Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.

Construction and self-activation detection of yeast two-hybrid bait plasmid of human programmed cell death ligand 1 immunoglobulin variable region domain gene / 中国生物制品学杂志

@#Objective To construct a yeast two-hybrid recombinant bait plasmid of human programmed cell death ligand 1(PD-L1)immunoglobulin variable region(IgV)domain gene,detect its expression in yeast and detect the cytotoxicity and self-activation of PD-L1 IgV protein as well as the interaction between PD-L1 IgV and human thioredoxin(hTrx).Methods Human PD-L1 was analyzed by bioinformatics method,and primers were designed to amplify PD-L1 IgV domain based on the coding region of PD-L1 gene registered in NCBI GenBank database. PCR amplification was carried out with pENTERPD-L1 plasmid as template,and then cloned into yeast two-hybrid bait vector pGBKT7. The recombinant bait plasmid and pGBKT7 empty vector were transformed into Y2HGold yeast cells respectively,and the PD-L1 IgV gene and its expression were detected by PCR and Western blot;Meanwhile,the protein toxicity and self-activation of PD-L1 IgV were detected,and the interaction between PD-L1 IgV and hTrx was detected by drip plate method.Results The bioinformatics analysis results of PD-L1 were consistent with related reports. The recombinant bait plasmid pGBKT7-PD-L1 IgV was correctly constructed,and Y2HGold positive clone was obtained,in which PD-L1 IgV was stably expressed. The empty vector pGBKT7 and recombinant bait plasmid pGBKT7-PD-L1 IgV grew well on SD/-Trp and SD/-Trp/X-α-Gal plates with the same colony size and number and white colony,but they did not grow on SD/-Trp/X-α-Gal/AbA plates,which indicated that PD-L1 IgV protein had no toxicity and no self-activation effect on yeast. The results of drip plates test showed that all experimental groups grew well on SD/-Trp/-Leu plate,while only positive control group grew on SD/-Trp/-Leu/X-α-Gal/AbA plate and showed blue color,which indicated that bait protein PD-L1 IgV and hTrx did not self-activate,and there was no interaction between them.Conclusion Recombinant human PD-L1 IgV bait plasmid was successfully constructed. PD-L1 IgV protein showed no toxicity and self-activation effect on yeast cells,and there was no interaction between PD-L1 IgV and hTrx. Subsequently,hTrx can be used to construct a peptide aptamer library,from which peptide aptamers that specifically bind to PD-L1 IgV can be screened.

The expression mechanism of programmed cell death 1 ligand 1 and its role in immunomodulatory ability of mesenchymal stem cells / 中华创伤杂志(英文版)

Programmed cell death 1 ligand 1 (PD-L1) is an important immunosuppressive molecule, which inhibits the function of T cells and other immune cells by binding to the receptor programmed cell death-1. The PD-L1 expression disorder plays an important role in the occurrence, development, and treatment of sepsis or other inflammatory diseases, and has become an important target for the treatment of these diseases. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells with multiple differentiation potential. In recent years, MSCs have been found to have a strong immunosuppressive ability and are used to treat various inflammatory insults caused by hyperimmune diseases. Moreover, PD-L1 is deeply involved in the immunosuppressive events of MSCs and plays an important role in the treatment of various diseases. In this review, we will summarize the main regulatory mechanism of PD-L1 expression, and discuss various biological functions of PD-L1 in the immune regulation of MSCs.

PD-L1 and PD-L2 expression in colorectal cancer

Context: The programmed death-1 (PD-1) is an immune checkpoint molecule that suppresses T-cell response. The binding of PD-1 to PD-L1/PD-L2 results cytokine production, and T-cell proliferation are reduced. Tumors expressing PD-L1 and PD-L2 escape from cytotoxic T-cells and are exposed to tumor progression. For this reason, immunotherapy has become a new option in the treatment of cancer. Aims: In this study, we examined the PD-L1 and PD-L2 expression in colorectal carcinoma (CRC), and evaluated the relationship between clinicopathological parameters and CD8+ T cells. Methods and Material: We evaluated CD8 expression in tumor-infiltrating lymphocytes and surrounding tumor lymphocytes with PD-L1, PD-L2 staining in tumor cells and immune cells formalin-fixed paraffin embedded samples of 124 patient diagnosed with CRC. Statistical Analysis Used: Pearson Chi-Square, Fisher Exact Chi-Square, and Pearson Exact Chi-Square analyses were used in the analysis of the cross tables. Survival distributions predicted Kaplan--Meier method and it was evaluated using log-rank statistics. Results: In our study, a significant correlation was found between PD-L1 expression and female sex and tumors with medullary morphology. No expression of PD-L2 was observed in tumors containing medullary morphology, and a statistically inverse relationship was observed between PD-L2 and the medullary component. PD-L1 positive tumor-infiltrating lymphocytes were determined to be an important predictor for recurrence-free survival. Conclusions: We believe that the evaluation of these parameters may be useful in the selection of patients who will benefit from immunotherapy in CRC cases.

