Construction and validation of a prognostic nomogram model of programmed death receptor 1 inhibitors in treatment of hepatitis B-related hepatocellular carcinoma / 肿瘤研究与临床

Objective:To investigate the factors influencing the prognosis of hepatitis B-related hepatocellular carcinoma treated with programmed death receptor 1 (PD-1) inhibitors, and to construct a prognostic nomogram model for these patients and evaluate its clinical significances.Methods:The clinical data of 121 patients with hepatitis B-related hepatocellular carcinoma treated with PD-1 inhibitors at the First Affiliated Hospital of Xinxiang Medical College from July 2018 to July 2021 were retrospectively analyzed. Follow-up was performed from the beginning of PD-1 inhibitor use, and the Kaplan-Meier method was used to analyze the overall survival of patients. The variables screened by the univariate Cox proportional hazards model analysis and variables clinically believed to be related to the prognosis were included in the multivariate Cox proportional hazards model for overall survival, and the stepwise regression method was used to screen the independent factors influencing overall survival. Based on the independent influencing factors of overall survival, R 3.5.1 software was used to construct a prognostic nomogram model for overall survival of hepatitis B-related hepatocellular carcinoma treated with PD-1 inhibitors. Calibration curve was used to the consistency of model prediction and practice. The Harrell consistency index and receiver operating characteristic (ROC) curve (with imaging diagnosis as the gold standard) were used to analyze the efficacy of model in predicting the 1-year and 2-year overall survival rates.Results:The median follow-up time of 121 patients was 12.40 months, and the median overall survival time was 14.30 months, with overall survival rates of 82.60% and 62.30% at 6 and 12 months. Multivariate Cox regression analysis showed that albumin (ALB) ( HR = 0.946, 95% CI 0.901-0.992), international normalized ratio (INR) ( HR = 32.034, 95% CI 5.046-203.362), aspartate aminotransferase (AST) ( HR = 1.010, 95% CI 1.007-1.012) were independent influencing factors for overall survival of patients. According to the three factors, a prognostic nomogram model for hepatitis B-related hepatocellular carcinoma treated with PD-1 inhibitors was constructed. The slope of the calibration curve of the model predicting 1-year and 2-year overall survival rates was close to 1. The Harrell consistency index of the nomogram model was 0.809 (95% CI 0.760-0.858). ROC curve analysis showed that the area under the curve (AUC) of the nomogram model predicting 1-year and 2-year overall survival rates of patients was 0.794 (95% CI 0.744-0.887, P < 0.001) and 0.791 (95% CI 0.708-0.860, P = 0.002). Conclusions:ALB, INR and AST are the influencing factors of prognosis of hepatitis B-related hepatocellular carcinoma patients treated with PD-1 inhibitors, and the nomogram model constructed based on prognostic influencing factors has a good effect on predicting the 1-year and 2-year overall survival rates of patients, which can be used to screen the population suitable for immunotherapy and is conducive to the clinical formulation of individualized and precise treatment plans.

Roles of PD-1/PD-L1 immune checkpoint in thyroid diseases / 中华核医学与分子影像杂志

Programmed cell death receptor 1 (PD-1)/PD-1 ligand (PD-L1) maintains immune tolerance of normal tissues and mediates immune escape of tumors. For autoimmune thyroiditis, thyroid follicular epithelial cells inhibit the damage of T cells by up-regulating PD-L1 expression. With the application of immune checkpoint inhibitors (ICIs) in the field of cancer therapy, the incidence of immune-related thyroid disorders caused by ICIs has increased. Thyroid function should be monitored during and after ICIs treatment to promptly diagnose primary and (or) secondary thyroid disorders. The PD-1/PD-L1 signaling directly stimulates thyroid cancer cells, and exerts inhibitory effects on tumor-infiltrating immune cells. Combination of ICIs targeting PD-1/PD-L1 with chemo-radiotherapy or targeted therapy is a promising therapeutic strategy in the treatment of refractory thyroid cancers.

Prognostic value of pretreatment 18F-FDG PET/CT in patients with metastatic melanoma treated with anti-PD1 immunotherapy / 中华核医学与分子影像杂志

