Efficacy and safety of radiotherapy combined with targeted therapy, immunotherapy and chemotherapy for unresectable intrahepatic cholangiocarcinoma / 中华放射医学与防护杂志

Objective:To evaluate the efficacy and safety of quadruple therapy involving radiotherapy (RT), lenvatinib, anti-PD-1 antibody and GEMOX (oxaliplatin and gemcitabine) chemotherapy (quadruple therapy) in treatment cohort of patients with unresectable intrahepatic cholangiocarcinoma (ICC).Methods:The patients with recurrent, metastatic, or unresectable ICC underwent quadruple therapy at Zhongshan Hospital, Fudan University between September 2018 and May 2022 were selected. The data about efficacy and safety of quadruple therapy were collected in the hospital electronic medical record system. All patients were followed up regularly to obtain the long-term prognostic data until December 31, 2022. The efficacy, prognosis, and toxicity data were collected and analyzed.Results:A total of 41 patients were included in the analysis. After a median follow-up period of 15 months, disease progression was diagnosed in 36 patients (18 patients died), while 3 patients were lost to follow-up. The causes of death included liver failure induced by intrahepatic tumor progression ( n=6), distant metastases (lungs or brain, n=6), abdominal lymph node metastases ( n=3), cancer cachexia ( n=2), and unknown cause ( n=1). The median progression-free survival (PFS) was 11 months (95% CI: 9.2-12.8), and the median overall survival (OS) was 35 months (95% CI: 17.0-52.0). All patients experienced treatment-related adverse events (AEs) during the study treatment period. Of the 41 patients, 13 patients experienced at least once grade 3 or worse treatment-related AE, but all were manageable with symptomatic treatment. No treatment-related deaths were reported during the follow-up period. Conclusions:Radiotherapy (RT), lenvatinib, anti-PD-1 antibody and GEMOX in the treatment of unresectable ICC shows significant efficacy and good safety, which is worthy of clinical application.

A Real-world Study of Anti-PD-1 Antibody Combination Therapy in Advanced Hepatocellular Carcinoma / 肿瘤防治研究

Objective To explore the efficacy, safety, and factors that might influence the efficacy of antiPD-1 antibody-based therapy in advanced hepatocellular carcinoma in the real world. Methods The clinical features, efficacy, and safety in patients with advanced hepatocellular carcinoma who received anti-PD-1 antibody-based therapy were retrospectively analyzed. The survival status was followed-up. Results The objective response and the disease control rate were 21.8% and 76.4%, respectively. The overall incidence of adverse events during treatment was 81.8%, of which the incidence of grade 3/4 adverse events was 14.5%. The incidence of immune-related adverse events was 58.2% and the incidence of grade 3/4 immune-related adverse events was 3.6%, and no treatment-related death was observed. The median PFS of the 55 patients was 5.0 (95%CI: 3.9-6.1) months, and the median OS was 11.4 (95%CI: 6.5-16.3) months. Univariate and multivariate analyses showed that liver function Child-Pugh scores and performance status ECOG score were the influencing factors of the objective response rate and survival. Conclusion In the real world anti-PD-1 antibody-based therapy is safe and effective in patients with advanced hepatocellular carcinoma, in which the performance status ECOG score and liver function Child-Pugh score before treatment are independent prognostic factors influencing survival.

Effect of expressing of anti-PD-1 antibody in mouse mammary gland on spleen T cells in transgenic mice / 生物工程学报

This study aims to investigate the effect of anti-PD-1 antibody expressed in mouse mammary gland on the surface antigen protein of spleen T cells, cytokine expression, spleen CD4+ T cell proliferation and proliferation related pathways of transgenic mice at the cellular level. Transgenic mice expressing anti-human PD-1 antibody at 8 weeks of age without pregnancy and 18 weeks of age with lactation were divided into two groups, with transgenic negative mice in each group as the control. Spleen lymphocytes were extracted and the changes of spleen lymphocytes were detected. Compared with transgenic negative mice, the proportion of effector T cells of spleen T cells in the immune system of transgenic mice with anti-PD-1 antibody expressed in breast increased, the proportion of Treg cells decreased, and the IFN-γ, IL-17 and IL-2 expressed in CD4+ T cells increased in varying degrees. Moreover, IL-4, IL-10 and TGF-β in CD4+ T cells did not change, nor did some cell surface protein molecules related to T cell stimulate. There was no significant difference in T cell proliferation between transgenic positive and transgenic negative mice. In transgenic positive mice, the expression of phosphorylated proteins in PI3K/Akt/mTOR and RAS/MEK/ERK pathways were partially up-regulated, but the whole pathway was not completely up-regulated. Therefore, it is feasible to use transgenic mice as host to express monoclonal antibodies related to immune system such as anti-PD-1 antibody.

