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; IC₅₀: 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.

中文翻译：

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铂类化学疗法与PD-1 / PD-L1抑制剂联用：临床前和临床研究以及作用机理

抽象的

介绍

铂化学疗法广泛用于各种癌症患者的一线治疗。PD-1 / PD-L1抑制剂已在多种癌症中显示出疗效，铂类化学疗法与PD-1 / PD-L1抑制剂的组合已逐渐成为人们关注的焦点。最近，联合疗法在临床前模型和临床试验中已显示出显着效果。

覆盖区域

这篇综述总结了各种癌症中联合疗法的临床前和临床研究，并进一步探讨了该疗法的机制。此外，对该机制的探索表明，联合疗法以两种方式发挥联合作用。一方面，可以利用铂类化学疗法对免疫调节的积极作用来增加肿瘤细胞对PD-1 / PD-L1抑制剂的敏感性。另一方面，基于铂的化学疗法可能会上调肿瘤组织中PD-L1的表达并发挥负的免疫调节作用，PD-1 / PD-L1抑制剂可通过其作用途径抵消这种作用。而且，不同类型的铂类化学疗法具有不同的免疫调节特性。

专家意见

这篇综述描述了PD-1 / PD-L1抑制剂与由载有铂的复合物组成的新型纳米颗粒的组合在大剂量范围内产生积极作用，从而实现更高的治疗效果和更低的副作用的潜力。

缩略语

Treg：调节性T细胞；MDSC：髓样抑制细胞；TAM：肿瘤相关巨噬细胞；IL：白介素；PD-1：程序性细胞死亡蛋白-1；PD-L1：程序化死亡配体1；NSCLC：非小细胞肺癌；SCLC：小细胞肺癌；HNSCC：头颈部鳞状细胞癌；ICD：免疫原性细胞死亡；TME：肿瘤微环境；CTL：细胞毒性T淋巴细胞；TCR：T细胞受体；MHC 1级：主要组织相容性复合体1级；DC：树突状细胞；APC：抗原呈递细胞；PD-L2：程序性死亡配体2；STAT6：信号转导子和转录激活子6；PLG：聚（L-谷氨酸）；mPEG：甲氧基聚（乙二醇）；LLC1：Lewis肺癌1；PI3K：磷酸肌醇3-激酶；AKT：蛋白激酶B；MOC1：小鼠口腔癌1；cGAS：环状鸟苷单磷酸-腺苷单磷酸合酶；STING：干扰素基因的刺激物；FDA：食品药品管理局；cHL：经典霍奇金淋巴瘤；PMBCL：原发性纵隔大B细胞淋巴瘤；HCC：肝细胞癌；MCC：默克尔细胞癌；RCC：肾细胞癌；ORR：总体响应率；或：总体反应；OS：总体生存率；PFS：无进展生存期；vs：vs；EFGR：表皮生长因子受体；ALK：间变性淋巴瘤激酶；ES：扩展阶段；CPS：综合阳性评分；DOR：反应持续时间；ITT：治疗意向；NMPA：国家医疗产品管理局；TKI：酪氨酸激酶抑制剂；NPC：鼻咽癌；DLT：剂量限制性毒性；MTD：最大耐受​​剂量；TNBC：三阴性乳腺癌；GC：胃癌；GEJC：胃食管连接癌；DCR：疾病控制率；BTC：胆道癌；TTR：响应时间；PR：部分反应；SD：疾病稳定；PD：进行性疾病；我知道了₅₀：最大抑制浓度的一半；干扰素：干扰素；HLA：人类白细胞抗原；NK：自然杀伤细胞；M6PR：6-磷酸甘露糖受体；GrzB：颗粒酶B；TNF：肿瘤坏死因子。