Objective:To assess the prognostic value of pretreatment 18F-FDG PET/CT metabolic parameters in patients with metastatic malignant melanoma treated with anti-programmed cell death-1 (PD1) immunotherapy. Methods:A retrospective analysis of 29 patients (15 males, 14 females, age (59.1±13.0) years) with pathologically diagnosed metastatic malignant melanoma in Nanjing Drum Tower Hospital between June 2017 and October 2020 was conducted. Anti-PD1 immunotherapy were performed in all patients after 18F-FDG PET/CT imaging. 18F-FDG PET/CT parameters including SUV max, bone marrow-to-liver SUV max ratio (BLR), spleen-to-liver SUV max ratio (SLR) were obtained. Total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) of primary lesions were measured automatically using the thresholds of 40%SUV max. The median value of each PET parameter was regarded as the threshold value and was used to divide patients into 2 groups (≥ and < the median value, respectively). Kaplan-Meier survival curve and Cox proportional risk model were used to analyze the overall survival (OS) differences between groups. Results:The median follow-up time was 15.0 months and 13 patients died. The median OS was 26.0(95% CI: 20.4-31.6) months. The median SUV max, TMTV, TLG, BLR and SLR were 6.2, 8.2 cm 3, 38.6 g, 0.82 and 0.84 respectively. Kaplan-Meier method and log-rank test showed that differences of OS between SUV max≥6.2 and <6.2 groups, TLG≥38.6 g and <38.6 g groups, BLR≥0.82 and <0.82 groups, SLR≥0.84 and <0.84 groups were not significant ( χ2 values: 0.01-0.35, P values: 0.061-0.929), while patients with TMTV≥8.2 cm 3 suffered from poorer OS compared with those with TMTV<8.2 cm 3 ( χ2=5.90, P=0.015). Cox multivariate analysis showed that TMTV (hazard risk ( HR)=6.347, 95% CI: 1.039-38.789) was a significant predictor of OS ( P=0.045). Conclusion:18F-FDG PET/CT parameter TMTV is the independent predictive factor of OS in metastatic melanoma treated with anti-PD1 immunotherapy.

Programmed cell death-1 inhibitor combined with immunochemotherapy in treatment of refractory primary mediastinal large B-cell lymphoma: report of 2 cases and review of literature / 白血病·淋巴瘤

Objective:To investigate the efficacy of programmed cell death-1 (PD-1) inhibitor combined with immunochemotherapy in the treatment of refractory primary mediastinal large B-cell lymphoma (PMBCL).Methods:The clinical data of 2 refractory PMBCL patients who were achieving remission after applying PD-1 inhibitor combined with immunochemotherapy in Qilu Hospital of Shandong University (Qingdao) in July 2019 and January 2020 were retrospectively analyzed, and the relevant literature was reviewed.Results:The two patients were initially treated with CDOPE and R-CDOPE regimens, respectively, but the disease did not reach remission state. Later, they were adjusted to PD-1 inhibitor combined with immunochemotherapy to achieve remission. Radiotherapy and autologous hematopoietic stem cell transplantation were used as consolidation treatment, and maintenance therapy with PD-1 inhibitors was effective and had a good safety profile.Conclusions:For refractory PMBCL patients, PD-1 inhibitor combined with immunochemotherapy may have good efficacy.

PD-1 inhibitor plus anlotinib for metastatic castration-resistant prostate cancer: a real-world study / 亚洲男科学杂志(英文版)

Management and treatment of terminal metastatic castration-resistant prostate cancer (mCRPC) remains heavily debated. We sought to investigate the efficacy of programmed cell death 1 (PD-1) inhibitor plus anlotinib as a potential solution for terminal mCRPC and further evaluate the association of genomic characteristics with efficacy outcomes. We conducted a retrospective real-world study of 25 mCRPC patients who received PD-1 inhibitor plus anlotinib after the progression to standard treatments. The clinical information was extracted from the electronic medical records and 22 patients had targeted circulating tumor DNA (ctDNA) next-generation sequencing. Statistical analysis showed that 6 (24.0%) patients experienced prostate-specific antigen (PSA) response and 11 (44.0%) patients experienced PSA reduction. The relationship between ctDNA findings and outcomes was also analyzed. DNA-damage repair (DDR) pathways and homologous recombination repair (HRR) pathway defects indicated a comparatively longer PSA-progression-free survival (PSA-PFS; 2.5 months vs 1.2 months, P = 0.027; 3.3 months vs 1.2 months, P = 0.017; respectively). This study introduces the PD-1 inhibitor plus anlotinib as a late-line therapeutic strategy for terminal mCRPC. PD-1 inhibitor plus anlotinib may be a new treatment choice for terminal mCRPC patients with DDR or HRR pathway defects and requires further investigation.

Short-term efficacy and safety of pembrolizumab combined with neoadjuvant chemotherapy for the treatment of non-small cell lung cancer / 中国胸心血管外科临床杂志

@#Objective    To explore the short-term efficacy and safety of pembrolizumab combined with chemotherapy in the neoadjuvant treatment of non-small cell lung cancer. Methods    The clinical data of 11 male patients with non-small cell lung cancer who underwent pembrolizumab combined with neoadjuvant chemotherapy in the Department of Thoracic Surgery, the First Affiliated Hospital of Xi'an Jiaotong University from December 2019 to June 2021 were retrospectively analyzed. The average age of the patients was 52.0-79.0 (62.0±6.9) years. The imaging data and pathological changes before and after neoadjuvant treatment were compared, and adverse reactions during neoadjuvant treatment were recorded. Objective remission rate (ORR) and main pathological remission rate (MPR) and pathological complete remission rate (pCR) were the main observation endpoints. Results    After preoperative neoadjuvant therapy with pembrolizumab combined with platinum or paclitaxel, all patients successfully underwent thoracoscopic radical resection of lung cancer. The ORR was 72.7%, and the MPR was 81.8%. Among them, 45.5% of patients achieved pCR. The main adverse reactions were hypoalbuminemia, decreased appetite and nausea. The mortality rate within 30 days after surgery was 0, and no tumor metastasis was observed. Conclusion    Pembrolizumab combined with neoadjuvant chemotherapy is safe and feasible to treat non-small cell lung cancer, and the short-term efficacy is beneficial.

