宫颈癌放化疗联合免疫治疗的研究进展

doi:10.3760/cma.j.cn371439-20250619-00124

摘要/Abstract

摘要：

在宫颈癌的临床研究中，放化疗联合免疫治疗取得了一定成果，程序性死亡受体1/程序性死亡受体配体1抑制剂在多项临床试验中亦展现出积极的结果。人乳头状瘤病毒多肽疫苗、DNA疫苗、肿瘤浸润淋巴细胞疗法和双特异性抗体等新型免疫疗法也在复发或转移性宫颈癌治疗中有所应用，展现出显著的抗肿瘤活性、重塑免疫微环境、适配个体化治疗及与多模式联合增效等潜力。深入探讨联合治疗方案的协同机制及多种疗法在宫颈癌治疗中的应用和发展限制因素，可为进一步优化宫颈癌的治疗策略提供思路。

关键词: 宫颈肿瘤, 免疫疗法, 化放疗, 肿瘤微环境, PD-1/PD-L1抑制剂

Abstract:

In clinical studies of cervical cancer， the combination of radiotherapy， chemotherapy， and immunotherapy has yielded certain results. Programmed death-1/programmed death-ligand 1 inhibitors have also demonstrated positive results in multiple clinical trials. Novel immunotherapies such as human papillomavirus peptide vaccines， DNA vaccines， tumor-infiltrating lymphocyte therapy， and bispecific antibodies have been applied in the treatment of recurrent or metastatic cervical cancer， demonstrating significant anti-tumor activity， the potential to reshape the immune microenvironment， adaptability to personalized treatment， and synergistic effects when combined with multi-modal therapies. A deeper exploration of the synergistic mechanisms of combined therapy regimens and the application and development limitations of various therapies in cervical cancer treatment can provide insights for further optimizing treatment strategies for cervical cancer.

Key words: Uterine cervical neoplasms, Immunotherapy, Chemoradiotherapy, Tumor microenvironment, PD-1/PD-L1 inhibitors

马永佳, 彭思雨, 孙鹏飞. 宫颈癌放化疗联合免疫治疗的研究进展[J]. 国际肿瘤学杂志, 2025, 52(11): 726-731.

Ma Yongjia, Peng Siyu, Sun Pengfei. Research progress on combined radiotherapy， chemotherapy， and immunotherapy for cervical cancer[J]. Journal of International Oncology, 2025, 52(11): 726-731.

