Immune Checkpoint Inhibitor Toxicities

Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.     

Association of PD-L1 gene rs4143815 C>G polymorphism and human cancer susceptibility: A systematic review and meta-analysis

Programmed death ligand 1(PD-L1) mediated immune escape play important roles in the development of cancer. The gene polymorphism of PD-L1, in particular rs4143815 C?>?G, has been associated with the cancer risks, but with conflicting results. Therefore, this meta-analysis was aimed to assess the association between rs4143815 C?>?G and cancer susceptibility. A systematic literature search was performed to select the studies and the pooled odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the strength of association. Eleven eligible studies containing 3711 cases and 3704 controls were enrolled in the meta-analysis. The results suggested that there is a strong association between rs4143815 C?>?G and the cancer risks (G vs. C: OR?=?1.386, 95% CI: 1.132–1.696, p?=?0.002; GG vs. CG?+?CC: OR?=?1.843 95% CI: 1.300–2.613, p?=?0.002; GG?+?CG vs. CC: OR?=?1.280, 95% CI: 1.040–1.576, p?=?0.020). Subgroup analysis based on cancer type suggested that PD-L1 rs4143815 C?>?G might increase the susceptibility to gastric cancer (G vs. C: OR?=?1.842, 95% CI: 1.403–2.418, p?<?0.001) and bladder cancer (G vs. C: OR?=?2.015, 95% CI: 1.556–2.608, p?<?0.001), and genotype GG carriers of PD-L1 rs4143815 C?>?G might have higher risks of HCC (GG vs. CG?+?CC: OR?=?2.226 95% CI: 1.562–3.172, p?<?0.001). PD-L1 rs4143815 C?>?G might confer an increased cancer risk, indicating this SNP may contribute to the pathogenesis of cancer and might be used as a potential biomarker to predict the susceptibility to cancer.     

Health-Related Quality of Life in KEYNOTE-010: a Phase II/III Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced,Programmed Death Ligand 1–Expressing NSCLC

Introduction

In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1–expressing (tumor proportion score ≥ 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here.

Multicentric Analytical and Inter-observer Comparability of Four Clinically Developed Programmed Death-ligand 1 Immunohistochemistry Assays in Advanced Clear-cell Renal Cell Carcinoma

BackgroundPrevious studies have suggested increased clinical benefit with inhibition of programmed death-ligand 1 (PD-L1)/programmed death-1 in patients with PD-L1–positive locally advanced/metastatic renal cell carcinoma (RCC). We examined the analytical and inter-observer comparability of PD-L1–positivity across 4 clinically developed immunohistochemistry assays in clear-cell RCC (CCRCC).Materials and MethodsRandomly selected archived, formalin-fixed, paraffin-embedded nephrectomy specimens from 201 patients with locally advanced CCRCC were screened using VENTANA SP142. From these, 30 cases were selected based on their tumor-infiltrating immune cell (IC) PD-L1 status (PD-L1-IC–positivity of < 1%, 1%-5%, or > 5%; 10 cases each). These cases were stained for PD-L1 using VENTANA SP142 and SP263, and DAKO 22C3 and 28-8, and scored for PD-L1 expression on IC and tumor cells (TC) by trained readers at 5 sites.ResultsAdjusted mean percentages of PD-L1-IC–positivity and PD-L1-TC–positivity varied from 4.0% to 4.9% and from 1.3% to 10.7%, respectively, between assays. Inter-assay differences in PD-L1-IC–positivity were small and non-significant (P = .1938 to .9963); for PD-L1-TC–positivity, significant differences were observed between VENTANA SP142 and the other assays (P ≤ .0001) and between VENTANA SP263 and DAKO 28-8 (P = .0248). Intra-class correlation values showed moderate-to-high inter-reader agreement for each assay for PD-L1-IC–positivity and for 3 assays for PD-L1-TC–positivity.ConclusionsIn this first multicenter analytical comparison study of PD-L1 assays in CCRCC, PD-L1–positivity could be assessed reproducibly using all 4 assays for IC and for 3 of the 4 assays for TC.     

Prognostic and clinicopathological utility of programmed death-ligand 1 in malignant pleural mesothelioma: A meta-analysis

ObjectiveProgrammed death ligand 1 (PD-L1) has been reported to be connected to prognosis in individuals with malignant pleural mesothelioma (MPM), although there is no consensus based on data from previous studies. Accordingly, this quantitative meta-analysis investigated prognostic and clinicopathological utility of PD-L1 in patients with MPM.MethodsA comprehensive search of the PubMed, Web of Science, Embase, and Cochrane Library databases for articles published up to October 4, 2019 was performed. Studies using immunohistochemical techniques to detect/quantify the expression of PD-L1 in MPM tissue were enrolled in the analysis. The combined hazard ratio (HR) and corresponding 95% confidence interval (CI) was applied to assess the association between PD-L1 expression and overall survival (OS).ResultsA total of 11 studies comprising 1606 patients was included in the present meta-analysis. For OS, pooled data revealed an HR of 1.50 (95% CI 1.32–1.70; p < 0.001), suggesting that patients with PD-L1 overexpression experience inferior OS. Subgroup analysis revealed that elevated PD-L1 remained a significant prognostic indicator for worse OS, irrespective of sample size, cut-off value, ethnicity, and Newcastle-Ottawa Scale score. Moreover, PD-L1 overexpression was associated with non-epithelioid histology (odds ratio 4.30 [95% CI 1.89–9.74]; p < 0.001).ConclusionsResults of this meta-analysis show that elevated expression of PD-L1 could be a factor predicting poorer survival in patients with MPM.     