Study on the mechanism of VEGF inducing tolerogenic dendritic cells in oral squamous cell carcinoma / 口腔医学

Objective@#To investigate the mechanism of vascular endothelial growth factor(VEGF) inducing tolerogenic dendritic cells(DCs) in oral squamous cell carcinoma (OSCC).@*Methods@#The DCs were divided into four groups: Control group (DC), VEGF group (VEGF added into DC), Co-culture group (DC co-cultured with SCC7) and Anti-VEGF group (anti-VEGF antibody added into DC co-cultured with SCC7). Flow cytometry (FCM) was used to detect DC surface markers. To detect the effect of DC on proliferation activity of T lymphocyte, the experiment included five groups: Nc group (T lymphocyte), Control group (T lymphocyte added into DC), VEGF group (T lymphocyte + DC + VEGF), Co-culture group (T lymphocyte + DC + supernatant of SCC7) and Anti-VEGF group (T lymphocyte + DC + supernatant of SCC7 + anti-VEGF antibody). Subsequently, the mixed lymphocyte reaction(MLR) was conducted. The expression levels of indole-2, 3-doxygenase(IDO)and programmed cell death 1 ligand 1(PD-L1)in DC were detected by western blot, real time PCR and FCM respectively. For the cytotoxic lymphocyte (CTL) assay, SCC7 cells and CTLs were mixed and CTL-mediated SCC7 cells cytotoxicity was tested. The experiment included four groups: Control group (T lymphocyte + DC), IDO inhibition group (T lymphocyte + DC + IDO inhibitor), Anti-PD-L1 antibody group (T lymphocyte + DC + anti-PD-L1 antibody) and Combination group (T lymphocyte + DC + IDO inhibitor + anti-PD-L1 antibody). The SCC7 tumor-bearing mice treated with IDO inhibitor and the anti-PD-L1 antibody were sacrificed and the tumor inhibition rate and the spleen index were determined. @*Results@#Compared with Control group, exogenous VEGF or SCC7 co-culture inhibited the relative number of DC expressing CD11C, CD80, CD86, CD40 and MHC Ⅱ. The positive DCs were increased in the Anti-VEGF group compared with VEGF or Co-culture group. In VEGF or Co-culture group, the number of T cells stimulated by SCC7-pulsed DCs was decreased compared with Control group. However, the ability of Anti-VEGF group to induce T cell proliferation was significantly increased compared with VEGF or Co-culture group. Significantly increased expression of IDO and PD-L1 were observed in VEGF and Co-culture group. However, this was partially reversed by addition of anti-VEGF antibody into the co-culture system. Compared with Control group, the expressions of CD11C and CD86 in DC in both the IDO inhibition group and Anti-PD-L1 antibody group were increased, and were significantly higher in the Combination group compared with the single drug groups. The similar results were exhibited in MLR and CTL assay. In vivo, the results revealed that the tumors obtained from the mice in three experimental groups were smaller than those in the control group. Furthermore, the tumor volume of the Combination group was the smallest. The spleen index of each group was calculated and the results showed the spleen index of the three experimental groups was significantly higher than that of Control group.@*Conclusion@#VEGF in OSCC micro-environment inhibits the maturation and function of DC that are transformed into tolerogenic DC by high expression of IDO and PD-L1.

Thoracic SMARCA4-deficient undifferentiated tumor-pathological diagnosis and combined immune checkpoint inhibitor treatment / 北京大学学报(医学版)

We explored clinicopathological features and treatment strategies for thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Thoracic SMARCA4-UT is a new entity recently acknowledged in the 2021 edition of World Health Organization Classification of Thoracic Tumors, and doctors are relatively unfamiliar with its diagnosis, treatment, and prognosis. Taking a case of SMARCA4-UT treated in Peking University First Hospital as an example, this multi-disciplinary discussion covered several hot issues on diagnosing and treating thoracic SMARCA4-UT, including histological features, immu- nohistochemical and molecular phenotype, immune checkpoint inhibitor (ICI) therapy, and pathological assessment of neoadjuvant therapy response. The patient was an older man with a long history of smoking and was admitted due to a rapidly progressing solid tumor in the lower lobe of the right lung. Histologically, tumor cells were epithelioid, undifferentiated, diffusely positive for CD34, and partially positive for SALL4.The expression of BRG1 protein encoded by SMARCA4 gene was lost in all of tumor cells, and next-generation sequencing(NGS)confirmed SMARCA4 gene mutation (c.2196T>G, p.Y732Ter). The pathological diagnosis reached as thoracic SMARCA4-UT, and the preoperative TNM stage was T1N2M0 (ⅢA). Tumor proportion score (TPS) detected by immunohistochemistry of programmed cell death 1-ligand 1 (PD-L1, clone SP263) was 2%. Tumor mutation burden (TMB) detected by NGS of 1 021 genes was 16. 3/Mb. Microsatellite detection showed the tumor was microsatellite stable (MSS). Neo-adjuvant therapy was implemented with the combined regimen of chemotherapy and ICI. Right lower lobectomy was performed through thoracoscopy after the two weeks' neoadjuvant. The pathologic assessment of lung tumor specimens after neoadjuvant therapy revealed a complete pathological response (CPR). The post-neoadjuvant tumor TNM stage was ypT0N0M0. Then, five cycles of adjuvant therapy were completed. Until October 2022, neither tumor recurrence nor metastasis was detected, and minimal residual disease (MRD) detection was negative. At present, it is believed that if BRG1 immunohistochemical staining is negative, regardless of whether SMARCA4 gene mutation is detected, it should be classified as SMARCA4-deficient tumors. SMARCA4-deficient tumors include a variety of carcinomas and sarcomas. The essential criteria for diagnosing SMARCA4-UT includes loss of BRG1 expression, speci-fic histological morphology, and exclude other common thoracic malignant tumors with SMARCA4-deficiency, such as squamous cell carcinoma, adenocarcinoma and large cell carcinoma. SMARCA4-UT is a very aggressive malignant tumor with a poor prognosis. It has almost no targeted therapy mutations, and little response to chemotherapy, but ICI is currently the only effective drug. The successful diagnosis and treatment for this case of SMARCA4-UT should enlighten significance for various kinds of SMARCA4-deficient tumors.

