嵌合抗原受体修饰T细胞治疗前列腺癌的研究进展

摘要：嵌合抗原受体修饰T细胞（CAR-T）是近年来免疫治疗的热点,在血液系统疾病的治疗中取得了显著的临床疗效。目前,CAR-T在前列腺癌（PCa）治疗的研究中也取得了较大进展,其中以前列腺特异性膜抗原（PSMA）和前列腺干细胞抗原（PSCA）为靶点的CAR-T治疗进展较快,其可显著抑制肿瘤细胞生长,一定程度地延缓疾病进展。本文综述了前列腺肿瘤相关抗原（TAA）在前列腺癌CAR-T治疗中的最新研究进展,并对CAR-T在前列腺癌治疗中的挑战予以简要探讨,以期为临床提供参考。     

Dendritic Cell Protection from Cisplatin Nephrotoxicity Is Independent of Neutrophils

Cisplatin is a very effective chemotherapeutic agent used against a wide range of solid tumors. A major adverse effect of cisplatin therapy is acute kidney injury (AKI). Neutrophils are reported to infiltrate and exacerbate injury in a wide range of sterile inflammatory models of tissue injury. Here, we studied the kinetics of neutrophil infiltration into kidneys and their role in cisplatin-mediated AKI. Mice treated with cisplatin showed an increase in circulating neutrophils 24 and 48 h after cisplatin administration. Cisplatin treatment caused an increase in kidney leukocytes with neutrophils accounting for the majority of the infiltrating leukocytes. The extent of neutrophil infiltration coincided with the severity of kidney injury and renal dysfunction. To examine the functional relevance of infiltrating neutrophils in cisplatin nephrotoxicity, we depleted neutrophils using a neutrophil-specific antibody (anti-Ly-6G). This antibody resulted in greater than 90% depletion of neutrophils in both the blood and kidney. Of note, depletion of neutrophils had no impact on the extent of cisplatin-induced AKI as compared to non-depleted mice. Earlier, we reported that dendritic cell depletion in CD11c-DTRtg mice causes exacerbation of AKI and a dramatic increase in renal neutrophils. Thus, we also examined the role of neutrophils in dendritic cell-depleted mice treated with cisplatin. Dendritic cell depletion exacerbated AKI in spite of neutrophil depletion. These data demonstrate that cisplatin nephrotoxicity is not mediated by neutrophils and that dendritic cells protect kidneys via neutrophil-independent mechanisms.     

CD22 CAR-T挽救治疗CD19 CAR-T治疗后短期复发的TP53突变阳性难治急性B淋巴细胞白血病一例 #br#

难治急性淋巴细胞白血病病死率极高,CAR-T 细胞免疫治疗为此提供新的选择。本文介绍 1 例 CD19 CAR-T细胞治疗缓解后短期复发的 TP53突变阳性难治急性 B淋巴细胞白血病,经 CD22 CAR-T联合单倍体异基因 造血干细胞移植治疗成功的病例。本研究采用流式细胞术观察患者 CD19 CAR-T细胞和 CD22 CAR-T细胞两次治 疗的外周血 CAR-T细胞比例,PCR法检测 CAR基因表达;临床观察患者 2次 CAR-T细胞治疗过程中的疗效和不良 反应。结果显示,CD19 CAR-T和 CD22 CAR-T细胞 2次治疗均于第 14天达到骨髓完全缓解,且不良反应轻微。但 CD19 CAR-T细胞治疗缓解后 2周骨髓复发,患者外周血检测到异常 19 CAR基因表达,同时 TP53突变水平亦增高。 最终 CD22 CAR-T 细胞挽救治疗桥接单倍体造血干细胞移植后成功。由此表明在细胞制备过程中应进一步提高 CD3+细胞纯度;CD22 CAR-T治疗可以作为CD19 CAR-T治疗复发的一个挽救治疗措施。     

CAR-T细胞治疗产品非临床研究动物模型的发展和应用概述

嵌合抗原受体T细胞（CAR-T,Chimeric Antigen Receptor T Cell）已成为近年来癌症免疫疗法领域的研究热点,由于其具有特异性高、选择性强等优点,在肿瘤治疗领域中具有巨大的潜力。同时,CAR-T疗法可能带来特殊毒性风险,包括细胞因子释放综合征、神经毒性、B细胞减少和靶向与脱靶毒性等。尽量在研发早期、在人体使用前获得CAR-T产品的有效性和安全性等非临床信息至关重要,选择合适的动物模型进行上述相关研究可以大大提高对临床结果的预测性。目前,已用于CAR-T产品研究和正处于探索阶段的动物模型主要包括同源小鼠模型、转基因小鼠、移植瘤小鼠模型、免疫系统重建人源化小鼠以及灵长类动物模型。但是,由于CAR-T细胞产品的个性化程度高,人和动物免疫系统特性存在差异,人源细胞在动物体内易受到免疫排斥等原因,人源产品在动物模型上的研究结果尚不能完全反映其在人体内的作用情况。因此,需要根据产品特点和研究目的,构建或者选择适当的动物模型,为CAR-T细胞治疗产品非临床研究提供有效的研究工具。     

