• 中国中文核心期刊
  • 中国科学引文数据库核心期刊
  • 中国科技核心期刊
  • 中国高校百佳科技期刊
高级检索

基于免疫检查点抑制剂的联合治疗策略研究进展

杨楠, 张哓, 吕慧, 霍美蓉, 徐巍

杨楠, 张哓, 吕慧, 霍美蓉, 徐巍. 基于免疫检查点抑制剂的联合治疗策略研究进展[J]. 中国药科大学学报, 2023, 54(2): 131-140. DOI: 10.11665/j.issn.1000-5048.20221028002
引用本文: 杨楠, 张哓, 吕慧, 霍美蓉, 徐巍. 基于免疫检查点抑制剂的联合治疗策略研究进展[J]. 中国药科大学学报, 2023, 54(2): 131-140. DOI: 10.11665/j.issn.1000-5048.20221028002
YANG Nan, ZHANG Xiao, LYU Hui, HUO Meirong, XU Wei. Advances in immune checkpoint inhibitors combined with other treatments[J]. Journal of China Pharmaceutical University, 2023, 54(2): 131-140. DOI: 10.11665/j.issn.1000-5048.20221028002
Citation: YANG Nan, ZHANG Xiao, LYU Hui, HUO Meirong, XU Wei. Advances in immune checkpoint inhibitors combined with other treatments[J]. Journal of China Pharmaceutical University, 2023, 54(2): 131-140. DOI: 10.11665/j.issn.1000-5048.20221028002

基于免疫检查点抑制剂的联合治疗策略研究进展

基金项目: 山东省中医药科技发展计划资助项目(No.2019-0372);济南市科技计划资助项目(临床医学科技创新计划)(No.202019176);山东省自然科学基金资助项目(No.ZR2021MH118);2021年山东省博士后创新资助项目(No.273219);中国博士后科学基金资助项目(No.2022M711972)

