Evaluation value of serum soluble programmed cell death protein 1, soluble B7 homolog 5 molecules combined with trefoil factor 2 on disease severity and death risk in patients with acute pancreatitis / 中国医师进修杂志

Objective:To investigate the value of serum soluble programmed cell death protein 1 (sPD-1), soluble B7 homolog 5 (sB7-H5) and trefoil factor 2 (TFF2) in evaluating the severity of disease and the risk of death in patients with acute pancreatitis (AP).Methods:A prospective research method was adopted. Three hundred and twenty-eight patients with AP (AP group) from February 2020 to February 2021 in Xiangyang Central Hospital were selected, including 124 patients with mild AP (MAP), 106 patients with moderately severe AP (MSAP) and 98 patients with severe AP (SAP). The serum levels of sPD-1, sB7-H5 and TFF2 were measured by enzyme-linked immunosorbent assay and compared with 60 healthy people (healthy control group). The patients with AP were followed up for 90 d, 284 patients survived and 44 died. The amylase, C-reactive protein (CRP), procalcitonin (PCT), acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ), sequential organ failure assessment (SOFA), modified CT severity index (MCTSI), sPD-1, sB7-H5 and TFF2 were compared between the two groups. Pearson method was used for correlation analysis. Multivariate Logistic regression was used to analyze the independent risk factors of death in patients with AP. The efficacy of sPD-1, sB7-H5 and TFF2 in predicting the death in patients with AP was evaluated using the receiver operating characteristics (ROC) curve.Results:The sPD-1, sB7-H5 and TFF2 in AP group were significantly higher than those in healthy control group: (177.99 ± 17.81) ng/L vs. (50.20 ± 10.81) ng/L, (2.69 ± 0.72) μg/L vs. (1.40 ± 0.35) μg/L and (569.97 ± 38.91) μg/L vs. (94.59 ± 11.98) μg/L, and there were statistical differences ( P<0.01). The amylase, sPD-1, sB7-H5 and TFF2 in patients with MSAP and SAP were significantly higher than those in patients with MAP: (639.36 ± 91.67) and (835.24 ± 109.30) U/L vs. (575.24 ± 89.78) U/L, (180.13 ± 20.61) and (221.17 ± 15.70) ng/L vs. (142.03 ± 16.76) ng/L, (2.85 ± 0.74) and (3.34 ± 0.82) μg/L vs. (2.05 ± 0.52) μg/L, (539.66 ± 36.58) and (763.55 ± 40.08) μg/L vs. (442.90 ± 35.79) μg/L, the indexes in patients with SAP were significantly higher than those in patients with MSAP, and there were statistical differences ( P<0.01). Pearson correlation analysis result showed that sPD-1 was positively correlated with sB7-H5 and TFF2 in patients with AP ( r = 0.552 and 0.641, P<0.01), and the sB7-H5 was positively correlated with TFF2 ( r = 0.610, P<0.01). The amylase, CRP, PCT, APACHE Ⅱ, SOFA, MCTSI, sPD-1, sB7-H5 and TFF2 in the dead patients were significantly higher than those in the living patients: (1 098 ± 105) U/L vs. (641 ± 93) U/L, (235.60 ± 40.17) mg/L vs. (118.04 ± 32.90) mg/L, (4.32 ± 0.52) μg/L vs. (3.14 ± 0.44) μg/L, (19.39 ± 3.14) scores vs. (11.18 ± 2.53) scores, (12.13 ± 2.78) scores vs. (7.40 ± 2.15) scores, (7.12 ± 1.73) scores vs. (4.31 ± 1.52) scores, (222.23 ± 22.30) ng/L vs. (171.14 ± 18.50) ng/L, (3.37 ± 0.89) μg/L vs. (2.59 ± 0.59) μg/L and (629.27 ± 39.63) μg/L vs. (560.78 ± 30.45) μg/L, and there were statistical differences ( P<0.01). Multivariate Logistic regression analysis result showed that CRP, PCT, APACHE Ⅱ, SOFA, sPD-1, sB7-H5 and TFF2 were independent risk factors death of in patients with AP ( OR = 1.339, 1.416, 1.285, 1.327, 1.092, 1.171 and 1.080; 95% CI 1.145 to 1.566, 1.146 to 1.751, 1.132 to 1.460, 1.150 to 1.531, 1.024 to 1.164, 1.072 to 1.280 and 1.031 to 1.131; P<0.01). The ROC curve analysis result showed that the area under the curve of sPD-1, sB7-H5 and TFF2 combined detection to predict the death in patients with AP was larger than that of sPD-1, sB7-H5, and TFF2 alone detection (0.870 vs. 0.771, 0.734 and 0.685). Conclusions:The increase of serum sPD-1, sB7-H5 and TFF2 levels in patients with AP is related to the severity of disease of patients with AP. The combined detection of the indexes can assist in evaluating the risk of death in patients with AP.

