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Abstract The aim of this study was to explore the association between differential percentages of dendritic cell (DC) subsets in peripheral blood and malignancy (grade and lymph node metastasis) of peritoneal adenocarcinoma patients and the frequencies of dendritic cell subsets in the normal controls. The peripheral blood of 30 patients with peritoneal adenocarcinoma and 12 healthy controls were collected for multicolor flow cytometry analysis. Peritoneal adenocarcinoma patients were grouped according to the malignant degree (grade and lymph node metastasis). Percentages of myeloid DCs (mDCs) and its subsets MDC1 and MDC2 in DCs were lower in peripheral blood of patients with peritoneal adenocarcinoma than in normal controls. The percentages of plasmacytoid dendritic cells (pDCs) and CD16+mDCs in DCs were higher than in normal controls. Compared with poor differentiation grade, patients with well/moderate differentiation grade had an increased percentage of CD16+mDCs. Contrary to CD16+mDCs, the percentage of MDC1 was lower in the well/moderate differentiation grade group. In patients with no lymph node metastasis, pDCs and CD16+mDCs levels were higher compared with patients with lymph node metastasis. mDCs and MDC1 levels had opposite results. pDCs were positively correlated with CD16+mDCs in peripheral blood of peritoneal patients, as was mDCs and MDC1. CD16+mDCs were negatively correlated with MDC1. The percentages of pDCs and CD16+mDCs in DCs were positively correlated with CD3+CD8+T cells, and pDCs also positively correlated with CD8+PD-1+T cells. Our results revealed that DCs subsets correlated with peritoneal adenocarcinoma malignancy. Dendritic cells play an independent role in the immune function of peritoneal adenocarcinoma.
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@#[摘 要] 目的：探讨程序性死亡受体-1（PD-1）单抗联合顺铂或吉西他滨在KRAS基因突变非小细胞肺癌（NSCLC）A549细胞移植瘤小鼠模型治疗中的作用。方法：构建免疫系统-肿瘤双人源化A549细胞小鼠移植瘤模型，将60只小鼠按随机数字表法分成6组（10只/组），分别为对照组（200 μL/kg PBS）、PD-1单抗组（20 mg/kg PD-1单抗）、顺铂组（3 mg/kg顺铂）、PD-1单抗+顺铂组（20 mg/kg PD-1单抗+3 mg/kg顺铂）、吉西他滨组（30 mg/kg吉西他滨）和PD-1单抗+吉西他滨组（20 mg/kg PD-1单抗+30 mg/kg吉西他滨）。TUNEL和DAPI双染色法检测移植瘤组织中细胞凋亡水平，测量移植瘤体积和质量并计算肿瘤生长抑制率，免疫组化法检测移植瘤微血管密度（MVD）。结果：成功构建免疫系统-肿瘤双人源化NSCLC A549细胞小鼠移植瘤模型，PD-1单抗+顺铂组移植瘤的细胞凋亡率、肿瘤生长抑制率均最高，移植瘤体积、质量和MVD均最小，与其他5组小鼠比较差异均有统计学意义（均P<0.05）。结论：顺铂与PD-1单抗具有协同活性，而吉西他滨拮抗PD-1单抗的治疗作用。提示PD-1单抗联合顺铂对KRAS突变NSCLC A549细胞移植瘤小鼠的疗效更好。
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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.
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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.