Preparation of CD73/PD-L1 bispecific antibody and evaluation of its antitumor function in vitro / 中国生物制品学杂志

@#Objective To prepare bispecific antibody targeting cluster of differentiation 73(CD73) and programmed cell death-ligand 1(PD-L1),and evaluate its binding ability and killing ability in vitro.Methods Using genetic engineering method,PD-L1 single-chain fragment variable(scFv) was inserted into the hinge region of CD73 monoclonal antibody to construct anti-CD73/PD-L1 bispecific antibody(BS-21),which was screened by CHO GS expression system to obtain highly expressed cell line.After purified by Protein A and molecular sieve,the purity of antibody was detected by size exclusion chromatography-high performance liquid chromatography(SEC-HPLC),the binding ability of antibody in vitro was detected by flow cytometry,and the killing ability in vitro was detected by using peripheral blood mononuclear cell(PBMC) to kill Calu 1 lung cancer cells in vitro.Results High-yield cell lines were obtained by pressure screening.A bispecific antibody BS-21 with a purity of 99.6% was obtained by purification,which bound to CD73 and PD-L1 molecules simultaneously.Compared with anti CD73 and anti PD-L1 groups,BS-21 group significantly increased the killing rate of immune cells to Calu 1 tumor cells(F=30.36,each P<0.001).Conclusion Bispecific antibody BS-21 reduced the immunosuppressive effect of CD73 and PD-Ll on immune cells simultaneously,and showed good anti-tumor function.

Effects and translatomics characteristics of a small-molecule inhibitor of METTL3 against non-small cell lung cancer / 药物分析学报

In non-small cell lung cancer(NSCLC),the heterogeneity promotes drug resistance,and the restricted expression of programmed death-ligand 1(PD-L1)limits the immunotherapy benefits.Based on the mechanisms related to translation regulation and the association with PD-L1 of methyltransferase-like 3(METTL3),the novel small-molecule inhibitor STM2457 is assumed to be useful for the treat-ment of NSCLC.We evaluated the efficacy of STM2457 in vivo and in vitro and confirmed the effects of its inhibition on disease progression.Next,we explored the effect of STM2457 on METTL3 and revealed its effects on the inhibition of catalytic activity and upregulation of METTL3 protein expression.Importantly,we described the genome-wide characteristics of multiple omics data ac-quired from RNA sequencing,ribosome profiling,and methylated RNA immunoprecipitation sequencing data under STM2457 treatment or METTL3 knockout.We also constructed a model for the regulation of the translation of METTL3 and PD-L1.Finally,we found PD-Ll upregulation by STM2457 in vivo and in vitro.In conclusion,STM2457 is a potential novel suppressor based on its inhibitory effect on tumor progression and may be able to overcome the heterogeneity based on its impact on the translatome.Furthermore,it can improve the immunotherapy outcomes based on PD-L1 upregulation in NSCLC.

The application value of p53 and PD-L1 detection in ultrasound-guided core needle biopsy specimens in breast cancer / 中华内分泌外科杂志