sPD-1 and changes of lymphocyte subsets in predicting the prognosis of patients with sepsis: a prospective cohort study / 中华急诊医学杂志

Objective:To observe the dynamic changes of soluble programmed cell death protein 1 (sPD-1) and cellular immunity and humoral immunity in patients with sepsis and septic shock, and to explore the relationship between sPD-1 and immunosuppression in sepsis.Methods:This study was a prospective cohort study. Patients with sepsis and septic shock admitted to the ICU of General Hospital of Ningxia Medical University from June 2018 to December 2018 were included as the study subjects, ordinary postoperative patients admitted to the ICU during the same period were included as the non-sepsis group, and healthy volunteers matched in age and sex were included as healthy controls. The sPD-1, lymphocyte count, serum immunoglobulin and lymphocyte subsets of peripheral blood on the first, third and seventh days after admission to the ICU were detected. The changes of sPD-1 and various immune indices in each group were compared, and the correlation between the indices was analyzed. For healthy controls and non-sepsis patients, only blood samples were tested on the day of inclusion.Results:A total of 90 patients [58 males and 32 females, aged (58.36±17.46) years] were included in this study, including 29 cases of sepsis, 31 cases of septic shock, 15 cases of non-sepsis, and 15 volunteers were recruited as healthy control group. The 28-day fatality rate of patients in the sepsis and septic shock groups was 28.3%. On the first day of ICU admission, the sPD-1 concentration were significantly higher in the septic shock group and sepsis group than those in the non-sepsis group and healthy control group [512.64 (216.85, 1039.41) pg/mL vs. 261.90 (191.96, 421.99) pg/mL vs. 191.56 (151.26, 232.66) pg/mL vs. 200.51 (162.14, 241.26) pg/mL, all P<0.05]. The sPD-1 concentration in the septic shock group was significantly higher than that in the sepsis group, and this phenomenon persisted for at least one week ( P<0.05). The lymphocyte count on the first day in the sepsis and septic shock groups were significantly lower than those in the healthy control and non-sepsis groups (all P<0.05), and the lymphocyte count in the septic shock group remained lower levels until the seventh day of ICU admission (all P<0.05). The percentage of lymphocytes and total T lymphocytes in the sepsis and septic shock groups were significantly lower than those in the healthy control and non-sepsis groups (all P<0.05), while the percentage of total B lymphocytes did not differ between groups (all P>0.05). The percentage of CD8+ T lymphocytes on the seventh day of ICU admission in the septic shock group was still significantly lower than that in the sepsis group [(18.36±2.23)% vs. (28.28±2.97)%, P<0.05]. The levels of serum immunoglobulin IgG and IgM were significantly lower in the sepsis and septic shock group than those in the healthy control and non-sepsis groups (all P<0.05), and the IgG and IgM in the sepsis and septic shock groups returned to normal on the seventh day of ICU admission. The area under the ROC curve was used to evaluate the predictive value of sPD-1 on poor prognosis, and the results showed that sPD-1 on the seventh day of ICU had a good predictive value for 28-day prognosis in patients with sepsis and septic shock, and the best cut-off value was 286.52 pg/mL, with a sensitivity of 100.00% and specificity of 56.25%. Conclusions:Immunosuppression occurs in patients with sepsis and septic shock in the early stage, and the duration of immunosuppression in patients with septic shock is prolonged, but humoral immunosuppression plays a major defense in the early stage, and cellular immunosuppression is dominant in the later stage.

Neoadjuvant immunotherapy combined with stereotactic body radiation therapy for stage Ⅲ/N2 non-small cell lung cancer: Three cases reports / 中国胸心血管外科临床杂志

@#We reported three cases of stageⅢ/N2 non-small cell lung cancer (NSCLC) treated with neoadjuvant immunotherapy and stereotactic body radiation therapy (SBRT) in our hospital, including 2 males and 1 female with a mean age of 65.7 years. The patients received two doses of the programmed cell death protein-1 inhibitor toripalimab after 1 week of SBRT. Thereafter, surgery was planned 4-6 weeks after the second dose. One patient achieved pathologic complete response, one achieved major pathologic response (MPR), and one did not achieve MPR with 20% residual tumor. There were few side effects of toripalimab combined with SBRT as a neoadjuvant treatment, and the treatment did not cause a delay of surgery.