嵌合抗原受体T细胞的代谢优化★

基因工程设计的嵌合抗原受体（CAR）T细胞对血液肿瘤的治疗取得了显著成效，但对实体肿瘤的疗效有限。肿瘤异质性、肿瘤微环境的代谢挑战和免疫抑制导致了CAR-T细胞的功能障碍，造成了CAR-T细胞疗法对实体肿瘤的治疗困境。本文综述了CAR-T细胞结构、CAR-T细胞制备和涉及的信号通路，简述了乳酸、谷氨酰胺和葡萄糖等代谢物对CAR-T细胞的影响。此外，本文还从CAR-T细胞设计、体内外扩增条件和克服CAR-T细胞治疗的毒性效应三个角度概括CAR-T细胞治疗的最新进展。通过对CAR-T细胞的代谢优化，打破传统CAR-T细胞治疗的局限性，突破其现有的肿瘤类型限制。     

Management of acute kidney injury in children: a guide for pediatricians

Acute kidney injury (AKI; previously called acute renal failure) is characterized by a usually reversible increase in the blood concentration of creatinine and nitrogenous waste products and by the inability of the kidney to appropriately regulate fluid and electrolyte homeostasis. The incidence of AKI in children appears to be increasing and the etiology of AKI over the past decades has shifted from primary renal disease to multifactorial causes, particularly in hospitalized children. Renal failure can be divided into prerenal failure, intrinsic renal disease including vascular insults, and obstructive uropathies. The history, physical examination, and laboratory studies including a urinalysis and radiographic studies can establish the likely cause(s) of AKI. Once intrinsic renal failure has become established, management of the metabolic complications of AKI requires meticulous attention to fluid balance, electrolyte status, acid-base balance, and nutrition. Many children with AKI will need renal replacement therapy to remove endogenous and exogenous toxins and to maintain fluid, electrolyte, and acid-base balance until renal function improves. Renal replacement therapy may be provided by peritoneal dialysis (PD), intermittent hemodialysis (HD), or hemofiltration with or without a dialysis circuit. Many factors--including the age and size of the child, the cause of renal failure, the degree of metabolic derangements, blood pressure, and nutritional needs--are considered in deciding when to initiate renal replacement therapy and which modality of therapy to use. The prognosis of AKI is highly dependent on the underlying etiology of the AKI. Children who have AKI as a component of multisystem failure have a much higher mortality rate than children with intrinsic renal disease. Recovery from intrinsic renal disease is also highly dependent on the underlying etiology of the AKI. Children who have experienced AKI from any cause are at risk for late development of renal failure long after the initial insult. Such children need life-long monitoring of their renal function, blood pressure, and urinalysis.     

CAR-T免疫疗法：肿瘤靶向治疗的新策略

嵌合抗原受体T细胞（CAR-T）细胞是一种全新的治疗恶性肿瘤的策略,它有别于传统的手术、放疗、化疗、抗体药物治疗。CAR-T细胞疗法在血液肿瘤的治疗中有显著疗效。本文将综述CAR-T的结构和抗肿瘤的原理、CAR-T细胞在临床上的应用以及CAR-T细胞治疗所面临的挑战及广阔前景。     

Current status and regulatory perspective of chimeric antigen receptor-modified T cell therapeutics

Chimeric antigen receptor-modified T cells (CAR-T) have emerged as a new modality for cancer immunotherapy due to their potent efficacy against terminal cancers. CAR-Ts are reported to exert higher efficacy than monoclonal antibodies and antibody–drug conjugates, and act via mechanisms distinct from T cell receptor-engineered T cells. These cells are constructed by transducing genes encoding fusion proteins of cancer antigen-recognizing single-chain Fv linked to intracellular signaling domains of T cell receptors. CAR-Ts are classified as first-, second- and third-generation, depending on the intracellular signaling domain number of T cell receptors. This review covers the current status of CAR-T research, including basic proof-of-concept investigations at the cell and animal levels. Currently ongoing clinical trials of CAR-T worldwide are additionally discussed. Owing to the lack of existing approved products, several unresolved concerns remain with regard to safety, efficacy and manufacturing of CAR-T, as well as quality control issues. In particular, the cytokine release syndrome is the major side-effect impeding the successful development of CAR-T in clinical trials. Here, we have addressed the challenges and regulatory perspectives of CAR-T therapy.     

