Relationship Between Peripheral Blood T Lymphocyte Subsets and Prognosis of Patients with Advanced Non-small Cell Lung Cancer Treated with Camrelizumab / 肿瘤防治研究

Objective To explore the relationship between peripheral blood T lymphocyte subsets and prognosis of patients with advanced non-small cell lung cancer (NSCLC) who received treatment with camrelizumab. Methods We retrospectively collected data from 88 patients with advanced NSCLC who underwent camrelizumab treatment. Peripheral blood lymphocyte subsets were collected from patients before and two months after treatment. Kaplan-Meier curves and Cox regression analysis were employed to investigate the relationship between peripheral blood T lymphocyte subsets and PFS and OS. Results Compared with non-responder group, the baseline peripheral blood CD4+/CD8+ ratio was higher (P=0.038), while the CD8+T lymphocyte percentage was lower (P=0.036) in the responder group. Kaplan-Meier curves showed that a high baseline CD4+/CD8+ ratio was associated with long PFS and OS (P=0.001, P=0.023). Multivariate Cox analysis revealed that the baseline CD4+/CD8+ ratio was a significant predictor for PFS and OS. Additionally, a high post-treatment CD4+/CD8+ ratio and high CD4+T lymphocyte percentage were associated with long PFS (P=0.005, P=0.015), whereas a low post-treatment CD8+T lymphocyte percentage was associated with long PFS and OS (P=0.001, P=0.016). Conclusion The peripheral blood CD4+/CD8+ ratio can serve as a predictive factor for survival of patients with NSCLC treated with camrelizumab.

Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

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.

Clinical analysis of immunotherapy rechallenge in advanced gastric cancer / 中华肿瘤杂志

Objective: To evaluate the efficacy and influencing factors of programmed death protein 1 (PD-1) monoclonal antibody rechallenge therapy in advanced gastric cancer (GC). Methods: The clinical data of patients with advanced GC who were treated with anti-PD-1 rechallenge in Henan Cancer Hospital from January 2020 to December 2021 were collected retrospectively. The progression-free survival (PFS) was defined as the time from the first or second used of anti-PD-1 treatment to the date of disease progression or the last follow-up, named PFS(1) and PFS(2), respectively. Kaplan-Meier method and Log rank test were used for survival analysis, Cox proportional hazard model was used to analyze the influencing factors. Results: A total of 60 patients with anti-PD-1 rechallenge therapy were collected, the median follow-up time was 12.2 months. The median progression-free survival (PFS(2)) of anti-PD-1 rechallenge therapy was 2.9 months, the objective response rate (ORR) was 16.7%, and the disease control rate (DCR) was 55.0%. The median PFS(2) of the first and second anti-PD-1 identical and different rechallenge treatment was 3.5 months and 1.9 months (P=0.007) respectively. The median PFS(2) of positive PD-L1 expression in rechallenge therapy was 3.4 months, ORR was 22.7%, and DCR was 63.6%; the median PFS(2) was 4.5 months, ORR was 27.3%, and DCR was 54.5% in patients with median PFS(1)≥6 months. Multivariate analysis showed that peritoneal metastasis was independently associated with anti-PD-1 rechallenge therapy with PFS(2) (HR=2.327, 95% CI, 1.066-5.082, P=0.034). The incidence of adverse reactions in grade 1-2 and grade 3-4 of anti-PD-1 rechallenge therapy was 83.3%, and 35.0%, respectively, and the safety was controllable. Conclusion: Rechallenge therapy with anti-PD-1 is a feasible treatment in advanced GC, but the screening of suitable population for rechallenge therapy still needs prospective data analysis and verification.

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.

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.

Study on protective effect of Shenqi Fuzheng injection on immune myocarditis injury induced by anti-PD-1 antibody / 中国药理学通报

Aim To investigate the effeot of Shenqi Fuzheng injection on the prevention of immune myocarditis induced by anti-PD-1 antibody by reducing the production of inflammatory factors and the expression of myocardial injury markers. Methods Thirty-two maie PD-1 humanized mice with C57BL/6 genetic background were randomly divided into control group, myocarditis model group, anti-PD-1 antibody group and Shenqi Fuzheng injection group (n = 8). Except the control group, mice in other groups were intraperitoneally injected with myocardial myosin heavy chain peptide (5 mg • kg

Liver-directed treatment is associated with improved survival and increased response to immune checkpoint blockade in metastatic uveal melanoma: results from a retrospective multicenter trial / 医学前沿