Quality evaluation of anti-PD-1/CTLA-4 bispecific antibody / 中国生物制品学杂志

@#Objective Establish quality control methods for critical quality attribute of bispecific antibody against programmed cell death protein 1(PD-1)/cytotoxic T-lymphocyte-associated protein 4(CTLA-4).Methods The biological activity of PD-1 target was determined by reporter gene assay,and the competitive binding activity of CTLA-4 target was determined by flow cytometry;The antibody molecular size variants were controlled by reducing/non-reducing capillary electrophoresis-sodium dodecyl sulfonate(CE-SDS) and size exclusion chromatography-high performance liquid chromatography(SEC-HPLC);Charge heterogeneity was determined by imaging capillary isoelectric focusing electrophoresis(iCIEF);Bispecific anti-PD-1/CTLA-4 antibody was identified by peptide map analysis;Glycosylation was analysed by high performance liquid chromatography(HPLC)Results The concentration for 50% of maximal effect(EC_(50)) of PD-1target was(6.91±0.78) nmol/L,and the relative biological potency to the reference was(103.50±13.08)% with the RSD of 12.64%;The EC_(50) of CTLA-4 target activity was(0.35±0.28) nmol/L,and the relative biological potency was(99.30±9.15)% with the RSD of 8.32%.The percentage of peak area of light chain and heavy chain of reducing CE-SDS was(98.86±0.02)%.The main peak area percentage of non-reducing CE-SDS was(93.07±0.13)%,fragment percentage was(4.44±0.13)%,and polymer percentage was(2.49±0.15)%.The peak area percentage of SEC-HPLC monomer and polymer were(97.20±0.01)% and(2.68±0.01)%,respectively.The area percentage of peak A group,peak B group,peak C group and peak D group were(38.43±0.54)%,(43.26±0.32)%,(11.31±0.14)% and(7.00±0.17)%,respectively.Peptide mapping showed the specific spectrum of the bispecific anti-PD-1/CTLA-4 antibody,which could be adopted for identification test.The highest proportion of glycotype was GOF,with a content of(41.06±0.11)%,There were three types of glycan containing sialic acid,namely G2F+G1F-NANA,G2F-NANA and G2F-2NANA,with the content of(12.44±0.12)%,(12.00±0.05)% and(5.37±0.05)%,respectively.The total content of glycan containing sialic acid was(29.80±0.20)%.Conclusion The critical quality attributes of bispecific anti-PD-1/CTLA-4 antibody were studied and the corresponding quality control methods were established to ensure its safety,effectiveness and quality control,which provides a reference for the quality control methods and strategies of this type of monoclonal antibody products.

Anticancer effect of therapy by antibiotic combined with programmed cell death protein 1 in H_(22) hepatocellular carcinoma mouse model / 中国生物制品学杂志

@#Objective To investigate the influence of immunotherapy by antibiotic(ATB) combined with programmed cell death protein 1(PD1) on curative effect of hepatocellular carcinoma in mice.Methods H_(22) tumor-bearing male BALB/c mouse model was established.Eight model mice were injected i.p.with anti-PD1,250 μg for each,and administered intragastrically with ceftriaxone sodium(100 mg/kg) plus lincomycin hydrochloride(200 mg/kg),using eight normal mice administered intragastrically with normal saline(0.2 mL for each) as control.The anticancer effect of ATB combined with PD1 was evaluated by tumor size,hematoxylin-eo sin(HE) staining of tumor tissue and spleen index.The secretion levels of IL-2,IL-10 and IFN_γ in sera of mice were determined by ELISA,while the proportions of CD3~+ and CD8~+ T cells in mouse lymphocytes by flow cytometry,and the expression levels of CD3 and CD8 in mouse tumor tissue by immunohistochemistry(IHC) method.Results The therapy by ATB combined with anti-PD 1 showed significantly inhibitory effect on tumor growth,which increased the proportions of CD3~+ and CD8~+ T cells in T lymphocytes,up-regulated the secretion levels of IL-2,IL-10 and IFN_γ,and regulated the immune function of T cells by up-regulating the expression levels of CD3 and CD8 in tumor tissue to continuously activate the immune system and suppress the tumor.Conclusion Narrow-spectrum ATB may promote the effect of anti-PD 1 immunotherapy on tumors by improving immune function.