人PD-L2基因克隆及其在大肠杆菌中的表达

目的 克隆人PD-L2基因并构建PD-L2胞外区的原核表达载体，在大肠杆菌中进行表达。方法 以RT-PCR方法从活化的人外周血单个核细胞总RNA中克隆PD-L2基因的cDNA，构建PD-L2胞外区的原核表达载体，在大肠杆菌BL21(ED3)中进行表达并鉴定。结果 克隆到PD-L2基因cDNA编码区全长序列，经DNA测序证明其与已报道的序列一致。进而构建了PD-L2胞外区的原核表达载体，并在大肠杆菌表达，免疫印迹分析表明在IPTG诱导后表达PD-L2胞外区蛋白，相对分子质量Mr为22000，与理论值大小相符。结论 成功克隆PD-L2基因，其胞外区蛋白在大肠杆菌中获得表达，为进一步研究PD-L2功能提供了条件。     

负性刺激分子PD-L对T细胞介导小鼠L929肿瘤细胞免疫效应的影响

目的：探讨负性刺激分子在肿瘤细胞逃避免疫效应中的作用.方法：以L929细胞为靶细胞,体内致敏C57BL/6小鼠,注入PD-L1、PD-L2抗体阻断,并设立未致敏对照组.分离小鼠脾细胞,体外采用3H-TdR掺入法、荧光标记双染色FCM以及PI染色FCM法分别检测淋巴细胞增殖反应、活化诱导的细胞凋亡以及脾细胞及其培养上清对肿瘤细胞的杀伤效应.结果：L929细胞表达PD-L1,而不表达PD-L2.体内与体外联合应用PD-L1抗体,能显著增强L929肿瘤细胞诱导的致敏组小鼠脾细胞的增殖活性和特异性杀伤效应,并可抑制活化诱导的T细胞凋亡;PD-L1抗体亦可增加L929细胞诱导的未致敏组小鼠脾细胞的增殖活性和促进其脾细胞培养上清对L929细胞的杀伤效应.结论：PD-L1抗体可通过阻断PD1/PDL途径促进初始T细胞和致敏T细胞介导的抗瘤效应.     

PD-L2剪切异构体与EGFP融合蛋白的表达及其亚细胞定位研究

目的　探讨PD L2的剪切异构体在哺乳动物细胞的表达和亚细胞定位。方法　以RT PCR方法克隆人PD L2基因的常规剪切体和新型剪切异构体的cDNA ,构建其与EGFP融合的表达载体 ,分别转染K5 6 2细胞进行表达 ,经抗PD L2抗体染色后以流式细胞仪和激光共聚焦显微镜分析融合蛋白的表达及其亚细胞定位。结果　从活化的人白细胞中克隆到常规剪切体PD L2Ⅰ和新型剪切异构体PD L2Ⅱ的cDNA ,后者删除了编码胞外区Ig C结构域的外显子 3。进而构建了PD L2Ⅰ EGFP和PD L2Ⅱ EGFP融合蛋白表达载体 ,分别转染K5 6 2细胞。流式细胞仪分析显示 ,转染前者的细胞中既可检测到EGFP的表达又可在细胞膜上检测到PD L2表达 ;而转染后者的细胞中只能检测到EGFP的表达 ,在其细胞膜上不能检测到PD L2表达。共聚焦显微镜观察显示 ,PD L2Ⅰ EGFP主要分布于细胞膜表面 ,PD L2Ⅱ EGFP则主要分布于细胞内。结论　常规剪切体PD L2Ⅰ能正确定位于细胞膜表面 ,而新型剪切异构体PD L2Ⅱ则位于细胞内 ,不能运输至细胞膜 ,提示不同PD L2剪切异构体可能与其功能的调变有关     

Nivolumab for the treatment of classical Hodgkin lymphoma after failure of autologous stem cell transplant and brentuximab

Cancer cells are able to escape surveillance from the immune system by co-opting physiologic mechanisms such as the programmed cell death-1 (PD-1) receptor pathway. Agents able to block the interaction between the PD-1 receptor and its ligands have the potential to release T cells from tumor-induced suppression and eradicate malignant cells. Nivolumab – a PD-1 inhibitor – is approved for the treatment of patients with metastatic melanoma and lung cancer. This agent has been tested in patients with advanced Hodgkin lymphoma (HL) and showed impressive results in a phase I trial. Here we review the profile of Nivolumab including its pharmacological properties, clinical efficacy and safety in patients with advanced classical HL.