Metastases of uveal melanoma (UM) spread predominantly to the liver. Due to low response rates to systemic therapies, liver-directed therapies (LDT) are commonly used for tumor control. The impact of LDT on the response to systemic treatment is unknown. A total of 182 patients with metastatic UM treated with immune checkpoint blockade (ICB) were included in this analysis. Patients were recruited from prospective skin cancer centers and the German national skin cancer registry (ADOReg) of the German Dermatologic Cooperative Oncology Group (DeCOG). Two cohorts were compared: patients with LDT (cohort A, n = 78) versus those without LDT (cohort B, n = 104). Data were analyzed for response to treatment, progression-free survival (PFS), and overall survival (OS). The median OS was significantly longer in cohort A than in cohort B (20.1 vs. 13.8 months; P = 0.0016) and a trend towards improved PFS was observed for cohort A (3.0 vs. 2.5 months; P = 0.054). The objective response rate to any ICB (16.7% vs. 3.8%, P = 0.0073) and combined ICB (14.1% vs. 4.5%, P = 0.017) was more favorable in cohort A. Our data suggest that the combination of LDT with ICB may be associated with a survival benefit and higher treatment response to ICB in patients with metastatic UM.

Dihydroartemisinin increased the abundance of Akkermansia muciniphila by YAP1 depression that sensitizes hepatocellular carcinoma to anti-PD-1 immunotherapy / 医学前沿

The effect of anti-programmed cell death 1 (anti-PD-1) immunotherapy is limited in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) expression increased in liver tumor cells in early HCC, and Akkermansia muciniphila abundance decreased in the colon. The response to anti-PD-1 treatment is associated with A. muciniphila abundance in many tumors. However, the interaction between A. muciniphila abundance and YAP1 expression remains unclear in HCC. Here, anti-PD-1 treatment decreased A. muciniphila abundance in the colon, but increased YAP1 expression in the tumor cells by mice with liver tumors in situ. Mechanistically, hepatocyte-specific Yap1 knockout (Yap1LKO) maintained bile acid homeostasis in the liver, resulting in an increased abundance of A. muciniphila in the colon. Yap1 knockout enhanced anti-PD-1 efficacy. Therefore, YAP1 inhibition is a potential target for increasing A. muciniphila abundance to promote anti-PD-1 efficacy in liver tumors. Dihydroartemisinin (DHA), acting as YAP1 inhibitor, increased A. muciniphila abundance to sensitize anti-PD-1 therapy. A. muciniphila by gavage increased the number and activation of CD8+ T cells in liver tumor niches during DHA treatment or combination with anti-PD-1. Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.

Abrogation of HnRNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8+ T cell-mediated ferroptosis in castration-resistant prostate cancer

Owing to incurable castration-resistant prostate cancer (CRPC) ultimately developing after treating with androgen deprivation therapy (ADT), it is vital to devise new therapeutic strategies to treat CRPC. Treatments that target programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for human cancers with clinical benefit. However, many patients, especially prostate cancer, fail to respond to anti-PD-1/PD-L1 treatment, so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy. In the present study, analyzing the data from our prostate cancer tissue microarray, we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L (HnRNP L). Hence, we further investigated the potential role of HnRNP L on the PD-L1 expression, the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC. Indeed, HnRNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo, on the contrary, HnRNP L overexpression led to the opposite effect in CRPC cells. In addition, consistent with the previous study, we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death, and HnRNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells. Furthermore, HnRNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8+ T cells and synergized with anti-PD-1 therapy in CRPC tumors. This study provided biological evidence that HnRNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.

Anti-PD-1 and anti-PD-l1 antibodies as immunotherapy against cancer: a structural perspective

ABSTRACT Programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand-1 (PD-L1), play key roles in the suppression of the cytotoxic activity of T cells. PD-L1 is overexpressed on various types of cancer cells, leading to immune evasion. In the past decade, therapeutic antibodies that target the PD-1/PD-L1 axis have been developed to inhibit the immune suppression triggered by these two proteins. At present, five antibodies (two anti-PD-1 and three anti-PD-L1) have received approval by regulatory agencies in the US and Europe. In this work, we aimed to review their clinical applications and adverse effects. Furthermore, using their reported crystal structures, we discuss the similarities and differences between the PD-1/PD-L1 interface and the epitopes that are recognized by the antibodies. Detailed analyses of the contact residues involved in the ligand-receptor and target-antibody interactions have shown partial overlap. Altogether, the data presented here demonstrate that: (1) in contrast to other therapeutic antibodies, anti-PD-1/PD-L1 has a wide range of clinical applications; (2) these targeted therapies are not exempt from adverse effects; and (3) the characterization of the structural domains that are recognized by the antibodies can guide the development of new PD-1- and PD-L1-blocking agents. (REV INVEST CLIN. 2021;73(1):8-16)