Advances in immune checkpoint inhibitors combined with other treatments

Funds: This study was supported by the Traditional Chinese Medicine Science and Technology Development Program of Shandong Province (No.2019-0372); the Program of Science and Technology Development of Ji''nan (Clinical Medicine Science and Technology Innovation Program) (No.202019176); the Provincial Natural Science Foundation of Shandong (No.ZR2021MH118); Shandong Provincial Postdoctoral Innovation Program in 2021 (No.273219); and China Postdoctoral Science Foundation (No.2022M711972)
  • 摘要: 免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)疗法是目前最受关注的肿瘤免疫疗法之一,已被批准为多种肿瘤治疗的一线用药。然而,单一的ICIs疗法具有疗效有限、易耐药等缺陷。因此,开发联合治疗策略以提高ICIs疗效,成为抗肿瘤领域的研究热点。文章首先介绍了ICIs的新型作用靶点,并结合ICIs产生治疗抵抗的机制,系统介绍了现有疗法(如化疗、放疗、热治疗、抗血管生成治疗、肿瘤疫苗、细胞因子治疗、过继细胞疗法等)与ICIs的联合治疗策略,并深入探讨了其增强肿瘤杀伤作用的机制,为临床针对患者病理特征进行个性化联合治疗提供参考。
    Abstract: As one of the most attention-attracting immunotherapy, immune checkpoint inhibitors (ICIs) have been approved as the first-line drugs for the therapy of various types of cancers.Nevertheless, the single application of ICIs exhibited limited efficacy, and it is easy to develop drug resistance.Therefore, the development of combination therapies become a hot topic in this field to improve the efficacy of ICIs therapy.This article describes some new ICIs targets, reveals the mechanisms of resistance, and introduces the current status of combination other therapies with ICIs therapy systematically including chemotherapy, radiotherapy, hyperthermia, antiangiogenic therapy, tumor vaccines, cytokine therapy and adoptive cellular therapy.Furthermore, the synergistic mechanism of combination therapy to enhance antitumor effect.Thus, this article provides solid references for personalized combination therapy according to the pathological characteristics of patients.
  • [1] Chen R, Hou XM, Yang LP, et al. Comparative efficacy and safety of first-line treatments for advanced non-small cell lung cancer with immune checkpoint inhibitors:a systematic review and meta-analysis[J]. Thorac Cancer, 2019, 10(4): 607-623.
    [2] Iravani A, Osman MM, Weppler AM, et al. FDG PET/CT for tumoral and systemic immune response monitoring of advanced melanoma during first-line combination ipilimumab and nivolumab treatment[J]. Eur J Nucl Med Mol Imaging, 2020, 47(12): 2776-2786.
    [3] Rizzo A, Mollica V, Massari F. Expression of programmed cell death ligand 1 as a predictive biomarker in metastatic urothelial carcinoma patients treated with first-line immune checkpoint inhibitors versus chemotherapy: a systematic review and meta-analysis[J]. Eur Urol Focus, 2022, 8(1): 152-159.
    [4] Yoneda K, Imanishi N, Ichiki Y, et al. Immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC)[J]. J UOEH, 2018, 40(2): 173-189.
    [5] He YD, Xu WD, Xiao YT, et al. Targeting signaling pathways in prostate cancer: mechanisms and clinical trials[J]. Signal Transduct Target Ther, 2022, 7(1): 198.
    [6] Kim TK, Vandsemb EN, Herbst RS, et al. Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities[J]. Nat Rev Drug Discov, 2022, 21(7): 529-540.
    [7] Yi M, Zheng XL, Niu MK, et al. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions[J]. Mol Cancer, 2022, 21(1): 28.
    [8] Maruhashi T, Sugiura D, Okazaki IM, et al. Binding of LAG-3 to stable peptide-MHC class II limits T cell function and suppresses autoimmunity and anti-cancer immunity[J]. Immunity, 2022, 55(5): 912-924.e8.
    [9] Goldberg MV, Drake CG. LAG-3 in cancer immunotherapy[J]. Curr Top Microbiol Immunol, 2011, 344: 269-278.
    [10] Sordo-Bahamonde C, Lorenzo-Herrero S, González-Rodríguez AP, et al. LAG-3 blockade with relatlimab (BMS-986016) restores anti-leukemic responses in chronic lymphocytic leukemia[J]. Cancers, 2021, 13(9): 2112.
    [11] Wen SQ, Lu HZ, Wang DK, et al. TCF-1 maintains CD8+ T cell stemness in tumor microenvironment[J]. J Leukoc Biol, 2021, 110(3): 585-590.
    [12] Acharya N, Sabatos-Peyton C, Anderson AC. Tim-3 finds its place in the cancer immunotherapy landscape[J]. J Immunother Cancer, 2020, 8(1): e000911.
    [13] Ganjalikhani Hakemi M, Jafarinia M, Azizi M, et al. The role of TIM-3 in hepatocellular carcinoma: a promising target for immunotherapy[J]? Front Oncol, 2020, 10: 601661.
    [14] De Mingo Pulido á, Gardner A, Hiebler S, et al. TIM-3 regulates CD103+ dendritic cell function and response to chemotherapy in breast cancer[J]. Cancer Cell, 2018, 33(1): 60-74.e6.
    [15] Banerjee S, Oaknin A, Sanchez-Simon I, et al. 518 Phase 1B trial of monalizumab (NKG2A inhibitor) plus durvalumab: safety and efficacy in patients with metastatic ovarian, cervical, and microsatellite-stable endometrial cancers[J]. Int J Gynecol Cancer, 2020, 30: A86-A87.
    [16] Tinker AV, Hirte HW, Provencher D, et al. Dose-ranging and cohort-expansion study of monalizumab (IPH2201) in patients with advanced gynecologic malignancies: a trial of the Canadian cancer trials group (CCTG): IND221[J]. Clin Cancer Res, 2019, 25(20): 6052-6060.