Tumor immune checkpoint therapy and the drug delivery strategies / 药学学报

Tumor immune checkpoint therapy is a clinical treatment strategy developed based on the new principle of the inhibition of negative immune regulation. In this article, the tumor immune checkpoint therapy and the drug delivery strategies were reviewed, mainly including immunity and tumor therapy, tumor immune checkpoint therapy and its mechanism of action, clinical application of tumor immune checkpoint therapy and therapeutic drugs, immune resistance of programmed cell death protein 1 (PD1)/programmed cell death ligand 1 (PDL1) treatment and countermeasures, drug delivery strategies for tumor immune checkpoint therapeutic agents, etc. As a revolutionary new immunotherapy strategy, tumor immune checkpoint therapy has shown obvious superior therapeutic efficacy in a variety types of tumor. However, tumor immune checkpoint therapy is also faced with a big challenge, namely, immunotherapy resistance. With the discovery of new mechanism, the continuous development of new therapeutic drugs and delivery strategies, tumor immune checkpoint therapy is expected to further improve the clinical efficacy of tumor.

Tumor microenvironment responsive liposomes blocking CXCL12/CXCR4 pathway and synergistically enhancing immune efficacy of anti-PD-L1 / 药学学报

Blocking immune checkpoint programmed cell death receptor 1 (PD-1) or programmed death receptor-ligand 1 (PD-L1) can enhance anti-tumor activity of effector T cells. However, the lack of response in many patients to PD-1/PD-L1 therapy remains a question. Improving the immunosuppressive tumor microenvironment (TME) to enhance the efficacy of immune checkpoint inhibitors has become a promising cancer treatment strategy. We constructed a liposome system (PD-L1/siCXCL12-Lp) of CXCL12 siRNA and anti-PD-L1 peptide with matrix metalloproteinases (MMPs) responsiveness, which combined the TME regulation of siCXCL12 and the immune regulation of anti-PD-L1 peptide. All animal experiments were approved by the Biomedical Ethics Committee of Peking University. The authors found that PD-L1/siCXCL12-Lp directly down-regulated the expression of CXCL12 in vitro (33.8%) and in vivo (15.5%). It also effectively increased the ratio of CD8+/Treg by 20.0%, which helped the anti-PD-L1 peptide to better exert its immune effect. The combination therapy significantly inhibited tumor growth (52.08%) with great safety, which explored a new idea for cancer immunotherapy.

A multicenter retrospective study of immunotherapy for metastatic renal cell carcinoma / 中华泌尿外科杂志

Objective:To evaluate the efficacy and side effects of PD-1 monoclonal antibody in the treatment of advanced metastatic renal cell carcinoma in China.Methods:The clinical data of 117 patients with advanced metastatic renal cell carcinoma (mRCC) treated with PD-1 monoclonal antibody from October 2016 to February 2022 were retrospectively analyzed. There were 87 males (74.4%) and 30 females (25.6%), with an average age of (57.9±10.9) years old, BMI of (23.6±3.4) kg/m 2and smoking history of 79 (67.5%). There were 44 cases (37.6%) with hypertension, 19 (16.2%) cases of diabetes. The ECOG score of 59.8% (70/117) patients was 0, 33.3% (39/117) was 1, 4.3% (5/117) was 2, and 2.5% (3/117) was 3. The pathological type of 104 cases were renal clear cell carcinoma (ccRCC), 8 cases of papillary renal cell carcinoma, 2 cases of chromophobe cell carcinoma, 2 cases of collecting duct carcinoma and 1 case of eosinophilic cell carcinoma. The general condition of the overall population and the overall survival (OS) of relevant subgroups were analyzed. Secondary goals included progression free survival (PFS), objective response rate (ORR), adverse reactions, overall survival (OS), and progression free survival (PFS). Results:65.8% (77 / 117) of the patients chose targeted combined with PD-1 monoclonal antibody in the first-line treatment. The main targeted drugs were acitinib (81.8%, 63 / 77), tirelizumab (37.6%, 29 / 77) and cindilimab (25.9%, 20 / 77). After first-line treatment, 19.6.1% (23 / 117) patients needed to be converted to second-line treatment, and 15 patients changed the type of PD-1 antibody during treatment. In addition, the targeted drug of combined therapy was replaced by acitinib in 8 patients. The main causes of drug withdrawal were disease progression (70.7%, 29 / 41) and death (29.2%, 12 / 41). The median OS of the overall population was 35.6 (19-60) months and PFS was 12.1 (1-60) months. The ORR of the overall population was 47.8% (56 / 117). 4.2% (5/117) patients had complete remission, another 17.0% (20/117) patients were in stable condition, and 43.5% (51 / 117) patients were in partial remission. In the first-line treatment, the median PFS time of targeted combined with PD-1 monoclonal antibody was 12.6 (1-30) months, the median PFS time of PD-1 single drug immunotherapy was 10.5 (1-60) months. In the second-line treatment, the PFS of patients treated with PD-1 monoclonal antibody was 10.1 (4-19) months, and that of patients treated with PD-1 monoclonal antibody combined with targeted therapy was 11.7 (1-25) months. The most common adverse reactions were elevated blood pressure (18.5%, 23 / 124), followed by hypothyroidism (15.3%%, 19/124), rash (14.5%, 18 / 124), elevated transaminase (10.5%, 13 / 124) and bone marrow suppression (9.7%, 12/124). 9.4% (11 / 117) patients needed to reduce the related adverse reactions by interrupting the treatment control of PD-1 monoclonal antibody.Conclusions:The safety and efficacy of PD-1 monoclonal antibody in domestic patients are better, and the side effects are less. The efficacy and safety of PD-1 monoclonal antibody combined with targeted therapy in the real world population are consistent with many key clinical trials abroad. PD-1 monoclonal antibody combined with targeted drugs can be popularized in the domestic MRCC population.