Objective:The aim of this study is to investigate the expression of p53 and PD-L1 in ultrasound-guided core needle biopsy specimens of breast cancer, and to analyze their application value.Methods:Ninety-eight patients who underwent ultrasound-guided coarse needle puncture biopsy and radical operation admitted to our hospital from Aug. 2021 to Sep. 2022 were selected as the study objects. The clinical data of patients were collected, the expression of p53 and PD-L1 in puncture biopsy specimens and radical surgical excision specimens were detected by immunohistochemical experiment, and the consistency was analyzed. Statistical test was used to analyze the relationship between the expression of p53 and PD-L1 and the pathological parameters of patients.Results:In 98 patients, the positive rate of p53 and PD-L1 in core needle biopsy specimens was 48.0% and 55.1%, respectively. The positive rate of p53 and PD-L1 in radical operative specimens was 62.2% and 61.2%, respectively. The concordance rates of p53 and PD-L1 were 63.6% ( κ=0.441, P<0.001) and 65.3% ( κ=0.505, P<0.001) between core needle biopsy specimens and radical operative specimens. Taking the results of radical operative specimens as the standard, the cases with positive expression of p53 and PD-L1 in core needle biopsy specimens were all positive in radical operative specimens, and the specificity was 100%. p53 was determined negative in 25 coarse needle biopsy specimens, however, p53 was positive in radical surgical specimens, and the false negative rate of coarse needle puncture was 49.0 %. PD-L1 was determined negative in 20 coarse needle biopsy specimens, but it was determined positive in radical operative specimens, and the false negative rate of coarse needle puncture was 41.7 %. There was no significant correlation between the consistency rate of p53 and PD-L1 expression and the number of puncture cores, the length of puncture cores, the length of invasive carcinoma and the proportion of invasive carcinoma (all P>0.05). The expressions of p53 and PD-L1 in core needle biopsy specimens were significantly correlated with tumor size, pTNM stage and Ki67 (all P<0.05), but not with age, BMI, family history, histological type or Nottingham histological grade (all P>0.05) . Conclusion:The concordance rates of p53 and PD-L1 expression between ultrasound-guided core needle biopsy specimens and radical resection specimens of breast cancer were 63.6% and 65.3%, respectively, and the specificity of positive detection results were both 100%, which has certain guiding significance for the clinical treatment of breast cancer.

Preparation and cellular uptake study of anemoside B4 and PD-L1 siRNA co-delivered cRGD-modified targeting liposomes / 中国药房

OBJECTIVE To prepare anemoside B4 （AB4） and programmed cell death ligand 1 （PDL1） siRNA （siP） co- delivered cRGD-modified targeting liposomes （AB4/siP-c-L）， and to study the cellular uptake in vitro. METHODS The cRGD- modified AB4-loaded targeted liposomes （AB4-c-L） were prepared by ethanol injection. AB4-c-L was mixed with 20 nmol/L siP in the same volume and AB4/siP-c-L was obtained through electrostatic adsorption. The particle size， Zeta potential， morphology， encapsulation efficiency and drug content， in vitro release behavior and serum stability of AB4/siP-c-L were investigated by laser scattering particle size tester， transmission electron microscopy， ultrafiltration centrifugation， dialysis and agar-gel electrophoresis block test. Cellular uptake of AB4/siP-c-L by Lewis lung cancer cells LLC and its intracellular localization were evaluated by flow cytometry and confocal laser scan technique. RESULTS The average particle size of AB4/siP-c-L was （187.4±3.1） nm， and the Zeta potential was （33.5±1.4） mV. AB4/siP-c-L was spheroidal in shape. The encapsulation efficiency and content of AB4 were （95.2±0.4） % and （1.0±0.2） mg/mL， respectively. AB4/siP-c-L could better package siP， and exhibited good serum stability， obvious pH sensitivity and sustained release property. The uptake rate of AB4/siP-c-L by LLC cells was significantly higher than that of free drug， and was able to accumulate in cytoplasm. CONCLUSIONS AB4/siP-c-L can effectively realize the co-loading of AB4 and gene drug siP， which has certain in vitro targeting to LLC cells.

Timosaponin A III promotes cisplatin sensitivity in A549/DDP cells via JAK-2/STAT3/PD-L1 signaling pathway / 中国药理学通报

Aim To explore the mechanism of timosaponin A III increasing cisplatin sensitization of non-small cell lung cancer cisplatin-resistant A549/DDP cells. Methods The cell proliferation was detected by CCK8,the cell apoptosis was detected by Annexin V/ PI,and the cell cycle distribution was measured by PI. The effect of the combined drug on cell proliferation was detected by cell clone formation. The mRNA expression levels of C-myc, cysteinyl aspartate-specific protease-3 (caspase-3) were detected by reverse transcription polymerase chain reaction (RT-PCR). Western blot and Flow Cytometry were performed for the mechanism study. Results The results of CCK8 and clone formation showed that the timosaponin AM group significantly increased the sensitivity of cisplatin to A549/DDP cells. Compared with the cisplatin group a-lone,the combination of timosaponin AM and cisplatin significantly elevated the apoptosis rate of A549/DDP cells (P < 0.05) , induced cell cycle arrest in G

Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms and strategies / 医学前沿

Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

Development and validation of a risk-prediction model for immune-related adverse events in patients with non-small-cell lung cancer receiving PD-1/PD-L1 inhibitors / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Lung cancer remains the leading cause of cancer deaths worldwide and is the most common cancer in males. Immune-checkpoint inhibitors (ICIs) that target programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have achieved impressive efficacy in the treatment of non-small-cell lung cancer (NSCLC) (Pardoll, 2012; Champiat et al., 2016; Gao et al., 2022). Although ICIs are usually well tolerated, they are often accompanied by immune-related adverse events (irAEs) (Doroshow et al., 2019). Non-specific activation of the immune system produces off-target immune and inflammatory responses that can affect virtually any organ or system (O'Kane et al., 2017; Puzanov et al., 2017). Compared with adverse events caused by chemotherapy, irAEs are often characterized by delayed onset and prolonged duration and can occur in any organ at any stage of treatment, including after cessation of treatment (Puzanov et al., 2017; von Itzstein et al., 2020). They range from rash, pneumonitis, hypothyroidism, enterocolitis, and autoimmune hepatitis to cardiovascular, hematological, renal, neurological, and ophthalmic irAEs (Nishino et al., 2016; Kumar et al., 2017; Song et al., 2020). Hence, we conducted a retrospective study to identify validated factors that could predict the magnitude of the risk of irAEs in patients receiving PD-1/PD-L1 inhibitors; our approach was to analyze the correlation between the clinical characteristics of patients at the start of treatment and relevant indicators such as hematological indices and the risk of developing irAEs. Then, we developed an economical, practical, rapid, and simple model to assess the risk of irAEs in patients receiving ICI treatment, as early as possible.

Efficacy and safety of PD-1/PD-L1 inhibitors-based immunocombination therapy versus sunitinib in the treatment of advanced renal cell carcinoma: a Meta-analysis / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：系统评价基于PD-1/PD-L1抑制剂的免疫联合治疗（以下称“免疫联合治疗”）对比舒尼替尼治疗晚期肾细胞癌（RCC）的安全性和有效性。方法：检索PubMed、Embase、Cochrane Library及中国知网（CNKI）数据库，收集国内外公开发表的免疫联合治疗对比舒尼替尼应用于晚期RCC的随机对照试验（RCT），检索时间均为自建库时间至2022年10月。由两名研究者独立评价纳入研究的质量、提取资料并交叉核对，采用StataMP16.0软件进行Meta分析。结果：共纳入6项RCT，Meta分析结果显示，（1）有效性：与舒尼替尼相比，免疫联合治疗显著提高了晚期RCC患者的总生存期[OS，HR=0.74，95% CI （0.67，0.80），P<0.01]和无进展生存期[PFS，HR=0.66，95% CI （0.51，0.81），P<0.01]；（2）安全性：两治疗组均有较高的不良反应（AE）发生率，差异无统计学意义。但免疫联合治疗组发生皮肤及内分泌系统AE显著高于舒尼替尼治疗组，而血液系统相关AE则明显低于舒尼替尼治疗组；（3）以1%为临界点，免疫联合治疗组的RCC患者，无论是PD-L1阳性或阴性的，其OS和PFS均高于舒尼替尼组。结论：免疫联合治疗可显著延长晚期RCC患者的OS和PFS，但不同系统发生AE有差异，且RCC患者PD-L1表达状态（1%为临界点）并不影响免疫联合治疗的获益。

Research progress on active ingredients from traditional Chinese medicine as inhibitors of PD-1/PD-L1 of cancer immune checkpoint / 药学实践杂志

Tumor immunotherapy has become a new cancer treatment which has been expected to eliminate tumors. Immune checkpoint inhibitors, especially programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) antibodies, have achieved significant clinical efficacy in the treatment of solid tumors. But biologics possess disadvantages such as strong immunogenicity and high cost. Therefore, the discovery of small molecule drugs as immune checkpoint inhibitors may overcome the shortcomings of biologics and become a new challenge for future tumor immunotherapy. The active small molecules from traditional Chinese medicine that inhibit the expression of PD-1/PD-L1 and their regulatory effects on the tumor immune microenvironment were reviewed in this paper.