Collaborative study to evaluate a reporter gene assay for anti-PD-1 antibody bioactivity / 药学学报

A collaborative inter-laboratory validation was carried out using a reporter gene assay to measure the bioactivity of anti-PD-1 monoclonal antibody, in order to study the applicability and transferability of the method. In this study, two collaborative schemes were designed to measure the precision, linearity and accuracy of the method. The results showed that the 95% confidence interval (CI) of the intra-assay precision was (1.72-16.89) %, inter-assay precision was (2.63-17.67) %, inter-laboratory precision was (9.00-14.26) %, all linear correlation coefficients were greater than 0.99, and the 95% CI for the accuracy at different potency levels was (91.83-104.40) % at 50%, (90.40-101.40) % at 75%, (94.71-105.60) % at 100%, (94.00-102.00) % at 125%, and (96.73-104.30) % at 150%. The collaborative validation results proved that the reporter gene assay for the bioactivity determination of anti-PD-1 monoclonal antibody has good precision, linearity and accuracy, and could be applied to the release and stability analysis of anti-PD-1 monoclonal antibodies in different laboratories.

Lichen Planus Developed During the Treatment with Nivolumab in a Patient with Lung Cancer: A Case Report and Literature Review / 대한피부과학회지

Nivolumab is a fully-humanized IgG4 monoclonal antibody that competitively binds to the programmed cell death receptor-1 protein (an immune check-point molecule) present on activated T cells. Nivolumab is approved for the treatment of advanced melanoma, lung cancer, and renal cell carcinoma. It attenuates the inactivation of cytotoxic CD8+ T cells and, produces an antitumor effect; however it may be associated with immune-related adverse events, including the development of lichen planus (LP). A 72-year-old man presented with a 2-month history of multiple, polygonal, purplish papules on the dorsal aspect of both hands. He was diagnosed with large cell neuroendocrine carcinoma (LCNEC) of the lung 4 years earlier and was treated with nivolumab (3 mg/kg every 2 weeks) for 9 months. By the 14th course of nivolumab therapy, the patient developed multiple rashes on the dorsal aspect of both hands, and biopsy was consistent with findings of LP. We report a rare case of LP in a patient with lung cancer treated with nivolumab.

The clinical reports on adrenal insufficiency of patients with advanced solid tumors accepting anti-PD-1 antibody, SHR-1210 therapy / 中华肿瘤杂志

Objective@#To investigate the adrenocortical function changes of patients with advanced solid tumors who received the anti- programmed cell death protein-1 (PD-1) antibody, SHR-1210 therapy.@*Methods@#The clinical data of 98 patients with advanced solid tumors who were enrolled in a prospective phase I trial of SHR-1210 therapy at our institution between April 27, 2016 and June 8, 2017 were collected. The levels of plasma adrenocorticotropic hormone (ACTH) and cortisol were evaluated in 96 patients. The clinical manifestations, laboratory tests and radiologic data were collected to define the immune-related adrenal insufficiency.@*Results@#Until December 14th, 2018, no SHR-1210 related primary adrenal insufficiency occurred, and the incidence of immune-related secondary adrenal insufficiency was 1.0% among the 96 patients, which was identified as grade 2. No patient developed grade 3-4 adrenal insufficiency. The main clinical manifestations of the patient who was diagnosed as secondary adrenal insufficiency were grade 2 fatigue, anorexia and headache.The patient developed fatigue and anorexia at the 267th day after receiving the first dose of SHR-1210, the hypocortisolism occurred on the 279th day, and the headache emerged on the 291th day. The anorexia of patient who treated by physiological replacement doses of glucocorticoid since the 457th day was attenuated.The patient whose cortisol level was still below the normal limit continued to accept the hormone replacement therapy up to 776 days after the initial administration of SHR-1210.@*Conclusions@#The incidence of SHR-1210 related adrenal insufficiency of patients with advanced solid tumors is low, and the symptoms can be effectively ameliorated by hormone replacement therapy. The potential adverse outcome of adrenal insufficiency following immunotherapy should be noticed by clinicians to avoid the occurrence of adrenal crisis.

Advances of toripalimab for the treatment of melanoma / 中国肿瘤临床

On December 27, 2018, the first domestic anti-PD-1 antibody, toripalimab, was approved by the State Food and Drug Ad-ministration for the treatment of advanced melanoma after the failure of standard treatment. This represented a major breakthrough in the field of biopharmaceuticals in China and laid the foundations for pharmaceutical research and development in the field of tu-mor immunotherapy. In this article, we summarize the clinical research of the treatment of melanoma, the application of toripalimab in this field, and the global development of other anti-PD-1 antibodies, to provide guidance for the research and treatment of melano-ma in China.