    [17] Yang S, Wei W, Zhao Q. B7-H3, a checkpoint molecule, as a target for cancer immunotherapy[J]. Int J Biol Sci, 2020, 16(11): 1767-1773.
    [18] Podojil JR, Glaser AP, Baker D, et al. Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma[J]. OncoImmunology, 2020, 9(1): 1744897.
    [19] Willingham SB, Hotson AN, Miller RA. Targeting the A2AR in cancer; early lessons from the clinic[J]. Curr Opin Pharmacol, 2020, 53: 126-133.
    [20] Ghalamfarsa G, Kazemi MH, Raoofi Mohseni S, et al. CD73 as a potential opportunity for cancer immunotherapy[J]. Exp Opin Ther Targets, 2019, 23(2): 127-142.
    [21] Murter B, Pan XY, Ophir E, et al. Mouse PVRIG has CD8+ T cell-specific coinhibitory functions and dampens antitumor immunity[J]. Cancer Immunol Res, 2019, 7(2): 244-256.
    [22] Garon EB, Rizvi NA, Hui RN, et al. Pembrolizumab for the treatment of non-small-cell lung cancer[J]. N Engl J Med, 2015, 372(21): 2018-2028.
    [23] Daud AI, Wolchok JD, Robert C, et al. Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma[J]. J Clin Oncol, 2016, 34(34): 4102-4109.
    [24] Bai RL, Chen NF, Li LY, et al. Mechanisms of cancer resistance to immunotherapy[J]. Front Oncol, 2020, 10: 1290.
    [25] Ngeow J, Eng C. PTEN in hereditary and sporadic cancer[J]. Cold Spring Harb Perspect Med, 2020, 10(4): a036087.
    [26] Zhuang Y, Liu C, Liu JQ, et al. Resistance mechanism of PD-1/PD-L1 blockade in the cancer-immunity cycle[J]. Oncol Targets Ther, 2020, 13: 83-94.
    [27] Chen KQ, Wang JM, Yuan RX, et al. Tissue-resident dendritic cells and diseases involving dendritic cell malfunction[J]. Int Immunopharmacol, 2016, 34: 1-15.
    [28] Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion[J]. Nat Rev Cancer, 2021, 21(5): 298-312.
    [29] Dahmani A, Delisle JS. TGF-β in T cell biology: implications for cancer immunotherapy[J]. Cancers, 2018, 10(6): 194.
    [30] Moesta AK, Li XY, Smyth MJ. Targeting CD39 in cancer[J]. Nat Rev Immunol, 2020, 20(12): 739-755.
    [31] Shi LS, Yang L, Wu ZY, et al. Adenosine signaling: next checkpoint for gastric cancer immunotherapy[J]? Int Immunopharmacol, 2018, 63: 58-65.
    [32] Ye Q, Wang CL, Xian J, et al. Expression of programmed cell death protein 1 (PD-1) and indoleamine 2, 3-dioxygenase (IDO) in the tumor microenvironment and in tumor-draining lymph nodes of breast cancer[J]. Hum Pathol, 2018, 75: 81-90.
    [33] Haist M, Stege H, Grabbe S, et al. The functional crosstalk between myeloid-derived suppressor cells and regulatory T cells within the immunosuppressive tumor microenvironment[J]. Cancers, 2021, 13(2): 210.
    [34] Zhang J, Endres S, Kobold S. Enhancing tumor T cell infiltration to enable cancer immunotherapy[J]. Immunotherapy, 2019, 11(3): 201-213.
    [35] Dai Phung C, Nguyen HT, Choi JY, et al. Reprogramming the T cell response to cancer by simultaneous, nanoparticle-mediated PD-L1 inhibition and immunogenic cell death[J]. J Control Release, 2019, 315: 126-138.
    [36] Showalter A, Limaye A, Oyer JL, et al. Cytokines in immunogenic cell death: applications for cancer immunotherapy[J]. Cytokine, 2017, 97: 123-132.
    [37] McKenzie JA, Mbofung RM, Malu S, et al. The effect of topoisomerase I inhibitors on the efficacy of T-cell-based cancer immunotherapy[J]. J Natl Cancer Inst, 2018, 110(7): 777-786.
    [38] Sistigu A, Yamazaki T, Vacchelli E, et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy[J]. Nat Med, 2014, 20(11): 1301-1309.
    [39] Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer[J]. N Engl J Med, 2018, 378(22): 2078-2092.
    [40] Reck M, Socinski MA, Cappuzzo F, et al. Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/- bevacizumab, with or without atezolizumab in 1L non-squamous metastatic nsclc (IMPOWER150)[J]. Ann Oncol, 2017, 28: xi31.
    [41] Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer[J]. N Engl J Med, 2018, 379(21): 2040-2051.
    [42] Adams S, Schmid P, Rugo HS, et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study[J]. Ann Oncol, 2019, 30(3): 397-404.
    [43] Schmid P, Rugo HS, Adams S, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable,locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2020, 21(1): 44-59.
    [44] Arina A, Beckett M, Fernandez C, et al. Tumor-reprogrammed resident T cells resist radiation to control tumors[J]. Nat Commun, 2019, 10(1): 3959.
    [45] Wang XH, Schoenhals JE, Li AL, et al. Suppression of type I IFN signaling in tumors mediates resistance to anti-PD-1 treatment that can be overcome by radiotherapy[J]. Cancer Res, 2017, 77(4): 839-850.
    [46] Liu Y, Dong YP, Kong L, et al. Abscopal effect of radiotherapy combined with immune checkpoint inhibitors[J]. J Hematol Oncol, 2018, 11(1): 104.
    [47] 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.
    [48] Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC[J]. N Engl J Med, 2018, 379(24): 2342-2350.