参考文献 42

[1]	Filho AM, Laversanne M, Ferlay J, et al. The GLOBOCAN 2022 cancer estimates: data sources, methods, and a snapshot of the cancer burden worldwide[J]. Int J Cancer, 2025, 156(7): 1336-1346. DOI: 10.1002/ijc.35278.
[2]	Chen SW, Liang JA, Yang SN, et al. Radiation injury to intestine following hysterectomy and adjuvant radiotherapy for cervical cancer[J]. Gynecol Oncol, 2004, 95(1): 208-214. DOI: 10.1016/j.ygyno.2004.07.003.
[3]	Assi S, Barling M, Al-Hamid A, et al. Exploring the adverse effects of chemotherapeutic agents used in the treatment of cervical and ovarian cancer from the patients' perspective: a content analysis of the online discussion forums[J]. Eur J Hosp Pharm, 2021, 28(Suppl 2): e35-e40. DOI: 10.1136/ejhpharm-2019-002162.
[4]	Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial[J]. Lancet, 2024, 403(10434): 1341-1350. DOI: 10.1016/s0140-6736(24)00317-9. pmid: 38521086
[5]	Xue J, Yan X, Ding Q, et al. Effect of neoadjuvant chemotherapy on the immune microenvironment of gynaecological tumours[J]. Ann Med, 2023, 55(2): 2282181. DOI: 10.1080/07853890.2023.2282181.
[6]	Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift[J]. J Natl Cancer Inst, 2013, 105(4): 256-265. DOI: 10.1093/jnci/djs629. pmid: 23291374
[7]	Dorta-Estremera S, Colbert LE, Nookala SS, et al. Kinetics of intratumoral immune cell activation during chemoradiation for cervical cancer[J]. Int J Radiat Oncol Biol Phys, 2018, 102(3): 593-600. DOI: 10.1016/j.ijrobp.2018.06.404.
[8]	Du SS, Chen GW, Yang P, et al. Radiation therapy promotes hepatocellular carcinoma immune cloaking via PD-L1 upregulation induced by cGAS-STING activation[J]. Int J Radiat Oncol Biol Phys, 2022, 112(5): 1243-1255. DOI: 10.1016/j.ijrobp.2021.12.162.
[9]	Melief CJM, Welters MJP, Vergote I, et al. Strong vaccine responses during chemotherapy are associated with prolonged cancer survival[J]. Sci Transl Med, 2020, 12(535): eaaz8235. DOI: 10.1126/scitranslmed.aaz8235.
[10]	Kim NR, Kim YJ. Oxaliplatin regulates myeloid-derived suppressor cell-mediated immunosuppression via downregulation of nuclear factor-κB signaling[J]. Cancer Med, 2019, 8(1): 276-288. DOI: 10.1002/cam4.1878.
[11]	Liang Y, Lü W, Zhang X, et al. Tumor-infiltrating CD8⁺ and FOXP3⁺ lymphocytes before and after neoadjuvant chemotherapy in cervical cancer[J]. Diagn Pathol, 2018, 13(1): 93. DOI: 10.1186/s13000-018-0770-4. pmid: 30474571
[12]	Kast F, Klein C, Umaña P, et al. Advances in identification and selection of personalized neoantigen/T-cell pairs for autologous adoptive T cell therapies[J]. Oncoimmunology, 2021, 10(1): 1869389. DOI: 10.1080/2162402x.2020.1869389.
[13]	Rodrigues M, Vanoni G, Loap P, et al. Nivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial[J]. Nat Commun, 2023, 14(1): 3698. DOI: 10.1038/s41467-023-39383-8.
[14]	Mayadev J, Zamarin D, Deng W, et al. Neoadjuvant or concurrent atezolizumab with chemoradiation for locally advanced cervical cancer: a randomized phase Ⅰ trial[J]. Nat Commun, 2025, 16(1): 553. DOI: 10.1038/s41467-024-55200-2.
[15]	Knisely A, Ahmed J, Stephen B, et al. Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies[J]. Cancer, 2024, 130(3): 400-409. DOI: 10.1002/cncr.35063.
[16]	Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet, 2024, 404(10460): 1321-1332. DOI: 10.1016/S0140-6736(24)01808-7. pmid: 39288779
[17]	How JA, Jazaeri AA. Immunotherapy in locally advanced cervical cancer: integrating KEYNOTE-A18 into management strategies[J]. Med, 2024, 5(6): 487-489. DOI: 10.1016/j.medj.2024.05.001. pmid: 38878765
[18]	Monk BJ, Toita T, Wu X, et al. Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial[J]. Lancet Oncol, 2023, 24(12): 1334-1348. DOI: 10.1016/s1470-2045(23)00479-5. pmid: 38039991
[19]	张露, 蒋华, 林州, 等. 免疫检查点抑制剂治疗复发转移性宫颈癌的疗效及预后分析[J]. 国际肿瘤学杂志, 2023, 50(8): 475-483. DOI: 10.3760/cma.j.cn371439-20230227-00091.
[20]	Li K, Chen J, Hu Y, et al. Neoadjuvant chemotherapy plus camrelizumab for locally advanced cervical cancer (NACI study): a multicentre, single-arm, phase 2 trial[J]. Lancet Oncol, 2024, 25(1): 76-85. DOI: 10.1016/s1470-2045(23)00531-4. pmid: 38048802
[21]	Zheng X, Gu H, Cao X, et al. Tislelizumab for cervical cancer: a retrospective study and analysis of correlative blood biomarkers[J]. Front Immunol, 2023, 14: 1113369. DOI: 10.3389/fimmu.2023.1113369.
[22]	Xia L, Wang J, Wang C, et al. Efficacy and safety of zimberelimab (GLS-010) monotherapy in patients with recurrent or metastatic cervical cancer: a multicenter, single-arm, phase Ⅱ study[J]. Int J Gynecol Cancer, 2023, 33(12): 1861-1868. DOI: 10.1136/ijgc-2023-004705.