Neoadjuvant chemoimmunotherapy combined with surgery for patients with non-small-cell lung cancer staged as ⅢA / 中华胸心血管外科杂志

Objective:To explore the efficacy and safety of neoadjuvant chemoimmunotherapy combined with surgery for stage ⅢA NSCLC patients.Methods:Six patients with NSCLC who were diagnosed as ⅢA and received two cycles of neoadjuvant chemoimmunotherapy and surgery between September 2019 and January 2020 were described in this study.Results:Five of them experienced AEs during neoadjuvant therapy. All of them received surgery and achieved an MPR of 50%. No viable tumor cells were found in the tissues of one patient. One patient with a small bronchopleural fistula after lobectomy.Conclusion:Neoadjuvant chemoimmunotherapy combined with surgery for stage ⅢA NSCLC patients is safe and efficient. Long-term outcomes of neoadjuvant chemoimmunotherapy combined with surgery should be further validated.

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

Immunotherapy has been applied successfully to treat B-cell lymphomas in preclinical models or clinical settings. However, immunotherapy resistance is a major challenge for B-cell lymphoma treatment. To overcome this issue, combinatorial therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas. One of such strategies is to combine immunotherapy with histone deacetylase (HDAC) inhibitors. HDAC inhibitors can potentially increase tumor immunogenicity, promote anti-tumor immune responses, or reverse immunosuppressive tumor environments. Thus, the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment. However, not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target. Hence, we suggest that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors. Here, we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.

HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

Immunotherapy has been applied successfully to treat B-cell lymphomas in preclinical models or clinical settings. However, immunotherapy resistance is a major challenge for B-cell lymphoma treatment. To overcome this issue, combinatorial therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas. One of such strategies is to combine immunotherapy with histone deacetylase (HDAC) inhibitors. HDAC inhibitors can potentially increase tumor immunogenicity, promote anti-tumor immune responses, or reverse immunosuppressive tumor environments. Thus, the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment. However, not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target. Hence, we suggest that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors. Here, we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.

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.

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.

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.

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.

Development of a Novel Optimization and Validation Method Based on DOE for the ADCC Potency of Anti-PD-1/PD-L1 Monoclonal Antibodies Using Reporter Genes / 中国药学杂志

OBJECTIVE: To develop a novel optimization and validation method based on design of experiment(DOE) for the antibody-dependent cell-mediated cytotoxicity (ADCC) potency of anti-programmed cell death 1 and anti-programmed cell death-ligand 1 (PD-1/PD-L1) monoclonal antibodies using reporter genes. METHODS: Jurkat-hFcγRIIIa-NFAT transgenic cell line was used as effector cells, 293FT-PD-1 cell line and CHO-PD-L1 cell line were used as target cells, respectively. The ADCC potency for anti-PD-1/PD-L1 monoclonal antibodies was detected with Luciferase detection system (BrightGloTM Luciferase Assay system), then the method was optimized and validated based on DOE. RESULTS: The anti-PD-1/PD-L1 monoclonal antibodies showed a dose-response relationship and the determination result complied with the following four-parameter equation: y=(A-D)/+D. The method was optimized and the testing parameters were determined as follows: the working concentration of anti-PD-1 monoclonal antibody was 10 000 ng•mL-1 to 4.833 ng•mL-1 and that of anti-PD-L1 was 2 000 ng•mL-1 to 0.488 ng•mL-1, the ratio of effector cells and target cells for anti-PD-1/PD-L1 monoclonal antibodies were 6:1 and 3:1, and the induction time for both of these antibodies was 20 h. The method possessed good specificity. The recovery rate test samples in the four different dilution groups were determined for 3 times, and the results showed that the relative potencies of anti-PD-1 monoclonal antibody were (51.74±2.22)%, (77.12±3.14)%, (118.71±2.83)% and (156.20±12.99)%, and the recoveries of which were (103.49±4.44)%, (102.83±4.19)%, (94.96±2.26)% and (104.14±8.66)%, respectively. While as for anti-PD-L1 monoclonal antibody, the relative potencies were (54.32±4.75)%, (75.24±4.25)%, (127.40±2.43)%, (156.82±3.27)% and the recoveries were (108.64±9.51)%, (100.33±5.67)%, (101.92±1.94)% and (104.55±2.18)%, respectively. The RSDs of the above results were all less than 10%. CONCLUSION: A novel optimization and validation method based on DOE for detecting ADCC potency of anti-PD-1/PD-L1 mAb is successfully developed. This detecting method based on reporter gene shows high specificity, good reproducibility and high accuracy, and might be used in the evaluation of ADCC potency of anti-PD-1/PD-L1 mAb.