CAR-T细胞治疗实体瘤的挑战与应对策略

嵌合抗原受体T细胞（CAR-T）作为肿瘤免疫治疗的新疗法,已在多种血液肿瘤的临床治疗中取得了突破性进展,但用于实体瘤的治疗仍面临着诸多挑战。本文根据CAR-T细胞在实体瘤中的应用情况,总结其疗效不佳的原因,包括缺乏肿瘤特异性靶抗原、T细胞的转运及肿瘤浸润障碍、肿瘤微环境的免疫抑制等;并以此分析可行的解决策略,如提高肿瘤细胞特异性、提高对实体瘤的转运及浸润、解除免疫抑制以及提高CAR-T细胞在体内的持久性等,以期为后续CAR-T细胞治疗实体肿瘤研究提供思路。     

Natural products: potential treatments for cisplatin-induced nephrotoxicity

Cisplatin is a clinically advanced and highly effective anticancer drug used in the treatment of a wide variety of malignancies, such as head and neck, lung, testis, ovary, breast cancer, etc. However, it has only a limited use in clinical practice due to its severe adverse effects, particularly nephrotoxicity; 20%–35% of patients develop acute kidney injury (AKI) after cisplatin administration. The nephrotoxic effect of cisplatin is cumulative and dose dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI result in impaired renal tubular function and acute renal failure, chronic kidney disease, uremia, and hypertensive nephropathy. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, apoptosis, oxidative stress, inflammation, and vascular injury in the kidneys. At present, there are no effective drugs or methods for cisplatin-induced kidney injury. Recent in vitro and in vivo studies show that numerous natural products (flavonoids, saponins, alkaloids, polysaccharide, phenylpropanoids, etc.) have specific antioxidant, anti-inflammatory, and anti-apoptotic properties that regulate the pathways associated with cisplatin-induced kidney damage. In this review we describe the molecular mechanisms of cisplatin-induced nephrotoxicity and summarize recent findings in the field of natural products that undermine these mechanisms to protect against cisplatin-induced kidney damage and provide potential strategies for AKI treatment.     

Potential nephrotoxicity of sofosbuvir-based treatment in patients infected with hepatitis C virus: a review on incidence,type and risk factors

Introduction: There was no report of nephrotoxicity during clinical trials assessed sofosbuvir for treatment of hepatitis C (HCV) infection. This may be due to excluding patients with severe kidney dysfunction, as a main population at risk for drug-induced nephrotoxicity from these studies. There are some reports of acute kidney injury (AKI) possibly related to sofosbuvir-containing treatments from real-life experiences.

Areas covered: Available data on epidemiology, type, and possible risk factors for nephrotoxicity of sofosbuvir-containing treatment are reviewed. Related articles were collected by searching Scopus, Pubmed, and Science direct. Search terms were ‘sofosbuvir’, ‘nephrotoxicity’, ‘acute kidney injury’, ‘renal impairment’, and “direct acting antiviral agents.

Expert commentary: AKI may happen in 1–15% of patients who are treated with sofosbuvir-containing regimens. Compared with patients with normal kidney function, higher incidences of AKI have been reported in patients with baseline moderate to severe kidney dysfunction. Median time to AKI is 9 weeks after starting sofosbuvir. Baseline renal impairment, presence of ascites, diabetes or concomitant use of nephrotoxic drugs are possible risk factors for sofosbuvir-induced AKI. AKI following sofosbuvir-containing treatment is characterized by histological feature of acute interstitial nephritis and may be reversible following drug discontinuation. Monitoring of kidney function is recommended in sofosbuvir-treated patients.     

CAR-T细胞治疗产品中复制型病毒的风险分析及控制

嵌合抗原受体T细胞（CAR-T细胞）因其在血液肿瘤中的显著疗效已成为肿瘤免疫治疗领域中的国际研究新热点,成为肿瘤治愈新的希望。目前,在CAR-T细胞产品的生产中,通常是利用逆转录病毒载体或慢病毒载体将CAR基因高效地导入T细胞中,但在使用这些病毒载体的同时也带来了CAR-T产品污染复制型逆转录病毒（RCR）或复制型慢病毒（RCL）的潜在风险。虽然随着病毒载体设计及生产体系的不断改进,这种风险已大大降低,但仍不能完全排除。因此,监管机构要求对于临床使用的慢病毒或逆转录病毒载体、转导的CAR-T细胞产品以及患者均要进行复制型病毒的检测。本文主要通过分析复制型病毒污染检测的必要性、降低复制型病毒污染风险的措施、复制型病毒检测的阶段以及检测方法等方面,提出在CAR-T细胞生产过程中控制RCR/RCL的策略,以供CAR-T细胞产品研发者参考。     