Blocking the PD-1/PD-L1 axis enhanced cisplatin chemotherapy in osteosarcoma in vitro and in vivo

BACKGROUND@#The blocking of the programmed cell death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis has been found to have an anticancer activity against various types of cancer by enhancing T cell immunity, while there are no studies linking the PD-1/PD-L1 axis to chemotherapy drugs in osteosarcoma (OS). The present study aimed to investigate the effects of blocking PD-1/PD-L1 axis on the cisplatin chemotherapy in OS in vitro and in vivo.@*METHODS@#Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied to detect PD-L1 mRNA in OS tissues. Cell proliferation and apoptosis were measured by Cell Counting Kit-8 (CCK-8) and flow cytometry assays, respectively. In vivo, the syngeneic mice were treated with cisplatin and anti-PD-1 antibody alone or jointly.@*RESULTS@#In this study, it revealed that PD-L1 mRNA was highly expressed in OS tissues. Further inhibitory evaluation showed that the K7M2-LV cells (PD-L1 overexpression) co-cultured with PD-1 lymphocytes could promote K7M2 cell proliferation. Meanwhile, the combination of anti-PD-1 antibody and cisplatin significantly decreased the proliferation and increased the apoptosis of K7M2 cells in a co-culture system. In vivo, the combination of anti-PD-1 antibody and cisplatin significantly inhibited tumor growth, while the mechanisms did not involve regulatory T cells.@*CONCLUSION@#The present data suggested that the blocking of PD-1/PD-L1 axis had a positive prognostic value, which can enhance the chemotherapeutic effect of cisplatin in OS. These findings provide a rationale for utilizing PD1/PD-L1 blocking antibodies as a single agent to cure refractory OS in patients receiving cisplatin treatment.

Clinical observation of thyroid-related adverse events induced by anti-PD-1 antibody SHR-1210 in patients with advanced solid tumor / 中华肿瘤杂志

Objective@#To assess the incidence and characteristics of thyroid dysfunction during anti-Programmed cell death 1 receptor (PD-1) antibody SHR-1210 therapy in patients with advanced solid tumor.@*Methods@#The medical records of 98 patients who initiated SHR-1210 treatment between April 27, 2016 and June 8, 2017 in the phase 1 trial to evaluate the safety, efficacy, and pharmacokinetics of SHR-1210 in patients with advanced solid tumors were retrospectively reviewed. Serological tests of thyroid stimulating hormone (TSH) and free thyroxine (fT4) were measured at baseline and prior to each SHR-1210 administration.@*Results@#A total of 86 patients had normal thyroid function before the first dose of SHR-1210 treatment. Nine out of 86 (10.5%) patients developed new onset hypothyroidism from euthyroid state. 12 patients presented thyroid dysfunction at baseline, 10 of whom were subclinical hypothyroid and 2 were hypothyroidism. Four out of 10 patients developed hypothyroidism from subclinical hypothyroid. Most patients with hypothyroidism were asymptomatic. Thyroid dysfunction occurred early (median, 55days) after the initiation of SHR-1210. The severity of hypothyroidism were all grade 1-2. No grade 3-4 hypothyroidism occurred. No patients discontinue the treatment of SHR-1210 due to clinical impact of the thyroid dysfunctions.@*Conclusions@#Thyroid-related adverse events were common during anti-PD-1 antibody SHR-1210 treatment . The incidence of hypothyroidism is lower in patients with euthyroid state than in patients with thyroid dysfunction at baseline during SHR-1210 treatment . Thyroid function can be improved after thyroid hormone replacement. During SHR-1210 treatment, it is necessary to pay attention to monitor the thyroid function, especially in the patients with thyroid dysfunction at baseline.@*Trial registration@#Chinese Clinical Trial Registry, 2016L01455

Advance development of immunotherapy on malignant melanoma with targeting inhibition of PD-L1/ PD-1 / 中国药学杂志

Malignant melanoma presents a significant therapeutic challenge to clinicians with characteristics of early metastasis, rapid development, poor prognosis and high mortality. Many therapies for metastatic melanoma are limited by these characteristics. With the development of immunotherapy mechanism for malignant melanoma, a large number of antibody agents for the treatment of malignant melanoma entered the clinical trials. To our great delight, the new drugs of pembrolizumab and nivolumab have been approved by FDA in 2014 after successfully passing phase III clinical trial, which bring a chance of survival to patients with unresectable or metastatic advance melanoma. This review briefly discusses recent development and advances of anti-PD-L1/PD-1 antibody drugs against melanoma.