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SUMMARY OBJECTIVE: Tumor-infiltrating lymphocytes are detectable in up to 75% of triple-negative breast cancer. The composition of these infiltrates may influence prognosis and is not known regarding regulatory or effector lymphocytes. The objectives of this study were to describe and quantify the composition of the tumor-infiltrating lymphocytes before and after chemotherapy (neoadjuvant chemotherapy) and to evaluate their association with complete pathological response and overall survival. METHODS: This was a retrospective observational study. Clinical and pathological data from 38 triple-negative breast cancer patients treated with neoadjuvant chemotherapy at the University Hospital (HUCFF/UFRJ), between November 2004 and November 2018, were analyzed. The Stromal tumor-infiltrating lymphocytes (Stromal tumor-infiltrating lymphocytes) have been identified on hematoxylin and eosin-stained sections according to the guidelines of the "International tumor-infiltrating lymphocytes Working Group." Immunohistochemistry studies were performed to identify T-cell subsets (i.e., CD3, CD4, CD8, and FOXP3) and T-cell exhaustion (i.e., programmed cell death protein 1). RESULTS: Statistically significant changes in stromal tumor-infiltrating lymphocyte categories were observed before and post-neoadjuvant chemotherapy, with 32% of intermediate cases becoming high. The correlation between pre-neoadjuvant chemotherapy stromal tumor-infiltrating lymphocytes and pathological response, pre-neoadjuvant chemotherapy and post-neoadjuvant chemotherapy, and stromal tumor-infiltrating lymphocytes and overall survival was not statistically significant. However, we noticed an increase of cells that favor the antitumor activity (i.e., CD3, CD8, and CD8/FOXP3 ratio) and decreased levels of cells inhibiting tumor activities (i.e., FOXP3 and programmed cell death protein 1) post-neoadjuvant chemotherapy. Importantly, programmed cell death protein 1 expression pre-neoadjuvant chemotherapy showed an association with pathological response. CONCLUSION: In this study, we observed that chemotherapy significantly increases stromal tumor-infiltrating lymphocytes, CD8 T cells, as well as CD8/FoxP3 ratio. Most importantly, programmed cell death protein 1 expression before neoadjuvant chemotherapy positively correlates with pathological response suggesting the use of programmed cell death protein 1 as a prognostic marker before neoadjuvant chemotherapy.
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Abstract Background The defect of B cell self-tolerance and the continuous antigen presentation by T cells (TCs) mediated by autoreactive B cells (BCs) play a key role in the occurrence and development of systemic lupus erythematosus (SLE). PD-1/PD-L1 signaling axis negatively regulates the immune response of TCs after activation and maintains immune tolerance. However, the effect of PD-1/PD-L1 signaling axis on the interaction between CD19+B/CD4+TCs in the peripheral blood of patients with SLE has not been studied in detail. Methods PD-1/PD-L1 and Ki-67 levels in peripheral blood (PB) of 50 SLE patients and 41 healthy controls (HCs) were detected through flow cytometry, and then the expression of PD-1+/−cells and PD-L1+/−cells Ki-67 was further analyzed. CD19+B/CD4+TCs were separated for cell culture and the supernatant was collected to determine proliferation and differentiation of TCs. IL-10 and IFN-γ secretion in the supernatant was also determined using ELISA. Results The PD-1, PD-L1, and Ki-67 levels on CD19+B/CD4+TCs in patients with SLE were higher than HCs. In CD19+B/CD4+TCs of SLE patients, the proliferative activity of PD-L1+ cells was higher than that of PD-L1− cells, and the proliferative activity of PD-1+ cells was higher than that of PD-1− cells. In the system co-culturing CD19+B/CD4+TCs from HCs/SLE patients, activated BCs promoted TCs proliferation and PD-L1 expression among TCs. Addition of anti-PD-L1 to co-culture system restored the proliferation of TCs, and inhibited IL-10/IFN-γ level. The addition of anti-PD-L1 to co-culture system also restored Tfh and downregulated Treg in HCs. Conclusions Axis of PD-1/PD-L1 on CD19+B/CD4+TCs in PB of SLE patients is abnormal, and cell proliferation is abnormal. In CD19+B/CD4+TCs of SLE patients, the proliferative activity of PD-L1+ and PD-1+ cells compared with PD-L1− and PD-1− cells in SLE patients, respectively. CD19+B/CD4+TCs in SLE patients can interact through PD-1/PD-L1.
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Abstract Objective To evaluate the efficacy of immunotherapy for GTN treatment after methotrexate-resistance or in cases of multiresistant disease, through a systematic review, as well as to present the first 4 Brazilian cases of immunotherapy for GTN treatment. Methods Three independent researchers searched five electronic databases (EMBASE, LILACS, Medline, CENTRAL and Web of Science), for relevant articles up to February/2023 (PROSPERO CRD42023401453). The quality assessment was performed using the Newcastle Ottawa scale for case series and case reports. The primary outcome of this study was the occurrence of complete remission. The presentation of the case reports was approved by the Institutional Review Board. Results Of the 4 cases presented, the first was a low-risk GTN with methotrexate resistance unsuccessfully treated with avelumab, which achieved remission with sequential multiagent chemotherapy. The remaining 3 cases were high-risk multiagent-resistant GTN that were successfully treated with pembrolizumab, among which there were two subsequent gestations, one of them with normal pregnancy and healthy conceptus. Regarding the systematic review, 12 studies were included, only one of them on avelumab, showing a 46.7% complete remission rate. The remaining 11 studies were on pembrolizumab, showing an 86.7% complete remission rate, regardless of tumor histology. Both immunotherapies showed good tolerability, with two healthy pregnancies being recorded: one after avelumb and another after pembrolizumab. Conclusion Immunotherapy showed effectiveness for GTN treatment and may be especially useful in cases of high-risk disease, where pembrolizumab achieves a high therapeutic response, regardless of the histological type, and despite prior chemoresistance to multiple lines of treatment.