提高CAR-T细胞疗法抗癌活性及安全性的研究进展

经过25年的研究,以嵌合抗原受体(CAR)为基础的细胞治疗目前在治疗恶性肿瘤方面展现了巨大潜力。近几年有大量的相关试验和临床数据被报道,本综述通过对这些数据的对比和分析,讨论如何增强CAR-T细胞疗法对不可切除的恶性肿瘤的治疗效果,也对CAR-T细胞技术在恶性肿瘤临床治疗领域存在的安全问题及解决策略进行概述。     

嵌合抗原受体T细胞免疫疗法在B细胞非霍奇金 淋巴瘤中的研究进展

摘要：非霍奇金淋巴瘤（NHL）是最常见的血液系统恶性肿瘤，复发难治患者预后欠佳。嵌合抗原受体T细胞免 疫疗法（CAR-T）是近年来新兴的免疫治疗方法，在恶性肿瘤尤其是血液系统恶性肿瘤治疗方面取得了较多突破，尤 其是给复发难治的B细胞NHL患者带来了希望。目前，美国食品药品监督管理局（FDA）已批准两款CAR-T细胞疗 法tisagenlecleucel和axicabtagene ciloleucel，其他几种产品仍在临床试验中。本文就CAR-T的结构及其在常见B细 胞NHL中的疗效、安全性及研究趋势做一综述。     

CAR-T细胞治疗产品非临床药效学研究关注点

CAR-T细胞（Chimeric Antigen Receptor T Cells,CAR-T）是一种表达嵌合抗原受体的基因工程T细胞,也称"活的药物",可以增强基因工程T细胞的特异性,能够以MHC （主要组织相容性复合体,Major Histocompatibility Complex,MHC）非依赖性的方式高度靶向肿瘤抗原,是治疗肿瘤的一种新手段。最近,临床上使用CAR-T细胞治疗复发、难治性血液恶性肿瘤和多发性骨髓瘤取得了很好的疗效;同时,采用CAR-T细胞治疗实体瘤的研发也在积极开展。根据所构建的CAR-T细胞不同的适应证和作用原理,构建不同的动物肿瘤模型,研究CAR-T细胞在动物模型的抗肿瘤活性,可以对CAR-T细胞进行概念验证性研究并证明其体内药效学活性,为临床研究提供有力的数据支持。     

克林霉素静脉滴注给药致急性肾损伤的危险因素分析

目的：对克林霉素静脉滴注致急性肾损伤（AKI）的危险因素进行分析,为临床安全用药提供参考。方法：回顾性分析2014年10月-2017年10月某院71例克林霉素致AKI和同期使用克林霉素但未发生AKI的582例患者的临床资料,采用单因素（t检验或χ²检验）及多因素（Logistic回归）对肾毒性危险因素进行分析。结果：AKI是克林霉素严重不良反应之一,发生率为10.87%。单因素分析显示,用药前血肌酐、肌酐清除率、入住ICU、合并严重心功能不全或呼吸衰竭、联合利尿剂或质子泵抑制剂、给药浓度和用药疗程与克林霉素肾毒性相关。多因素分析显示,入住ICU、给药浓度、联用质子泵抑制剂或利尿剂、基线肌酐清除率是克林霉素引起AKI的独立危险因素。大部分AKI患者转归较好,无继发严重肾功能衰竭或尿毒症患者。结论：临床实践中应重点关注有独立危险因素的患者,以保证克林霉素临床安全用药。     

CAR-T治疗诱导细胞因子释放综合征的机制及临床前安全性评价

嵌合抗原受体T细胞（CAR-T）疗法极大地改变了癌症的治疗前景,细胞因子释放综合征（CRS）是病理性免疫系统激活的严重全身炎症反应,也是CAR-T治疗过程中最常见且致命的毒性反应。目前CRS机制尚未完全阐明,临床前研究的实验模型主要包括异种移植免疫缺陷小鼠模型、同源小鼠模型、转基因小鼠模型、人源化小鼠模型和非人灵长类动物模型。由于种属差异且缺乏体外细胞模型,临床前预测CAR-T细胞引起CRS的风险仍是亟待解决的问题。从CRS的相关指导原则及法规、机制及临床前安全性评价方法和模型3个方面对CAR-T诱发的CRS进行综述,以期为CAR-T细胞治疗产品的临床前安全性评价策略提供新的思路。     

Induced Pluripotent Stem Cells (iPSCs) Provide a Potentially Unlimited T Cell Source for CAR-T Cell Development and Off-the-Shelf Products

Pharmaceutical Research - Chimeric antigen receptor T (CAR-T) cell therapy has been increasingly conducted for cancer patients in clinical settings. Progress in this therapeutic approach is...