Consistency comparison of programmed cell death 1-ligand 1 in different immuno-histochemical staining methods / 北京大学学报(医学版)

OBJECTIVE@#To compare the consistency of programmed cell death 1-ligand 1 (PD-L1, clone E1L3N, 22C3, SP263) in different immunohistochemical staining methods.@*METHODS@#The first step was to select the optimal process: The PD-L1(clone E1L3N) antibody recommended process, self-built process ①, self-built process ② and self-built process ③ were used to perform immunohistochemical staining in 5 cases of tonsil tissue. The quality of all slides was scored by expert pathologists (0-6 points). The process with the highest score was selected. The second step was to compare the consistency between the optimal procedure and the two standard procedures. Thirty-two cases of lung non-small cell carcinoma diagnosed by pathology in Peking University First Hospital in the past two years were randomly selected. The 32 cases were stained in parallel with the SP263 and 22C3 standard procedures, and all stained slides were scored by specialized pathologists for tumor proportion score (TPS). The scoring results were grouped according to < 1%, ≥1% to < 10%, ≥10% to < 50%, and ≥50%. The consistency of PD-L1 detection antibody clone E1L3N and 22C3, E1L3N and SP263 staining results was analyzed.@*RESULTS@#Tonsil stained slides scores (0-6 points) were as follows: The recommended protocol was 5, 5, 5, 5 and 5. The self-built process ① was 5, 6, 6, 5 and 6. The self-built process ② was 4, 4, 4, 4 and 4.The self-built process ③ was 3, 3, 3, 3 and 3. The self-built process ① was the best with the highest score. The TPSs of 32 non small cell lung carcinoma (NSCLC) cases were as follows: Of self-built process ①, 6 cases were lower than 1%, 5 cases were from 1% to 10%, 10 cases were from 10% to 50%, and 11 cases were higher than 50%; of 22C3 standard procedure, 5 cases were lower than 1%, 3 cases were from 1% to 10%, 13 cases were from 10% to 50%, 11 cases were higher than 50%; of SP263 standard procedure, 7 cases were lower than 1%, 4 cases were from 1% to 10%, 11 cases were from 10% to 50%, 10 cases were higher than 50%. The results of the consistency test were as follows: The κ value for self-built process ① and 22C3 standard procedure was 0.736 (P < 0.001), the agreement was good; the κ value for self-built process ① and SP263 standard procedure was 0.914 (P < 0.001), the agreement was very good.@*CONCLUSION@#The immunostaining using PD-L1(E1L3N) with validated self-built staining protocol ① by Ventana Benchmark GX platform can obtain high quality of slides, and the TPSs based on these slides are in good agreement with 22C3 and SP263 standard procedures.

Supervivencia extendida con pembrolizumab en un paciente con cáncer de pulmón no microcítico estadio IV: Reporte de caso / Extendedsurvival with pembrolizumab in a patient with stage IV non-small cell lung cancer:A case report

Introducción:La inmunoterapia con pembrolizumab ha mejorado el pronóstico del cáncer de pulmón metastásico. En el presente caso se presenta la supervivencia extendidad y evolución de un paciente específico.Caso clínico:Hombre de 66 años, fumador. Diagnosticado de masa pulmonar en lóbulo infe-rior izquierdo de dimensiones 9 x 8 cm, con metástasis supra e infratentoriales intraaxiliares. Taller diagnóstico: Establecida como neoplasia de pulmón en estadio IVc, se comprobó el estado de PDL1 que positivo en un 80 % de la muestra de masa pulmonar. Debuta con me-tástasis cerebrales.Evolución: Se inció inmunoterapia con Pembrolizumab, el cual se mantubo hasta la presencia de un efecto secundario atribuido al pembrolizumab, cumpliendo 30meses de supervivencia hasta el cierre de esta observación no se reportó la muerte del paciente.Conclusiones:En el presente reporte, la determinación del biomarcador histológico PDL1 po-sitivo en cáncer de pulmón ayudo a prescribir un tratamiento con inmunoterpia dirigida, lo que demostró aumentar la supervivencia más allá que el tratamiento convencional con quimiote-rapia