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Pancreatic cancer remains as one of the most lethal malignancies. Resistance to conventional therapies has led to little improvement in the survival of pancreatic cancer patients over the past few decades. Immune-based treatment strategies for pancreatic cancer, such as immune-checkpoint inhibitors, therapeutic vaccines, and combination immunotherapies show promise. Many immunotherapies have been explored in clinical trials, but they have yet to show significant therapeutic effects. Nevertheless, immunotherapy is inevitably the future of pancreatic cancer cure. This article introduces the current research progress and bottlenecks of immunotherapy for pancreatic cancer and puts forward further optimization directions and solutions. We hope to provide a reference for the future use of immunotherapy for pancreatic cancer.
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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.
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Objective To explore the expression of PD-1 and CTLA-4 in osteosarcoma and their clinical significance. Methods Fifty-eight cases of osteosarcoma encountered from 2007 to 2016 were enrolled. The expression levels of PD-1 and CTLA-4 were detected through immunohistochemistry (EnVision method). Results PD-1 was positively expressed in 31 (53.4%) cases and negatively expressed in 27 (46.6%) cases. CTLA-4 was positively expressed in 19 (32.8%) cases and negatively expressed in 39 (67.2%) cases. A total of 12 (20.7%) cases were PD-1 and CTLA-4 double positive, whereas 20 (34.5%) cases were double negative, and 26 (44.8%) cases were single positive. The positive expression of PD-1 was correlated with neoadjuvant chemotherapy, tumor metastasis and relapse, and shortened survival time (P < 0.05). The positive expression of CTLA-4 was partly related with late Ennecking stage (P=0.051). Double positive expression was related to the highest tumor metastasis and relapse rates and the worst prognosis (P < 0.05), compared with double negative and single positive expression. Conclusion Positive expression of PD-1 and CTLA-4 in osteosarcoma is associated with worse prognosis, whereas double positive expression is associated with the highest tumor relapse and metastasis rates and shortest survival time. These results are potential valuable references for osteosarcoma immunotherapy.
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PD-1 and PD-L1 together constitute the stimulus signaling pathway of adaptive immune response, which has been widely used in the research on the mechanism of tumor immune escape and tumor therapy. At the same time, its signaling pathway has been proved to be closely associated with the immune escape of hepatic echinococcosis. This article reviews the chemical structures of PD-1 and PD-L1, the mechanism of the PD-1/PD-L1 signaling pathway, and the role of the PD-1/PD-L1 signaling pathway in immune escape of hepatic echinococcosis, i.e., the PD-1/PD-L1 signaling pathway is involved in immune escape of hepatic echinococcosis under three theories, so as to explore the immune escape of hepatic echinococcosis from a new perspective and provide a basis and ideas for the diagnosis and treatment of hepatic echinococcosis.