Short-term outcome of programmed cell death protein1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high risk factors / 中华胃肠外科杂志

Objective: Total neoadjuvant chemoradiotherapy is one of the standard treatments for locally advanced rectal cancer. This study aims to investigate the safety and feasibility of programmed cell death protein 1 (PD-1) antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced middle-low rectal cancer with high-risk factors. Methods: A descriptive cohort study was conducted. Clinicopathological data of 24 patients with locally advanced middle-low rectal cancer with high-risk factors receiving PD-1 antibody combined with neoadjuvant chemoradiotherapy in Gastrointestinal Cancer Center, Unit III, Peking University Cancer Hospital between January 2019 and April 2021 were retrospectively analyzed. Inclusion criteria: (1) rectal adenocarcinoma confirmed by pathology; patient age of ≥ 18 years and ≤ 80 years; (2) the distance from low margin of tumor to anal verge ≤ 10 cm under sigmoidoscopy; (3) ECOG performance status score 0-1; (4) clinical stage T3c, T3d, T4a or T4b, or extramural venous invasion (EMVI) (+) or mrN2 (+) or mesorectal fasciae (MRF) (+) based on MRI; (5) no evidence of distant metastases; (6) no prior pelvic radiation therapy, no prior chemotherapy or surgery for rectal cancer; (7) no systemic infection requiring antibiotic treatment and no immune system disease. Exclusion criteria: (1) anticipated unresectable tumor after neoadjuvant treatment; (2) patients with a history of a prior malignancy within the past 5 years, or with a history of any arterial thrombotic event within the past 6 months; (3) patients received other types of antitumor or experimental therapy; (4) women who were pregnant or breast-feeding; (5) patients with any other concurrent medical or psychiatric condition or disease; (6) patients received immunotherapy (PD-1 antibody). The neoadjuvant therapy consisted of three stages: PD-1 antibody (sintilimab 200 mg, IV, Q3W) combined with CapeOx regimen for three cycles; long-course intensity modulated radiation therapy (IMRT) with gross tumor volume (GTV) 50.6 Gy/CTV 41.8 Gy/22f; CapeOx regimen for two cycles after radiotherapy. After oncological evaluation following the end of the third stage of treatment, surgery or watch and wait would be carried out. Surgical safety, histopathological changes and short-term oncological outcome were analyzed. Results: There were 15 males and 9 females with a median age of 65 (47-78) years. Median distance from the lower margin of the tumor to the anal verge was 4 (3-7) cm. The median maximal diameter of the tumor was 5.1 (2.1-7.5) cm. Twenty patients were cT3, 4 were cT4, 8 were cN1, 5 were cN2a, 11 were cN2b. Ten cases were MRF (+) and 10 were EMVI (+). All the patients were mismatch repair proficient (pMMR). During the neoadjuvant treatment period, 6 patients (25.0%) developed grade 1-2 treatment-related adverse events, including 3 immune-related adverse events. As of April 30, 2021, 20 patients (83.3%, 20/24) had received surgical resection, including 19 R0 resections and 16 sphincter-preservation operations. Morbidity of postoperative complication was 25.0% (5/20), including 2 cases of Clavien-Dindo grade II (1 of anastomotic bleeding and 1 of pseudomembranous enteritis), 3 cases of grade I anastomotic stenosis. Pathological complete response (pCR) rate was 30.0% (6/20) and major pathological response rate was 20.0% (4/20). None of Ras/Raf mutants had pCR or cCR (0/5), while 6 of 17 Ras/Raf wild-type patients had pCR and 3 had cCR, which was significantly higher than that of Ras/Raf mutants (P<0.01). Nine of 16 patients with Ras/Raf wild-type and differentiated adenocarcinoma had pCR or cCR. Among other 4 patients without surgery, 3 patients preferred watch and wait strategy because their tumors were assessed as clinical complete response (cCR), while another one patient refused surgery as the tumor remained stable. After a median follow-up of 11 (6-24) months, only 1 patient with signet ring cell carcinoma had recurrence. Conclusions: PD-1 antibody combined with total neoadjuvant chemoradiotherapy in the treatment of locally advanced rectal cancer has quite good safety and histopathological regression results. Combination of histology and genetic testing is helpful to screen potential beneficiaries.