Introduction: Immunotherapy with pembrolizumab has improved the prognosis of metastatic lung cancer. A specific patient's extended survival and evolution is presented in the present case.Clinical case: 66-year-old man, smoker. Diagnosed with a lung mass in the left lower lobe measuring 9 x 8 cm, with supra and infratentorial intra-axial metastases.Diagnostic workshop: To establisha stage IVc lung neoplasm, 80% of the lung mass sample was confirmed to be positive for PDL1.Evolution: Immunotherapy was started with Pembrolizumab, which was maintained until the presence of a side effect attributed to pembrolizumab, completing 30 months of survival until the closure of this observation, the patient's death was not reported.Conclusions: In the present report, the determination of the positive histological biomarker PDL1 in lung cancer helped prescribe treatment with targeted immunotherapy, which was shown to increase survival beyond conventional treatment with chemotherapy

La inhibición de los puntos de control inmunológico, una terapia en evolución: remembranza del Premio Nobel de Medicina 2018 / Immune checkpoint inhibitors: a breakthrough in cancer therapy

Professors James P. Allison and Tasuku Honjo were awarded with the 2018 Nobel Prize in Medicine for their contributions in cancer immunotherapy. The latter is a breakthrough in cancer therapy, aimed to overcome tumor-induced immunosuppression, leading to the reactivation of the immune system against cancer cells. Under physiological conditions, the CTLA-4 and PD-1 proteins expressed on T-cells and discovered by the awarded scientists, lead to immune tolerance. Cancer cells exploit these control points to enhance the inhibition of T-cells. The expression of PD ligands (PD-L1) in tumor cells and CTLA-4 ligands in antigen presenting cells, which bind the PD-1 receptor and CTLA-4 respectively, block anti-tumor immunity. This situation led to a biotechnological race focused on the development of effective antibodies able to "turn-on" the immune system cheated by the tumor. Anti-CTLA-4 and anti-PD-1 antibodies improve life-expectancy in cancer patients. In this review, we perform an historical overview of Professors Allison and Honjo contribution, as well as the immunological basis of this new and powerful therapeutic strategy, highlighting the clinical benefits of such intervention.

Cutaneous immune-related adverse reactions induced by immune checkpoint inhibitors / 中华皮肤科杂志

As a new type of anti-cancer drugs, immune checkpoint inhibitors have been widely used for the treatment of various tumors in recent years, but they have also caused a variety of immune-related adverse reactions, among which cutaneous adverse reactions are the most common. The onset of cutaneous adverse reactions is usually early, and most are mild, but some can also be life-threatening. This review summarizes recent advances in cutaneous immune-related adverse reactions induced by immune checkpoint inhibitors.

Programmed death-1/programmed death ligand-1 signaling pathway in idiopathic inflammatory myopathies / 中华皮肤科杂志

After the specific binding of programmed death-1 (PD-1) to programmed death ligand 1 (PD-L1) , the PD-1/PD-L1 complex can exert a co-suppressive/co-stimulatory immunoregulatory effect, which can inhibit the activation and proliferation of T cells and their cytokine secretion, and play a key role in tumor immunity, autoimmunity and immune tolerance. This review summarizes structures and regulatory mechanisms of the PD-1/PD-L1 signaling pathway, aimming to facilitate the understanding of immune pathogenesis of idiopathic inflammatory myopathies complicated by malignant tumors, and to seek potential therapeutic targets and diagnostic strategies.

Site-specific labelling and biological evaluation of PD-L1 targeted single-domain antibody / 中华核医学与分子影像杂志

Objective:To synthesize a novel site-specifically labelled probe 68Ga-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-Cys-Asp-Val (CDV)-Nb109 and explore its potential for detection of the programmed cell death ligand 1 (PD-L1) expression level in different tumors. Methods:Firstly, CDV was inserted into the tail of the sequence of Nb109 by genetic engineering. Then the precursor DOTA-CDV-Nb109 was prepared by mixing the maleimide-DOTA and the single-domain antibody CDV-Nb109 (amount of substance ratio 1∶1) via the maleimide-cysteine site-specific coupling strategy. Subsequently, the DOTA-CDV-Nb109 was labeled with 68Ga and purified by PD-10 column. Human melanoma A375, human PD-L1 transfected melanoma A375-hPD-L1 and human glioma U87 tumor-bearing mice models were established, and the diagnostic value of 68Ga-DOTA-CDV-Nb109 was evaluated by stability assay, cellular uptake, and microPET imaging. One-way analysis of variance and the least significant difference t test were used to analyze the data. Results:The probe 68Ga-DOTA-CDV-Nb109 was obtained with the radiochemical yield of (69.79±4.69)%, radiochemical purity more than 97%, and molar activity of (12.85±1.51) GBq/μmol. 68Ga-DOTA-CDV-Nb109 had strong binding affinity for A375-hPD-L1 with the dissociation constant ( Kd) of (66.43±17.89) nmol/L. The uptake of 68Ga-DOTA-CDV-Nb109 in A375-hPD-L1 and U87 cells were (3.17±0.15) percentage of the added radioactivity dose (%AD) and (2.08±0.03) %AD respectively, which were significantly higher than that in A375 cells ((1.21±0.14) %AD; F=82.87, t values: 15.23, 9.98, P values: <0.001, 0.003). The tumor uptake of the probe in A375-hPD-L1 ((5.21±0.35) percentage of injected dose per ml (%ID/ml)) and U87 tumor-bearing mice ((3.44±0.69) %ID/ml) were significantly higher than that in A375 tumor-bearing mice ((2.17±0.36) %ID/ml; F=249.72, t values: 35.70, 3.43, both P<0.001). Conclusion:The site-specifically labelled probe 68Ga-DOTA-CDV-Nb109, which can non-invasively and dynamically monitor the change of PD-L1 expression level in different tumors and help screen patients who can benefit from PD-L1 immune checkpoint blocking therapy, is successfully synthesized with high radiochemical purity.