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@#[摘 要] 肝细胞癌（HCC）的发病率和病死率正在逐年增长，严重威胁人类的健康和生命。近年来，以PD-1/PD-L1抑制剂为代表的免疫治疗迅速发展，但对晚期HCC疗效有限。治疗中实时监测循环肿瘤细胞（CTC）PD-L1表达，是评估免疫治疗有效性的重要指标之一。本案例通过TumorFisher检测技术实时监测1例HCC患者免疫治疗前后总CTC数及PD-L1+ CTC个数，结合影像学和血清学检查结果进一步评估患者免疫治疗疗效。患者治疗前总CTC数为5个/2 mL，PD-L1+ CTC为5个/2 mL，PD-L1+ CTC/总CTC为100%。用PD-1/PD-L1抑制剂行3周期免疫治疗后，PD-L1+ CTC/总CTC逐渐降低，肿瘤缩小，血清AFP及PIVKA-Ⅱ逐渐下降，PD-L1+ CTC/总CTC变化与肿瘤标志物、MRI检查结果一致。PD-L1+ CTC/总CTC可作为HCC免疫治疗疗效评估的辅助指标。
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@#[摘 要] 目的：评估多种PD-1抑制剂联合化疗用于晚期、复发或转移性食管鳞状细胞癌（ESCC）患者一线治疗的成本效用。方法：基于4项晚期ESCC一线Ⅲ期临床试验（JUPITER-06、ESCORT-1st、ORIENT-15和KEYNOTE-590研究），应用TreeagePro 2011软件建立传统的马尔科夫（Markov）模型，包括无进展生存期（PFS）、疾病进展（PD）和死亡3种状态，以质量调整生命年（QALY）为主要效用指标衡量健康结果，以增量成本-效用比（ICER）为治疗策略经济学效益的评价指标，进一步通过敏感性分析验证结果可靠性。结果：特瑞普利单抗联合化疗组、卡瑞利珠单抗联合化疗组、信迪利单抗联合化疗组、帕博利珠单抗联合化疗组和安慰剂联合化疗组的总成本分别为66 327.58、63 473.64、62 268.18、295 515.26和32 753.79元，效用值分别为0.648、0.605、0.673、0.585和0.536 QALY；其中，信迪利单抗联合化疗组的ICER值为217 018.13元/QALY，低于中国患者意愿支付阈值的242 928元/QALY，是一种相对可接受的治疗策略。敏感性分析显示，贴现率及信迪利单抗的成本对模型影响最大。结论：在中国目前的经济形势下，信迪利单抗联合化疗是ESCC患者可接受的一种一线PD-1抑制剂免疫治疗的策略。
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@#[摘 要] PD-1/PD-L1抑制剂在乳腺癌免疫治疗中的应用已逐渐成为一种重要的治疗手段，然而对乳腺癌，尤其是三阴性乳腺癌（TNBC）的免疫治疗仍存在某些亟待解决的科学问题，包括PD-1/PD-L1抑制剂单药治疗的有效率欠佳，目前尚无明确的生物标志物来有效筛查治疗敏感人群，免疫相关不良反应（irAE）的发生率高。为了提高疗效和减少irAE的发生，采取以下措施是非常重要的：探讨PD-1/PD-L1抑制剂与其他药物的联合应用方案；采用纳米技术开发选择性靶向肿瘤细胞的纳米载体，降低抗肿瘤药物毒性并提高疗效；探寻开发可预测免疫治疗反应潜力的生物标志物；早期识别和诊疗irAE并建设多学科诊疗协作组（MDT）模式。随着这些措施的积极推进和问题的不断解决，PD-1/PD-L1抑制剂在乳腺癌的治疗中必将呈现出更为广阔的应用前景。
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@#Abstract：Programmed death receptor⁃ 1（PD⁃1）belongs to the family of immunoglobulin B7⁃CD28，which plays an important role in regulating immune response in human body. Since the first PD⁃1／PD⁃ligand 1（PD⁃L1）monoclonal antibody was approved for marketing in China in 2018，the value of PD⁃1／PD⁃L1 immunotherapy in oncotherapy has attracted wide attention. Based on the introduction of the action mechanism of PD⁃1／PD⁃L1 mAbs，this paper reviews the application progress of 8 on ⁃ market PD ⁃ 1／PD ⁃ L1 mAbs in China in oncotherapy from the perspectives of approved indications，clinical trials，usage and dosage，and adverse reactions，in order to provide reference for the rational appli⁃ cation of PD⁃1／PD⁃L1 monoclonal antibodies in clinic.
