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铂类化疗联合 PD-1/PD-L1 抑制剂:临床前和临床研究及作用机制。

Platinum-based chemotherapy in combination with PD-1/PD-L1 inhibitors: preclinical and clinical studies and mechanism of action.

机构信息

Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China.

Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China.

出版信息

Expert Opin Drug Deliv. 2021 Feb;18(2):187-203. doi: 10.1080/17425247.2021.1825376. Epub 2020 Oct 5.


DOI:10.1080/17425247.2021.1825376
PMID:32954856
Abstract

INTRODUCTION: Platinum chemotherapy is widely used in first-line treatment of patients with various cancers. PD-1/PD-L1 inhibitors have shown efficacy in several cancers, and the combination of platinum-based chemotherapy and PD-1/PD-L1 inhibitors has gradually become the focus of attention. Recently, the combination therapy has exhibited significant effects in preclinical models and clinical trials. AREAS COVERED: This review summarizes preclinical and clinical studies of the combination therapy in various cancers, and further explores mechanisms of the treatment. Furthermore, exploration of the mechanism demonstrates that the combination therapy plays a combination role in two ways. On the one hand, the positive effects of platinum-based chemotherapy on immunomodulation can be harnessed to increase the sensitivity of tumor cells to PD-1/PD-L1 inhibitors. On the other hand, platinum-based chemotherapy may upregulate PD-L1 expression in tumor tissue and exert a negative immunomodulatory effect, which can be counteracted by PD-1/PD-L1 inhibitors through their action pathway. What's more, different types of platinum-based chemotherapy exert different immunomodulation properties. EXPERT OPINION: This review describes a potential for the combination of PD-1/PD-L1 inhibitors and novel nanoparticles composed of platinum-loaded complex to yield positive effects in a wide range of doses, thus achieving higher therapeutic effects and lower side effects. ABBREVIATIONS: Treg: regulatory T cell; MDSC: myeloid-derived suppressor cell; TAM: tumor-associated macrophage; IL: interleukin; PD-1: programmed cell death protein-1; PD-L1: programmed death-ligand-1; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer; HNSCC: head and neck squamous cell cancer; ICD: immunogenic cell death; TME: tumor microenvironment; CTLs: cytotoxic T lymphocytes; TCR: T cell receptor; MHC class 1: major histocompatibility complex class 1; DC: dendritic cell; APC: antigen-presenting cell; PD-L2: programmed death-ligand-2; STAT6: signal transducers and activators of transcription 6; PLG: poly (L-glutamic acid); mPEG: methoxy poly (ethylene glycol); LLC1: Lewis lung carcinoma 1; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; MOC1: mouse oral cancer 1; cGAS: cyclic guanosine monophosphate-adenosine monophosphate synthase; STING: stimulator of interferon genes; FDA: food and drug administration; cHL: classical Hodgkin's lymphoma; PMBCL: primary mediastinal large B-cell lymphoma; HCC: hepatocellular carcinoma; MCC: merkel cell carcinoma; RCC: renal cell carcinoma; ORR: overall response rate; OR: overall response; OS: overall survival; PFS: progression-free survival; vs: versus; EFGR: epidermal growth factor receptor; ALK: anaplastic lymphoma kinase; ES: extensive stage; CPS: combined positive score; DOR: duration of response; ITT: intention to treat; NMPA: national medical products administration; TKI: tyrosine kinase inhibitor; NPC: nasopharyngeal cancer; DLT: dose-limiting toxicity; MTD: maximum tolerated dose; TNBC: triple-negative breast cancer; GC: gastric cancer; GEJC: gastroesophageal junction carcinoma; DCR: disease control rate; BTC: biliary tract cancer; TTR: time to response; PR: partial response; SD: stable disease; PD: progressive disease; IC: half maximal inhibitory concentration; IFN: interferon; HLA: human leukocyte antigen; NK: natural killer cell; M6PR: mannose-6-phosphate receptor; GrzB: granzyme B; TNF: tumor necrosis factor.

摘要

简介:铂类化疗广泛应用于多种癌症的一线治疗。PD-1/PD-L1 抑制剂在多种癌症中显示出疗效,铂类化疗与 PD-1/PD-L1 抑制剂的联合治疗逐渐成为关注焦点。最近,该联合治疗在临床前模型和临床试验中均显示出显著效果。

涵盖领域:本文综述了各种癌症中联合治疗的临床前和临床研究,并进一步探讨了其作用机制。此外,机制研究表明,该联合治疗通过两种方式发挥协同作用。一方面,铂类化疗对免疫调节的积极作用可被利用,以提高肿瘤细胞对 PD-1/PD-L1 抑制剂的敏感性。另一方面,铂类化疗可能上调肿瘤组织中 PD-L1 的表达,发挥负性免疫调节作用,而 PD-1/PD-L1 抑制剂可通过其作用途径拮抗这一作用。此外,不同类型的铂类化疗具有不同的免疫调节特性。

专家意见:本文描述了 PD-1/PD-L1 抑制剂与新型载铂复合物纳米颗粒联合应用的潜力,有望在广泛的剂量范围内产生积极效果,从而提高治疗效果,降低副作用。

缩写:Treg:调节性 T 细胞;MDSC:髓系来源的抑制细胞;TAM:肿瘤相关巨噬细胞;IL:白细胞介素;PD-1:程序性细胞死亡蛋白-1;PD-L1:程序性死亡配体-1;非小细胞肺癌;小细胞肺癌;头颈部鳞状细胞癌;免疫原性细胞死亡;肿瘤微环境;CTLs:细胞毒性 T 淋巴细胞;TCR:T 细胞受体;MHC 类 1:主要组织相容性复合体 1 类;树突状细胞;抗原呈递细胞;PD-L2:程序性死亡配体-2;STAT6:信号转导和转录激活因子 6;PLG:聚(L-谷氨酸);mPEG:甲氧基聚乙二醇;Lewis 肺癌 1 号;PI3K:磷酸肌醇 3-激酶;AKT:蛋白激酶 B;MOC1:小鼠口腔癌 1 号;cGAS:环鸟苷酸-腺苷酸合成酶;STING:干扰素基因刺激物;FDA:美国食品和药物管理局;经典霍奇金淋巴瘤;原发性纵隔大 B 细胞淋巴瘤;肝细胞癌;默克尔细胞癌;肾细胞癌;总缓解率;总缓解;总生存期;无进展生存期;与……相比;表皮生长因子受体;间变性淋巴瘤激酶;广泛期;联合阳性评分;缓解持续时间;意向治疗;国家药品监督管理局;酪氨酸激酶抑制剂;鼻咽癌;剂量限制毒性;最大耐受剂量;三阴性乳腺癌;胃癌;胃食管交界癌;疾病控制率;胆道癌;反应时间;部分缓解;稳定疾病;进展性疾病;半最大抑制浓度;干扰素;人类白细胞抗原;自然杀伤细胞;甘露糖-6-磷酸受体;颗粒酶 B;肿瘤坏死因子。

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