SPECT/CT imaging of tumor-infiltrating CD8 + T cell to predict the efficacy of anti-PD-1 immunotherapy in mice / 中华核医学与分子影像杂志

Objective:To prepare 99Tc m-hydrazinonicotinamide(HYNIC)-αCD8/Fab ( 99Tc m-αCD8/Fab), and explore the predictive value of 99Tc m-αCD8/Fab SPECT/CT imaging for the efficacy of anti-programmed death-1 (PD-1) immunotherapy. Methods:The αCD8/Fab was modified with HYNIC- N-hydroxysuccinimide (NHS) and IRDye800-NHS to form HYNIC-αCD8/Fab and IRDye800-αCD8/Fab (Dye-αCD8/Fab), respectively. 99Tc m-αCD8/Fab was prepared in sodium bicarbonate buffer (pH=8.5), with SnCl 2 being used as the reducing agent. The labeling yield and radiochemical purity of 99Tc m-αCD8/Fab and its stability in PBS and fetal bovine serum (FBS) were tested in vitro. The mouse spleen and human peripheral blood lymphocytes were isolated for cell-specific binding and blocking experiments of 99Tc m-αCD8/Fab in vitro. SPECT/CT imaging was used to analyze the specific binding ability of the 99Tc m-αCD8/Fab probe in CT26 colon cancer mouse models (BALB/c). The near infrared fluorescence imaging and SPECT/CT imaging were performed to detect the intra-tumoral CD8 + T cell infiltration after anti-PD-1 therapy in tumor bearing mice, and the results were further verified by HE and immunofluorescence staining. CD8 + T cell depletion study was performed to determine the role of CD8 + T cells in the tumor responses to anti-PD-1 therapy. Two-way analysis of variance was used to compare the data difference. Results:The labeling yield of 99Tc m-αCD8/Fab was 90% with a high radiochemical purity (95%) and good stability in vitro (radiochemical purity still more than 80% after 720 min in PBS and FBS). 99Tc m-αCD8/Fab could specifically bind to mouse CD8 + T cells ((10.30±0.81) percent added radioactive dose (%AD)/10 6 cells), compared with the binding ability in human peripheral blood lymphocytes group and CD8 antibody blocking group ((1.78±0.61) and (1.59±0.25) %AD/10 6 cells; F=10.07, P<0.001). SPECT/CT imaging showed that 99Tc m-αCD8/Fab had markedly higher tumor uptake in the CT26 colon cancer mouse models. Near-infrared fluorescence imaging showed that the tumor uptake of 99Tc m-αCD8/Fab in the responsive group was significantly higher than in the nonresponsive group after anti-PD-1 treatment ((8.9±1.1)% vs (7.1±0.8)%; F=4.69, P=0.024), and SPECT/CT imaging found the similar result. HE and immunofluorescence staining of tumor and lymph nodes showed that the proportion of lymphocyte infiltration was higher in the responsive group. Furthermore, CD8 + T cell depletion significantly reversed the therapeutic effect of anti-PD-1 immunotherapy in tumor-bearing mice. Conclusions:In this study, 99Tc m-αCD8/Fab was successfully obtained. CD8-specific SPECT imaging could sensitively visualize the tumor-infiltrating CD8 + T cells, suggesting the potential application value to predict and evaluate the efficacy of immunotherapy in the clinical settings.

Clinical effect of anti-PD-1/PD-L1 immunotherapy combined with concurrent radiotherapy and chemotherapy in the treatment of locally advanced cervical cancer / 中国医师杂志

