐力, 聂柳燕, 汪胡燕, 等. 自身免疫性疾病中程序性细胞死亡因子1及其配体的研究进展[J]. 中华全科医学, 2022, 20(5): 832-835, 843. doi: 10.16766/j.cnki.issn.1674-4152.002466 XU L, NIE L Y, WANG H Y, et al. Research progress of programmed cell death-1 and its ligand in autoimmune diseases[J]. Chinese Journal of General Practice, 2022, 20(5): 832-835, 843. doi: 10.16766/j.cnki.issn.1674-4152.002466
[32]	高五岳, 郭园园, 刘贝贝, 等. 不同距离癌旁组织PD-1和PD-L1表达对肾部分切除术边距选择的临床意义[J]. 中华全科医学, 2019, 17(12): 2004-2007, 2034. doi: 10.16766/j.cnki.issn.1674-4152.001113 GAO W Y, GUO Y Y, LIU B B, et al. The clinical significances of PD-1 and PD-L1 expressions in different distant tumor adjacent tissues for selecting safe surgical margins in partial nephrectomy[J]. Chinese Journal of General Practice, 2019, 17(12): 2004-2007, 2034. doi: 10.16766/j.cnki.issn.1674-4152.001113