    [49] Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer[J]. N Engl J Med, 2017, 377(20): 1919-1929.
    [50] Germano G, Lamba S, Rospo G, et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth[J]. Nature, 2017, 552(7683): 116-120.
    [51] Mantso T, Goussetis G, Franco R, et al. Effects of hyperthermia as a mitigation strategy in DNA damage-based cancer therapies[J]. Semin Cancer Biol, 2016, 37/38: 96-105.
    [52] Lerner EC, Edwards RM, Wilkinson DS, et al. Laser ablation: heating up the anti-tumor response in the intracranial compartment[J]. Adv Drug Deliv Rev, 2022, 185: 114311.
    [53] Liu P, Jia SG, Lou Y, et al. Cryo-thermal therapy inducing MI macrophage polarization created CXCL10 and IL-6-rich pro-inflammatory environment for CD4+ T cell-mediated anti-tumor immunity[J]. Int J Hyperth, 2019, 36(1): 407-419.
    [54] Liu K, He K, Xue T, et al. The cryo-thermal therapy-induced IL-6-rich acute pro-inflammatory response promoted DCs phenotypic maturation as the prerequisite to CD4+ T cell differentiation[J]. Int J Hyperth, 2018, 34(3): 261-272.
    [55] Newton JM, Flores-Arredondo JH, Suki S, et al. Non-invasive radiofrequency field treatment of 4T1 breast tumors induces T-cell dependent inflammatory response[J]. Sci Rep, 2018, 8(1): 3474.
    [56] Peng JR, Xiao Y, Li WT, et al. Photosensitizer micelles together with IDO inhibitor enhance cancer photothermal therapy and immunotherapy[J]. Adv Sci (Weinh), 2018, 5(5): 1700891.
    [57] Shi LR, Chen LJ, Wu CP, et al. PD-1 blockade boosts radiofrequency ablation-elicited adaptive immune responses against tumor[J]. Clin Cancer Res, 2016, 22(5): 1173-1184.
    [58] Li XY, Liu JW, Zhang WY, et al. Biogenic hybrid nanosheets activated photothermal therapy and promoted anti-PD-L1 efficacy for synergetic antitumor strategy[J]. ACS Appl Mater Interfaces, 2020, 12(26): 29122-29132.
    [59] Yi M, Jiao DC, Qin S, et al. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment[J]. Mol Cancer, 2019, 18(1): 60.
    [60] B?ckelmann LC, Schumacher U. Targeting tumor interstitial fluid pressure: will it yield novel successful therapies for solid tumors[J]? Expert Opin Ther Targets, 2019, 23(12): 1005-1014.
    [61] Lee WS, Yang H, Chon HJ, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity[J]. Exp Mol Med, 2020, 52(9): 1475-1485.
    [62] Bourhis M, Palle J, Galy-Fauroux I, et al. Direct and indirect modulation of T cells by VEGF-A counteracted by anti-angiogenic treatment[J]. Front Immunol, 2021, 12: 616837.
    [63] Rahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression[J]. Clin Cancer Res, 2019, 25(18): 5449-5457.
    [64] Wu FTH, Xu P, Chow A, et al. Pre- and post-operative anti-PD-L1 plus anti-angiogenic therapies in mouse breast or renal cancer models of micro- or macro-metastatic disease[J]. Br J Cancer, 2019, 120(2): 196-206.
    [65] Ansari MJ, Bokov D, Markov A, et al. Cancer combination therapies by angiogenesis inhibitors; a comprehensive review[J]. Cell Commun Signal, 2022, 20(1): 49.
    [66] Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426):extended follow-up from a randomised, open-label, phase 3 trial[J]. Lancet Oncol, 2020, 21(12): 1563-1573.
    [67] Chesney J, Puzanov I, Collichio F, et al. Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma[J]. J Clin Oncol, 2018, 36(17): 1658-1667.
    [68] Sheikh NA, Petrylak D, Kantoff PW, et al. Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer[J]. Cancer Immunol Immunother,2013,62(1): 137-147.
    [69] Fong L, Carroll P, Weinberg V, et al. Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer[J]. J Natl Cancer Inst, 2014, 106(11): dju268.
    [70] Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer[J]. N Engl J Med, 2010, 363(5): 411-422.
    [71] Ku J, Wilenius K, Larsen C, et al. Survival after sipuleucel-T (SIP-T) and low-dose ipilimumab (IPI) in men with metastatic, progressive, castrate-resistant prostate cancer (M-CRPC)[J]. J Clin Oncol, 2018, 36(6 suppl): 368.
    [72] Knudson KM, Hicks KC, Alter S, et al. Mechanisms involved in IL-15 superagonist enhancement of anti-PD-L1 therapy[J]. J Immunotherapy Cancer, 2019, 7(1): 82.
    [73] Adusumilli PS, Zauderer MG, Rivière I, et al. A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab[J]. Cancer Discov, 2021, 11(11): 2748-2763.
    [74] Rafiq S, Yeku OO, Jackson HJ, et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo[J]. Nat Biotechnol, 2018, 36(9): 847-856.
    [75] Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma[J]. N Engl J Med, 2015, 373(1): 23-34.
    [76] Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma[J]. N Engl J Med, 2015, 372(21): 2006-2017.
    [77] Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma[J]. N Engl J Med, 2019, 381(16): 1535-1546.
    [78] Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma[J]. N Engl J Med, 2022, 386(1): 24-34.
  • 期刊类型引用(8)