Objective:To investigate the clinical effect of programmed death receptor-1 (PD-1)/programmed death receptor ligand-1 (PD-L1) immunotherapy combined with concurrent radiotherapy and chemotherapy in the treatment of locally advanced cervical cancer (LACC).Methods:From November 2018 to October 2019, 51 LACC patients in Qinhuangdao First Hospital who received anti-PD-1/PD-L1 immunotherapy (pembrolizumab) combined with concurrent radiotherapy and chemotherapy [intensity modulated radiotherapy (IMRT)+ TP (taxol+ carboplatin) chemotherapy] were selected as the observation group. 51 LACC patients who received concurrent chemotherapy and radiotherapy were selected as the control group. The objective remission rate, disease control rate, tumor markers [squamous cell carcinoma antigen (SCCAg), soluble cytokeratin 19 fragment (CYFRA21-1), and carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125)], proliferation and apoptosis indicators [survivin (Survivin), B-cell lymphoma-2 (Bcl-2), Caspase-3 (Caspase-3), apoptosis-promoting substance (Bax)], PD-1/PD-L1 [soluble PD-L1 (sPD-L1), CD4 + T cell surface PD-1 expression (PD-1 CD4 + T cells), CD8 + T cell surface PD-1 expression (PD-1 CD8 + T cell) and CD14 + monocyte surface PD-L1 expression (PD-L1 CD14 + monocyte)], safety and survival rate within 1 year were compared between the two groups. Results:(1) Disease control and safety: the objective response rate and disease control rate of the observation group were 80.39%(41/51) and 92.16%(47/51), respectively, which were higher than those of the control group by 39.22%(20/51) and 70.59%(36/51) (all P<0.05), but there was no significant difference in the incidence of side effects between the groups (all P>0.05). (2) Tumor markers and proliferation and apoptosis indexes: compared with those before treatment, the levels of serum SCCAg, CYFRA21-1, CEA, CA125, survivin and Bcl-2 in the two groups after treatment were significantly lower, and the levels of Caspase-3 and Bax were significantly higher; the above indexes in the observation group were better than those in the control group after treatment (all P<0.05). (3) PD-1/PD-L1: after treatment, sPD-L1, PD-1 CD4 + T cells, PD-1 CD8 + T cells and PD-L1 CD14 + monocytes in the observation group were significantly lower than those before treatment (all P<0.05). After treatment, the sPD-L1, PD-1 CD4 + T cells, PD-1 CD8 + T cells, PD-L1 CD14 + monocytes in the observation group were lower than those in the control group (all P<0.05). (4) Survival: the survival rate of the observation group was higher than that of the control group within 1 year ( P<0.05). Conclusions:The clinical effect of anti-PD-1/PD-L1 immunotherapy combined with concurrent radiotherapy and chemotherapy in the treatment of LACC is significant. It can effectively inhibit the progression of the disease by regulating tumor markers, proliferation and apoptosis indicators and PD-1/PD-L1 expression without increasing the risk of treatment, and has a positive effect on improving the survival rate of patients.

Efficacy and safety of programmed death-1/programmed death-ligand 1 inhibitors in treatment of hepatitis B virus-associated hepatocellular carcinoma / 临床肝胆病杂志

Combined immunotherapy for hepatocellular carcinoma (HCC) based on immune checkpoint inhibitors (ICIs), especially programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors, has achieved a remarkable clinical effect in clinical research and practice. Hepatitis B virus (HBV) infection is considered a major risk factor in the process of HCC. Studies are being conducted to investigate the efficacy and safety of PD-1/PD-L1 ICIs used alone or in combination in the treatment of patients with HBV-associated HCC, and some studies have shown that the patients with HBV-associated HCC receiving PD-1/PD-L1 inhibitors have achieved a similar treatment outcome to those without HBV infection; however, no consensus has been reached on the safety issues related to HBV activation. This article reviews the clinical trials of PD-1/PD-L1 blockade immunotherapy for HCC, so as to clarify the safety and efficacy of this new treatment regimen in the particular circumstances of HBV infection.

Efficacy and safety of programmed death-1 inhibitor combined with transarterial chemoembolization and anti-angiogenic drugs in treatment of advanced hepatocellular carcinoma / 临床肝胆病杂志

Objective To investigate the efficacy and safety of programmed death receptor-1 (PD-1) inhibitor combined with transarterial chemoembolization (TACE) and anti-angiogenic drug tyrosine kinase inhibitor (TKI) versus TACE combined with TKI in the treatment of advanced hepatocellular carcinoma (HCC) and related influencing factors for prognosis. Methods An analysis was performed for all patients who received TACE+TKI+PD-1 inhibitor and some patients who received TACE+TKI in The First Affiliated Hospital of Air Force Medical University from June 2018 to July 2021. Related clinical data were collected, and propensity score matching (PSM) was used to balance the baseline characteristics between groups. The chi-square test was used for comparison of categorical data between two groups; the Wilcoxon rank-sum test was used for comparison of the number of TACE procedures between two groups; the Kaplan-Meier method was used to analyze overall survival (OS), and univariate and multivariate Cox regression models were used to analyze the influencing factors for prognosis. Results A total of 181 patients with advanced HCC were screened out, among whom 50 patients were treated with TACE+TKI+PD-1 inhibitor; after PSM, 40 patients treated with TACE+TKI+PD-1 inhibitor were enrolled as observation group and 40 patients treated with TACE+TKI were enrolled as control group. At the end of follow-up, the median follow-up time was 28.6 (95% confidence interval [ CI ]: 22.1-35.1) months, and the median OS was 15.9 (95% CI : 7.5-24.2) months in the observation group and 11.2 (95% CI : 5.0-17.5) months in the control group. The Cox regression analysis showed that the application of PD-1 inhibitor (hazard ratio [ HR ]=0.42, 95% CI : 0.23-0.80, P =0.008), the number of TACE procedures ( HR =0.67, 95% CI : 0.46-0.99, P =0.043), Child-Pugh class ( HR =2.40, 95% CI : 1.15-5.00, P =0.019), and vascular invasion ( HR =3.42, 95% CI : 1.11-9.42, P =0.031) were independent influencing factors for prognosis. The incidence rate of grade > 2 adverse events was 40% for both the observation group and the control group, and there was no significant difference between the two groups ( P =0.818). Conclusion Compared with TACE+TKI, TACE+TKI+PD-1 inhibitor can significantly prolong the OS of patients in advanced HCC, with relatively controllable adverse events.