Design and antitumor activity of programmed cell death ligand 1 epitope peptide vaccine / 中国药科大学学报

@#Several programmed cell death protein 1 (PD-1) or its ligand (PD-L1) immune checkpoint blocking antibodies are available for clinical treatment, but only some patients show clinical response, so an alternative strategy for tumor immunotherapy is needed.A therapeutic tumor vaccine targeting PD-L1 is a meaningful attempt.In this study, we designed an epitope peptide vaccine targeting PD-L1, and then screened the immunogenic PD-L1 epitope peptide based on the humanized immune system (HIS) mouse model and further investigated its anti-tumor activity.The results show that the designed and screened PD-L1-B1 epitope peptide vaccine not only successfully induced PD-L1-specific humoral and cellular immunity, but also exhibit anti-tumor activity.In addition, immunotherapy increased T-lymphocyte infiltration of tumors and reshaped the tumor immunosuppressive microenvironment.In conclusion, PD-L1-B1 epitope peptide vaccine exhibits potent anti-tumor activity and may be an effective alternative immunotherapeutic strategy for patients insensitive to PD-1/PD-L1 blockade.

PBRM1 loss promotes PD-L1 secretion in renal cell carcinoma cells through TNF-α/exosome signaling axis / 现代泌尿外科杂志

【Objective】 To explore the expressions of PBRM1 and PD-L1 in renal cell carcinoma (RCC), and the molecular mechanism of PBRM1 regulating PD-L1, in order to provide experimental results for clinical immunotherapy. 【Methods】 The protein expressions of PBRM1 and PD-L1 were detected with immunohistochemistry, and their mRNA expressions were determined by analyzing TCGA database. Meanwhile, the relationship between overall survival and mRNA expressions of PBRM1 and PD-L1 were analyzed in TCGA database. The exosomes were extracted with exoEasy Maxi Kit. Expressions of exosomal biomarkers CD63 and CD9 were detected with Western blotting, and their morphology was observed with transmission electron microscope. PD-L1 expression after IFN-γ, IL-6 and TNF-α treatment was detected with Western blotting. 【Results】 The expression of PBRM1 was significantly lower in canver tissue than in paracancerous tissue (P<0.001). The loss rate of PBRM1 was up to 76.4%. PBRM1 expression was not correlated with PD-L1 expression. PBRM1 deletion activated TNF-α/exosome signaling pathway, leading to increase of PD-L1 secretion in exosomes, which was then transported to the outside of cells. 【Conclusion】 There is no relationship between PBRM1 and PD-L1 protein expressions in RCC. However, PBRM1 mutation can lead to inflammatory signaling pathway activation, inducing PD-L1 secretion, which is encapsulated in exosomes and transported to the outside of cells, and affects the response of immunotherapy.

TumorFisher CTC detection technology for the treatment decision of anti-PD-1/PD-L1 in advanced hepatocellular carcinoma and its efficacy evaluation：a case report and literature review / 中国肿瘤生物治疗杂志

@#[摘 要] 肝细胞癌（HCC）的发病率和病死率正在逐年增长，严重威胁人类的健康和生命。近年来，以PD-1/PD-L1抑制剂为代表的免疫治疗迅速发展，但对晚期HCC疗效有限。治疗中实时监测循环肿瘤细胞（CTC）PD-L1表达，是评估免疫治疗有效性的重要指标之一。本案例通过TumorFisher检测技术实时监测1例HCC患者免疫治疗前后总CTC数及PD-L1+ CTC个数，结合影像学和血清学检查结果进一步评估患者免疫治疗疗效。患者治疗前总CTC数为5个/2 mL，PD-L1+ CTC为5个/2 mL，PD-L1+ CTC/总CTC为100%。用PD-1/PD-L1抑制剂行3周期免疫治疗后，PD-L1+ CTC/总CTC逐渐降低，肿瘤缩小，血清AFP及PIVKA-Ⅱ逐渐下降，PD-L1+ CTC/总CTC变化与肿瘤标志物、MRI检查结果一致。PD-L1+ CTC/总CTC可作为HCC免疫治疗疗效评估的辅助指标。

PD-1/PD-L1 inhibitors for breast cancer: current status, problems and countermeasures / 中国肿瘤生物治疗杂志