[23]	Ni BQ, Pan MM, He LX, et al. Zimberelimab combined with systemic therapy extended tumor control in post-radiotherapy cervical cancer with brain metastases: a case report[J]. J Obstet Gynaecol Res, 2024, 50(4): 740-745. DOI: 10.1111/jog.15887.
[24]	Ou D, Cai R, Qi WX, et al. Toripalimab combined with definitive chemoradiotherapy for locally advanced cervical squamous cell carcinoma patients (TRACE): a single-arm, phase Ⅰ/Ⅱ trial[J]. Cancer Immunol Immunother, 2024, 73(12): 244. DOI: 10.1007/s00262-024-03823-1.
[25]	Massarelli E, William W, Johnson F, et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer: a phase 2 clinical trial[J]. JAMA Oncol, 2019, 5(1): 67-73. DOI: 10.1001/jamaoncol.2018.4051. pmid: 30267032
[26]	Hasan Y, Furtado L, Tergas A, et al. A phase 1 trial assessing the safety and tolerability of a therapeutic DNA vaccination against HPV16 and HPV18 E6/E7 oncogenes after chemoradiation for cervical cancer[J]. Int J Radiat Oncol Biol Phys, 2020, 107(3): 487-498. DOI: 10.1016/j.ijrobp.2020.02.031.
[27]	Huang H, Nie CP, Liu XF, et al. Phase Ⅰ study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer[J]. J Clin Invest, 2022, 132(15): e157726. DOI: 10.1172/jci157726.
[28]	O'Malley DM, Neffa M, Monk BJ, et al. Dual PD-1 and CTLA-4 checkpoint blockade using balstilimab and zalifrelimab combination as second-line treatment for advanced cervical cancer: an open-label phase Ⅱ study[J]. J Clin Oncol, 2022, 40(7): 762-771. DOI: 10.1200/jco.21.02067.
[29]	Wu X, Sun Y, Yang H, et al. Cadonilimab plus platinum-based chemotherapy with or without bevacizumab as first-line treatment for persistent, recurrent, or metastatic cervical cancer (COMPASSION-16): a randomised, double-blind, placebo-controlled phase 3 trial in China[J]. Lancet, 2024, 404(10463): 1668-1676. DOI: 10.1016/s0140-6736(24)02135-4. pmid: 39426385
[30]	Berenguer Frances MA, Linares-Galiana I, Cañas Cortés R, et al. Changes of CD68, CD163, and PD-L1 tumor expression during high-dose-rate and pulsed-dose-rate brachytherapy for cervical cancer[J]. Brachytherapy, 2020, 19(1): 51-59. DOI: 10.1016/j.brachy.2019.09.009. pmid: 31690516
[31]	Da Silva DM, Enserro DM, Mayadev JS, et al. Immune activation in patients with locally advanced cervical cancer treated with ipilimumab following definitive chemoradiation (GOG-9929)[J]. Clin Cancer Res, 2020, 26(21): 5621-30. DOI: 10.1158/1078-0432.Ccr-20-0776.
[32]	Li R, Liu Y, Yin R, et al. The dynamic alternation of local and systemic tumor immune microenvironment during concurrent chemoradiotherapy of cervical cancer: a prospective clinical trial[J]. Int J Radiat Oncol Biol Phys, 2021, 110(5): 1432-1441. DOI: 10.1016/j.ijrobp.2021.03.003.
[33]	Ma CY, Zhao J, Qian KY, et al. Analysis of nutritional risk, skeletal muscle depletion, and lipid metabolism phenotype in acute radiation enteritis[J]. World J Gastrointest Surg, 2023, 15(12): 2831-2843. DOI: 10.4240/wjgs.v15.i12.2831.
[34]	Dover L, Dulaney C. Spine stereotactic radiosurgery, prostate radiation frequency, adjuvant chemotherapy for cervical cancer, bacteria and radiation dermatitis, and breast conservation therapy for multi-focal disease[J]. Pract Radiat Oncol, 2023, 13(5): 379-383. DOI: 10.1016/j.prro.2023.06.002.
[35]	Tu Y, Luo L, Zhou Q, et al. Fecal microbiota transplantation repairs radiation enteritis through modulating the gut microbiota-mediated tryptophan metabolism[J]. Radiat Res, 2024, 201(6): 572-585. DOI: 10.1667/rade-23-00189.1.
[36]	Monk BJ, Colombo N, Tewari KS, et al. First-line pembrolizumab+chemotherapy versus placebo+chemotherapy for persistent, recurrent, or metastatic cervical cancer: final overall survival results of KEYNOTE-826[J]. J Clin Oncol, 2023, 41(36): 5505-5511. DOI: 10.1200/jco.23.00914.
[37]	Gutiérrez-Hoya A, Soto-Cruz I. NK cell regulation in cervical cancer and strategies for immunotherapy[J]. Cells, 2021, 10(11): 3104. DOI: 10.3390/cells10113104.
[38]	Monk BJ, Tewari KS, Dubot C, et al. Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2023, 24(4): 392-402. DOI: 10.1016/s1470-2045(23)00052-9. pmid: 36878237
[39]	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.
[40]	张力忆, 蒋奉希, 桂定清. 贝伐珠单抗联合紫杉醇+卡铂治疗持续性或复发性宫颈癌的临床观察[J]. 中国药房, 2024, 35(17): 2126-2130. DOI: 10.6039/j.issn.1001-0408.2024.17.12.
[41]	向阳, 曹金龙, 聂桂梅, 等. 贝伐珠单抗联合紫杉醇和卡铂治疗复发/转移性宫颈癌患者的临床研究[J]. 中国临床药理学杂志, 2024, 40(8): 1121-1125. DOI: 10.13699/j.cnki.1001-6821.2024.08.007.
[42]	Zhang Z, Ma Q, Zhang L, et al. Human papillomavirus and cervical cancer in the microbial world: exploring the vaginal microecology[J]. Front Cell Infect Microbiol, 2024, 14: 1325500. DOI: 10.3389/fcimb.2024.1325500.