Excavation and evaluation of adverse reaction signals of 4 kinds of imported PD- 1/PD-L1 inhibitors / 中国药房

OBJECTIVE To exc avate and evaluate the adverse reaction signals of 4 kinds of imported programmed cell death 1 （PD-1）and its ligand （PD-L1）inhibitors，and to guide rational drug use in clinic. METHODS OpenVigil 2.1 software was used to obtain the adverse event reports of four drugs as nivolumab ，pembrolizumab，atezolizumab and durvalumab from the first quarter of 2013 to the fourth quarter of 2020 in the US FDA adverse event reporting system. The reporting odds ratio and proportional reporting ratio were used for signal mining to evaluate new or potential adverse reaction signals. RESULTS A total of 46 840 reports of adverse events with PD- 1/PD-L1 inhibitors as the primary suspected drug were collected ，including 28 896 reports of nivolumab，13 298 reports of pembrolizumab ，3 398 reports of atezolizumab ，and 1 248 reports of durvalumab. From the general characteristics of these reports ，the gender distribution was more men than women ，and the age distribution was mainly in the range of 51-85 years old. The reporting year was mainly in the nearly 4-5 years，and the main reporting countries were the US and Japan，with“death”and“hospitalization or prolonged hospitalization ”as the main serious adverse events which were over 50％ of the whole of 4 kinds of adverse events. A total of 1 597 adverse reaction signals were obtained ，involving 26 systems，focusing on “benign，malignant and unspecified neoplasms （cystic and polypoid tumor ）”，“infections and infestations ”and“investigations”， etc. The analysis of the top 50 adverse reaction signals showed that the largest number of report was endocrine system disease ，the most frequency signal was “malignant neoplasm progression ”and the strongest adverse reaction signal was “radiation pneumonitis ”. And it was also found that 13 adverse reaction signals ，such as “radiation pneumonitis ”“cholangitis”“fulminant type 1 diabetes mellitus” “blood creatine phosphokinase increased ” “disseminated intravascular coagulation ”“cardiac failure ”and “cerebral infarction ”，etc.，were not reported in the drug instructions. CONCLUSIONS PD-1/PD-L1 inhibitors mediate a large number of adverse reaction signals，resulting in high safety risks in “benign，malignant and unspecified neoplasms （cystic and polypoid tumor ）”，“infections and infestations ”and “investigations”，etc. The newly discovered 13 adverse reaction signals ，such as “radiation pneumonitis ”“cholangitis”“blood creatine phosphokinase increased ”“cardiac failure ”and“cerebral infarction ”are of great significance for guiding rational drug use in clinic.

SPECT/CT imaging of PD-L1 expression in non-small cell lung cancer based on 99Tc m labeled anti-PD-L1 nanoantibodies / 中华核医学与分子影像杂志

Objective:To explore the value of SPECT/CT imaging on programmed death receptor 1 ligand (PD-L1) expression in patients with non-small cell lung cancer (NSCLC) based on 99Tc m labeled anti-PD-L1 nanoantibodies (NM-01). Methods:From January 2019 to March 2020, a total of 14 patients (11 males, 3 females; age: (61.9±11.0) years) with pathologically confirmed NSCLC in Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine were prospectively enrolled. NM-01 were labeled with 99Tc m, and patients were recruited for SPECT/CT imaging 2 h after injection with 99Tc m-NM-01((359.1±68.0) MBq). The differences of SUV max in primary and metastatic lesions between PD-L1 positive and negative patients were compared by independent sample t test. The correlation between the SUV max and PD-L1 expression of primary lesions was analyzed by Pearson correlation analysis. Results:Of 14 patients, 6 were PD-L1 positive and 8 were PD-L1 negative. 99Tc m-NM-01 showed obviously increased uptake in kidneys and liver, while mildly increased uptake in spleen and bone marrow. The SUV max of primary lesions was 4.69±1.88 and the SUV max of metastatic lesions was 2.04±1.32. The SUV max of primary lesions in PD-L1 positive patients was significantly higher than that of PD-L1 negative patients (5.99±1.99 vs 3.72±1.10; t=5.98, P=0.039). There was no significant difference in the SUV max of metastatic lesions between PD-L1 positive and negative patients (1.66±1.03 vs 2.35±1.46; t=-1.77, P=0.084). The SUV max of primary lesions was positively correlated with PD-L1 expression ( r=0.648, P=0.042). Conclusion:99Tc m-NM-01 can demonstrate the expression of PD-L1 in primary and metastatic lesions in NSCLC.