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

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.