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Objective@# To investigate the clinical manifestations, pathological features, and treatment of oral and maxillofacial pyogenic granulomas induced by camrelizumab. @*Methods@# A case of pyogenic granuloma of the gums and lips caused by camrelizumab was reported along with a literature review. @*Results@# After 4 months of treatment with camrelizumab for liver cancer, the patient developed systemic reactive capillary hyperplasia (RCH), followed by multiple masses on the lower lip and gingiva. After periodontal therapy, the masses on the lower lip and the gingiva were removed, and camrelizumab administration was stopped. The pathological result was gingival pyogenic granuloma/granulomatous hemangioma. No new masses were found in the oral cavity during postoperative follow-up. A review of the literature showed that RCH is the most common adverse drug reaction to camrelizumab but it occurs infrequently in the oral cavity. At present, the etiology of RCH has not been clarified, but the research has shown that camrelizumab may trigger tissue proliferation into hemangiomas by activating vascular endothelial cells, and the combined use of camrelizumab is safer than single use. RCH is self-limiting and most cases resolve spontaneously after discontinuation of the drug. If the mass causes dysfunction, surgical excision is feasible.@*Conclusion @#Camrelizumab can cause oral and maxillofacial reactive capillary hyperplasia complicated by pyogenic granuloma.
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@#[摘 要] 目的：探讨食管恶性黑色素瘤（MEM）患者的临床特征，分析以PD-1单抗为基础的免疫治疗疗效及预后的影响因素。方法：收集2011年5月至2022年6月在北京大学肿瘤医院黑色素瘤暨肉瘤内科收治的手术不可切除或者转移性MEM患者的临床资料，包括基本信息、病理资料、实验室指标、治疗方案和生存情况等。采用实体瘤疗效评价标准1.1进行疗效评估，用Kaplan-Meier曲线进行生存分析，用单因素和多因素COX回归进行预后分析。结果：共收集到有完整资料的MEM患者79例，中位年龄59.0岁。大部分患者发病时伴有进食哽噎和吞咽困难等症状，以食管下段发病最为常见，NRAS和KIT基因突变的比例较高，乳酸脱氢酶（LDH）水平升高占21.5%；其中，17例患者接受化疗为主的治疗方案，62例患者接受PD-1单抗为主的免疫治疗方案，客观有效率分别为5.9%和28.8%，疾病控制率分别为35.3%和72.9%，总生存期（OS）分别为7个月[95%CI（0，16.7）个月]和13.2个月[95%CI（9.5，16.9）个月]（P<0.05）。多因素分析显示，就诊时LDH水平、ECOG评分、是否有临床症状、是否接受PD-1单抗治疗与OS显著相关（P<0.05）。结论：MEM患者对PD-1单抗为主的免疫治疗应答较好，LDH升高、ECOG评分≥2分、就诊时有临床症状可能是预后的不良因素。
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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.
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Humanos , Neoplasias Gástricas/patología , Estudios Retrospectivos , Estudios Prospectivos , Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia/efectos adversosRESUMEN
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.
Asunto(s)
Ratones , Animales , Femenino , Ratones Transgénicos , Bazo/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Citocinas/metabolismoRESUMEN
Objective: To investigate the clinical characteristics of abnormal liver function in patients with advanced esophageal squamous carcinoma treated with programmed death-1 (PD-1) antibody SHR-1210 alone or in combination with apatinib and chemotherapy. Methods: Clinical data of 73 patients with esophageal squamous carcinoma from 2 prospective clinical studies conducted at the Cancer Hospital Chinese Academy of Medical Sciences from May 11, 2016, to November 19, 2019, were analyzed, and logistic regression analysis was used for the analysis of influencing factors. Results: Of the 73 patients, 35 had abnormal liver function. 13 of the 43 patients treated with PD-1 antibody monotherapy (PD-1 monotherapy group) had abnormal liver function, and the median time to first abnormal liver function was 55 days. Of the 30 patients treated with PD-1 antibody in combination with apatinib and chemotherapy (PD-1 combination group), 22 had abnormal liver function, and the median time to first abnormal liver function was 41 days. Of the 35 patients with abnormal liver function, 2 had clinical symptoms, including malaise and loss of appetite, and 1 had jaundice. 28 of the 35 patients with abnormal liver function returned to normal and 7 improved to grade 1, and none of the patients had serious life-threatening or fatal liver function abnormalities. Combination therapy was a risk factor for patients to develop abnormal liver function (P=0.007). Conclusions: Most of the liver function abnormalities that occur during treatment with PD-1 antibody SHR-1210 alone or in combination with apatinib and chemotherapy are mild, and liver function can return to normal or improve with symptomatic treatment. For patients who receive PD-1 antibody in combination with targeted therapy and chemotherapy and have a history of long-term previous smoking, alcohol consumption and hepatitis B virus infection, liver function should be monitored and actively managed in a timely manner.