Systematic Review of Cost-utility Analysis Methodology for PD- 1/PD-L1 Inhibitors in the Treatment of Non- small Cell Lung Cancer / 中国药房

OBJECTIVE：To provide reference for impro ving the quality of programmed cell death protein 1 （PD-1）/ programmed cell death 1 ligand（PD-L1）inhibitors in the treatment of non-small cell lung cancer related pharmacoeconomic studies in China. METHODS ：Retrieved from Embase ，PubMed，Medline，Cochrane Library ，CNKI，Wanfang database ，VIP and other Chinese and English database ，cost-utility studies about PD- 1/PD-L1 inhibitors in the treatment of non-small cell lung cancer published during Jan. 2016-Jan. 2021 were collected. The data of the included studies were extracted. After the quality of the included studies was evaluated by using the Consolidated Health Economic Evaluation Reporting Standards list ，the relevant data were summarized and compared from the aspects of model framework ，model parameters and uncertainty analysis. RESULTS & CONCLUSIONS：A total of 17 studies were finally included ，the overall quality of them was high but the differences in methodology were great. Markov model or partition survival model based on three states was adopted for 16 studies. The time horizon ranged from 5 years to lifetime ；the cycle length ranged from 1 week to 6 weeks. A total of 8 studies used the standard parameter distribution method for parameter fitting ，and 7 studies additionally adopted other parameters estimation methods as KM curves or spline models. Eleven studies performed the validation of model extrapolation. All studies considered the direct medical costs and reported the incremental cost-effectiveness ratio using quality-adjusted life years as the health outcome. Sixteen studies conducted the deterministic sensitivity analysis and probabilistic sensitivity analysis to improve the stability of the model. It is suggested that studies should keep the integrity of the report ； format，choose the appropriate positive comparators ，selectthe health economic model and construct reasonable assumptions according to the available data format ， use Cholesky decomposition to explore the uncertainty of the parameter fitting ， perform the validation of extrapolation combined with external data and use the appropriate indirect comparison in the absence of the head-to-head clinical trials to improve the quality of related pharmacoeconomic studies in China.

Research progress on malignant tumor after lung transplantation / 器官移植

Lung transplantation has become the most effective treatment of end-stage lung diseases. Along with persistent optimization of lung transplantation technique and perioperative management, the short-term clinical efficacy after lung transplantation has been significantly improved, whereas the long-term clinical prognosis remains unoptimistic. Besides chronic lung allograft dysfunction, postoperative malignant tumors also threaten the long-term survival of the recipients. Common malignant tumors following lung transplantation include nonmelanoma skin cancer, posttransplant lymphoproliferative disease and lung cancer. After solid organ transplantation, a large majority of the recipients require lifelong immunosuppressive therapy. The intensity of immunosuppressive therapy for the lung transplant recipients is generally higher than other organ transplant recipients. Immunosuppression is the main factor which leads to the impairment of anti-tumor immune monitoring function and promotes the incidence and development of malignant tumors. In this article, the risk factors, prevention and treatment of the most common malignant tumors after lung transplantation were reviewed, aiming to provide reference for comprehensive diagnosis and treatment of malignant tumors following lung transplantation.

Immunotherapy of recurrence and metastasis after liver transplantation for liver cancer / 器官移植

Primary liver cancer (liver cancer) is one of the main indications of liver transplantation in China. Nevertheless, the 5-year survival rate of liver transplant recipients is lower than 50%. Recurrence and metastasis after operation are the main causes affecting the long-term survival of the recipients. At present, immunotherapy, represented by programmed cell death protein 1(PD-1)/programmed cell death protein-ligand 1(PD-L1) immune checkpoint inhibitor, has achieved remarkable clinical efficacy in the treatment of middle-stage and advanced liver cancer. However, whether it can be applied in recipients with recurrence and metastasis after liver transplantation for liver cancer remains controversial. The main reason is that it may cause acute rejection at the same time. In this article, the research progresses on the application of immunotherapy in recipients with recurrence and metastasis after liver transplantation for liver cancer were reviewed, aiming to improve the survival rate of recipients undergoing liver transplantation forliver cancer.