@#[摘 要] PD-1/PD-L1抑制剂在乳腺癌免疫治疗中的应用已逐渐成为一种重要的治疗手段，然而对乳腺癌，尤其是三阴性乳腺癌（TNBC）的免疫治疗仍存在某些亟待解决的科学问题，包括PD-1/PD-L1抑制剂单药治疗的有效率欠佳，目前尚无明确的生物标志物来有效筛查治疗敏感人群，免疫相关不良反应（irAE）的发生率高。为了提高疗效和减少irAE的发生，采取以下措施是非常重要的：探讨PD-1/PD-L1抑制剂与其他药物的联合应用方案；采用纳米技术开发选择性靶向肿瘤细胞的纳米载体，降低抗肿瘤药物毒性并提高疗效；探寻开发可预测免疫治疗反应潜力的生物标志物；早期识别和诊疗irAE并建设多学科诊疗协作组（MDT）模式。随着这些措施的积极推进和问题的不断解决，PD-1/PD-L1抑制剂在乳腺癌的治疗中必将呈现出更为广阔的应用前景。

Progress on application of PD⁃1／PD⁃L1 monoclonal antibodies in oncotherapy / 中国生物制品学杂志

@#Abstract：Programmed death receptor⁃ 1（PD⁃1）belongs to the family of immunoglobulin B7⁃CD28，which plays an important role in regulating immune response in human body. Since the first PD⁃1／PD⁃ligand 1（PD⁃L1）monoclonal antibody was approved for marketing in China in 2018，the value of PD⁃1／PD⁃L1 immunotherapy in oncotherapy has attracted wide attention. Based on the introduction of the action mechanism of PD⁃1／PD⁃L1 mAbs，this paper reviews the application progress of 8 on ⁃ market PD ⁃ 1／PD ⁃ L1 mAbs in China in oncotherapy from the perspectives of approved indications，clinical trials，usage and dosage，and adverse reactions，in order to provide reference for the rational appli⁃ cation of PD⁃1／PD⁃L1 monoclonal antibodies in clinic.

Expression of PD-L1 in Primary Colorectal Cancer and Its Predictive Value for Recurrence After Microwave Ablation of Liver Metastases / 肿瘤防治研究

Objective To investigate the expression of programmed death ligand 1(PD-L1) in primary tumor cells(TCs) and tumor-infiltrating immune cells(TICs) in patients with liver metastases from colorectal cancer(CRC) and determine its predictive value for recurrence after microwave ablation(MWA) of liver metastases. Methods The paraffin-embedded specimens of 28 patients with CRC liver metastasis were collected retrospectively. The expression of PD-L1 in the primary lesions was detected by immunohistochemistry, and the relationship between PD-L1 and clinical features was analyzed. Recurrence-free survival(RFS) was analyzed by Kaplan-Meier method and Log rank test. Cox proportional hazards regression model was used to analyze the factors influencing recurrence. Results The positive rates of PD-L1 in TCs and TICs in primary CRC were 14.3%(4/28) and 46.4%(13/28), respectively. PD-L1 expression in primary TICs of CRC patients with liver metastases was significantly correlated with the largest hepatic tumor diameter (P < 0.05). PD-L1 expression in primary TICs of CRC patients with liver metastasis was correlated with poor RFS after MWA (P < 0.05). PD-L1 expression in primary TICs and the largest hepatic tumor diameter > 3 cm in CRC patients with liver metastases were the risk factors for recurrence after MWA (P < 0.05). Conclusion PD-L1 expression in primary TICs of CRC patients with liver metastasis may increase the risk of recurrence after MWA for liver metastasis.

Expert consensus on PD-L1 expression testing in esophageal carcinoma in China / 中华肿瘤杂志

In recent years, immunotherapy represented by immune checkpoint inhibitors programmed death 1 (PD-1) has made great progress in the treatment of esophageal cancer and is rewriting the global paradigm for the treatment of esophageal cancer. According to current data, only a small number of patients with esophageal cancer could benefit from immunotherapy. Therefore, it is a challenge to screen the potential beneficiaries of PD-1 inhibitors. Studies have shown that the expression level of programmed death-ligand 1 (PD-L1) in esophageal cancer is closely associated with the efficacy of PD-1 inhibitors, and PD-L1 is the most important predictive biomarker of the efficacy of PD-1 inhibitors. With the clinical application of different PD-1 inhibitors and PD-L1 protein expression detection platforms, clarifying the clinical significance and timing of detection of PD-L1 protein expression in esophageal cancer, and establishing a standardized PD-L1 testing procedure, are of great significance to improve the accuracy of detection and reduce the difference between laboratories, so as to maximize the therapeutic benefits for patients. This consensus was finally reached, based on the combination of literature, expert experience, and internal discussion and voting of committee members, to provide an accurate and reliable evidence for clinicians to make decisions.