    1. 王绍娟,周玲,邓泽辉,任林. 我国免疫检查点抑制剂研究现状与热点的CiteSpace可视化图谱分析. 中国药业. 2025(01): 32-36 . 百度学术
    2. 于敏,徐婕,朱淼,闫韶花,周天. 基于“脾为之卫”探讨中药对免疫检查点抑制剂治疗肿瘤的影响. 中医学报. 2025(03): 515-522 . 百度学术
    3. 井丽,许翠萍,赵军燕,黄蕊. 1例膀胱癌患者应用替雷利珠单抗致免疫重叠综合征的护理. 当代护士(上旬刊). 2025(03): 102-105 . 百度学术
    4. 徐向宁,王引弟,吕珍,郑贵森,吴建军. 基于PD-1/PD-L1免疫检查点通路中西医结合抗肿瘤治疗的研究进展. 中国中医基础医学杂志. 2024(07): 1258-1264 . 百度学术
    5. 孙蕾. 肿瘤免疫治疗:让你的免疫系统战胜癌症. 大医生. 2024(14): 146-147 . 百度学术
    6. 戚锐锋,张明,王浩,王莹,阿迪拉,冷越,钟丽,马遥远,谢倩云,覃建萍. 免疫检查点抑制剂对晚期肺癌患者凝血功能的影响. 西部医学. 2024(09): 1323-1326 . 百度学术
    7. 段雪玉,刘晓波,温瑾,佟晓娜,张婷,普艳姣,余宏秀,陈瑞祥. 二甲双胍单用或辅助治疗恶性肿瘤患者疗效的Meta分析. 中国医院药学杂志. 2023(24): 2792-2803 . 百度学术
    8. 吴迪,李明霞,闫志风. 基于分子标志的子宫内膜癌免疫治疗模式临床研究进展. 解放军医学院学报. 2023(10): 1172-1176 . 百度学术

    其他类型引用(4)

计量
  • 文章访问数:  653
  • HTML全文浏览量:  55
  • PDF下载量:  943
  • 被引次数: 12
出版历程
  • 收稿日期:  2022-10-27
  • 修回日期:  2023-04-03
  • 刊出日期:  2023-04-24

目录

    /

    返回文章
    返回