Chinese Experts Consensus on Immune Checkpoint Inhibitors for Non-small Cell Lung Cancer (2020 Version) / 中国肺癌杂志

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. The systemic antitumor therapy of advanced NSCLC has undergone renovations of chemotherapy, targeted therapy and immunotherapy, which results in greatly improved survival for patients with advanced NSCLC. Immune checkpoint inhibitors (ICIs), especially targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), has changed the treatment paradigm of NSCLC. ICIs have become the standard treatment for advanced NSCLC without epidermal growth factor receptor(EGFR) mutation or anaplastic lymphomakinase(ALK) translocation in the first- or second-line setting, and for locally advanced NSCLC following concurrent radiotherapy and chemotherapy. ICIs are also promising in adjuvant/neoadjuvant therapy. More and more ICIs have been approved domestically for the treatment of NSCLC. Led by the NSCLC expert committee of Chinese Society of Clinical Oncology (CSCO), this consensus was developed and updated based on thoroughly reviewing domestic and foreign literatures, clinical trial data, systematic reviews, experts' discussion and the consensus(2019 version). This consensus will aid domestic clinicians in the treatment of NSCLC with ICIs.
.

Role of PD-1/PD-L1 signaling pathway in immune response of liver transplantation / 器官移植

Primary liver cancer (liver cancer) is one of the main indications of liver transplantation. However, postoperative recurrence of liver cancer severely affects the long-term clinical efficacy of liver transplantation. Programmed cell death protein 1 (PD-1) is an immunosuppressive molecule. Activation of PD-1/programmed cell death protein-ligand 1 (PD-L1) signaling pathway plays a pivotal role in the immune tolerance of grafts. In recent years, immune checkpoint inhibitor(ICI), such as PD-1/PD-L1 inhibitor, has become one of the effective approaches to treat advanced liver cancer, whereas ICI can be applied in liver transplant recipients is highly controversial, and the efficacy and safety remain to be studied. In this article, the expression of PD-1/PD-L1 in liver allograft tissues, the mechanism of PD-1/PD-L1 inducing transplantation immune tolerance and clinical application of PD-1/PD-L1 inhibitor in liver transplantation for liver cancer were reviewed.

Safety of PD-1 inhibitor in preoperative treatment of liver transplantation for liver cancer / 器官移植

Objective To evaluate the safety of programmed cell death protein 1 (PD-1) inhibitor in the treatment of primary liver cancer (liver cancer) before liver transplantation. Methods Clinical data of 7 recipients given with PD-1 inhibitor before liver transplantation for liver cancer were retrospectively analyzed. The incidence of immune-related adverse event (irAE) and clinical prognosis of the recipients were summarized. The safety of PD-1 inhibitor in recipients prior to liver transplantation for liver cancer was evaluated. Results Seven recipients were treated with PD-1 inhibitor with 1-20 courses before liver transplantation for liver cancer. The time interval from drug withdrawal to liver transplantation was 6-120 d. Five recipients suffered from irAE of different degrees, including fatigue in 3 cases, fever in 2 cases, alopecia in 2 cases, rash in 1 case, nausea in 1 case and myocarditis in 1 case, respectively. A majority of these irAE were classified as grade Ⅰ-Ⅱ. One recipient died from grade Ⅴ irAE (fatal myocarditis). One recipient developed rejection at postoperative 7 d, which were mitigated after glucocorticoid pulse therapy combined with increased dosage of tacrolimus. Conclusions PD-1 inhibitor can be applied in preoperative treatment before liver transplantation for liver cancer. Nevertheless, the incidence of irAE and postoperative rejection should be intimately monitored.

Analysis of the Correlation between Molecular Structural Differences of PD-1/PD-L1 Inhibitors and Adverse Events / 中国肺癌杂志

As a new method, immunotherapy which is targeting programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) plays a more and more important role in the treatment of malignant tumors. Immunotherapy is more effective than traditional chemotherapy. However, there are also many adverse events during the application of immunocheckpoint inhibitors targeting PD-1/PD-L1, and the incidence rate of these adverse events among different drugs is different. Because the molecular structure of these drugs is an important indicator to distinguish them, this paper will analyze the correlation between molecular structure and adverse events of PD-1/PD-L1 immunocheckpoint inhibitors through reviewing some meta-analyses and retrospective analyses from the perspective of different structures.

Construction of a novel lentiviral vector knocking down PD-1 via microRNA and its application in CAR-T cells / 生物工程学报

By inserting microRNAs into the intron of EF1α promoter, we constructed a novel lentiviral vector knocking down PD-1 gene via microRNA and applied it to CAR-T cells. Lentiviral transduction efficiency and PD-1-silencing efficiency were detected by flow cytometry. PD-1 expression was detected by Western blotting. Relative expression of microRNA was measured by Q-PCR. Cytotoxicity of CAR-T cells based on this vector was tested by luciferase bioluminescence and flow cytometry. Compared with lentiviral vector with microRNA transcribed by U6 promotor, the transduction efficiency of lentiviral vector with microRNA which was inserted into the intron of EF1α promoter was more significant, and the knockdown rate of PD-1 was more than 90%, which was validated by flow cytometry and Western blotting. And the relative expression level of microRNA in Jurkat cells transduced with this novel lentiviral vector was shown by Q-PCR. Compared with normal CAR-T cells, CAR-T cells based on this vector showed stronger cytotoxicity against PD-L1 positive Raji cells. We successfully constructed a novel lentiviral vector that knocked down PD-1 via microRNA and verified the superiority of its transduction efficiency and knockdown efficiency of PD-1. CAR-T cells based on this vector can exert a more powerful cytotoxicity, thus providing theoretical support for the subsequent treatment of PD-L1 positive tumors.

Value of programmed cell death ligand 1 and soluble programmed cell death ligand 1 in predicting the prognosis of hepatocellular carcinoma and related controversies / 临床肝胆病杂志

At present, there are various treatment methods for hepatocellular carcinoma (HCC), including surgical treatment, interventional treatment, and immunotherapy, and even so, the five-year survival rate of HCC patients is only 12.5%. Influencing factors for the prognosis of HCC have always been the focus of research. With the in-depth research on programmed cell death protein 1 (PD-1) inhibitors in the treatment of HCC in recent years, the role of programmed cell death ligand 1 (PD-L1) and soluble programmed cell death ligand 1 (sPD-L1), as the ligands of PD-1, in immune escape and their value in predicting prognosis have attracted more and more attention. This article elaborates on the current controversies, consensus, and advances in PD-L1 and sPD-L1 as immune markers in evaluating the prognosis of HCC.

Immunotherapy for Non-small Cell Lung Cancer: Current Landscape and Future Perspectives

Immune checkpoint inhibitors (ICIs) have shown remarkable benefit in the treatment of patients with non-small-cell lung cancer (NSCLC) and have emerged as an effective treatment option even in the first-line setting. ICIs can block inhibitory pathways that restrain the immune response against cancer, restoring and sustaining antitumor immunity. Currently, there are 4 PD-1/PD-L1 blocking agents available in clinics, and immunotherapy-based regimen alone or in combination with chemotherapy is now preferred option. Combination trials assessing combination of ICIs with chemotherapy, targeted therapy and other immunotherapy are ongoing. Controversies remain regarding the use of ICIs in targetable oncogene-addicted subpopulations, but their initial treatment recommendations remained unchanged, with specific tyrosine kinase inhibitors as the choice. For the majority of patients without targetable driver oncogenes, deciding between therapeutic options can be difficult due to lack of direct cross-comparison studies. There are continuous efforts to find predictive biomarkers to find those who respond better to ICIs. PD-L1 protein expressions by immunohistochemistry and tumor mutational burden have emerged as most well-validated biomarkers in multiple clinical trials. However, there still is a need to improve patient selection, and to establish the most effective concurrent or sequential combination therapies in different NSCLC clinical settings. In this review, we will introduce currently used ICIs in NSCLC and analyze most recent trials, and finally discuss how, when and for whom ICIs can be used to provide promising avenues for lung cancer treatment.

Predictive factors for the clinical effect of PD-1/PD-L1 checkpoint inhibitors in treatment of hepatocellular carcinoma / 临床肝胆病杂志

At present, there is still a lack of uniform treatment strategies for hepatocellular carcinoma (HCC). Immunotherapy, especially PD-1/PD-L1 checkpoint inhibitors, is a novel therapy for HCC and can bring survival benefits to patients with advanced HCC. However, research data show that only a small number of HCC patients can benefit from this treatment regimen. To date, few biomarkers have been reported to predict the clinical effect of PD-1/PD-L1 checkpoint inhibitors in HCC patients. This article reviews the biomarkers studied for HCC and other tumors and explores the possible predictive factors for the clinical effect of PD-1/PD-L1 checkpoint inhibitors in HCC, in order to optimize the selection of treatment population and improve the clinical effect of PD-1/PD-L1 checkpoint inhibitors in the treatment of HCC.