Quantifying the limits of CAR T-cell delivery in mice and men

CAR (Chimeric Antigen Receptor) T cells have demonstrated clinical success for the treatment of multiple lymphomas and leukaemias, but not for various solid tumours, despite promising data from murine models. Lower effective CAR T-cell delivery rates to human solid tumours compared to haematological malignancies in humans and solid tumours in mice might partially explain these divergent outcomes. We used anatomical and physiological data for human and rodent circulatory systems to calculate the typical perfusion of healthy and tumour tissues, and estimated the upper limits of immune cell delivery rates across different organs, tumour types and species. Estimated maximum delivery rates were up to 10 000-fold greater in mice than humans yet reported CAR T-cell doses are typically only 10–100-fold lower in mice, suggesting that the effective delivery rates of CAR T cells into tumours in clinical trials are far lower than in corresponding mouse models. Estimated delivery rates were found to be consistent with published positron emission tomography data. Results suggest that higher effective human doses may be needed to drive efficacy comparable to mouse solid tumour models, and that lower doses should be tested in mice. We posit that quantitation of species and organ-specific delivery and homing of engineered T cells will be key to unlocking their potential for solid tumours.     

Investigating T Cell Immunity in Cancer: Achievements and Prospects

T cells play a key role in tumour surveillance, both identifying and eliminating transformed cells. However, as tumours become established they form their own suppressive microenvironments capable of shutting down T cell function, and allowing tumours to persist and grow. To further understand the tumour microenvironment, including the interplay between different immune cells and their role in anti-tumour immune responses, a number of studies from mouse models to clinical trials have been performed. In this review, we examine mechanisms utilized by tumour cells to reduce their visibility to CD8⁺ Cytotoxic T lymphocytes (CTL), as well as therapeutic strategies trialled to overcome these tumour-evasion mechanisms. Next, we summarize recent advances in approaches to enhance CAR T cell activity and persistence over the past 10 years, including bispecific CAR T cell design and early evidence of efficacy. Lastly, we examine mechanisms of T cell infiltration and tumour regression, and discuss the strengths and weaknesses of different strategies to investigate T cell function in murine tumour models.     

Pharmacologic Control of CAR T Cells

Chimeric antigen receptor (CAR) therapy is a promising modality for the treatment of advanced cancers that are otherwise incurable. During the last decade, different centers worldwide have tested the anti-CD19 CAR T cells and shown clinical benefits in the treatment of B cell tumors. However, despite these encouraging results, CAR treatment has also been found to lead to serious side effects and capricious response profiles in patients. In addition, the CD19 CAR success has been difficult to reproduce for other types of malignancy. The appearance of resistant tumor variants, the lack of antigen specificity, and the occurrence of severe adverse effects due to over-stimulation of the therapeutic cells have been identified as the major impediments. This has motivated a growing interest in developing strategies to overcome these hurdles through CAR control. Among them, the combination of small molecules and approved drugs with CAR T cells has been investigated. These have been exploited to induce a synergistic anti-cancer effect but also to control the presence of the CAR T cells or tune the therapeutic activity. In the present review, we discuss opportunistic and rational approaches involving drugs featuring anti-cancer efficacy and CAR-adjustable effect.     

计算机辅助试验研究系统

１９８１年我们研制了可在我校４４１Ｂ－Ⅲ和ＤＰＳ８／４９电子计算机上运行的多变量橡胶配方试验程序（ｔ－ｓ），为了微型计算机普遍使用的形势，根据在生产和科学研究中应用统计方法实际情况，我们改写、扩展，组成了计算机辅助试验研究（ＣＯＭＰＵＥＲＡＩＤＥＤ ＲＥＳＥＡＲＣＨ，简称ＣＡＲ）系统，其主要内容包含正交试验法和回归分析法等，具有实验设计、配方（配合）开发、实验拟合模型等功能，可作多因素试验的定性     

High‐resolution technology for FPD manufacturing

Using shorter wavelength for exposure light is one way to achieve high resolution while keeping sufficient depth of focus. We show exposure results for high resolution to confirm the effect of deep UV exposure light. With deep UV light, 1.2‐µm line and space pattern and 1.8‐µm contact hole pattern are resolved while keeping sufficient depth of focus.     

QoS二次流量监管实现

流量监管TP（Traffic Policing）就是对流量进行控制,它通过监督进入网络的流量速率,确保进入的流量被限制在一个合理的范围内。为满足网络中多用户多业务对流量监管的要求,通过对QoS流量监管的模式方法CAR（Committed Access Rate,约定访问速率）的分析研究,在路由平台上实现了QoS二次的流量监管功能,经在三层交换机上测试,证明了监管的有效性。     

基于CAR构件编程的自动生成Singleton模式的实现

设计模式是一种对设计过程中经常遇到的一些问题的总结及其通用的解决方法,使人们可更加简单方便地复用成功的设计和体系结构。Singleton模式属于设计模式中的一种方法。文中通过基于CAR构件编程的方法,设计了一种基于CAR构件编程中实现自动生成Singleton模式的方法,并通过具体实例来证明此方法的可行性与有效性。用户只需要在类设计时指定类属性为Singleton,就可以自动生成Singleton模式的相关实现代码,从而降低了用户编程的复杂度。     

Does stock repurchase declaration affect stock price? Differences between the electrics industry and other industries

This study is to discuss the impact of stock repurchase declaration and purpose of repurchase on the stock price in the backdrop of listed companies on Taiwan’s stock market. Event Study Method is employed to discuss stock price fluctuations while GARCH (Generalized Autoregressive Conditional Heteroscedasticity) is applied to estimate the Market Model regressive coefficients. The samples consisted of companies declaring first stock repurchase are selected from August 9, 2000 to December 31, 2005 with a precondition that all the companies shall be listed ones 150 days prior to declaration. The study results reveal that companies from other industries have considerably bigger average CAR than companies of the electrics industry before and after the declaration of stock repurchase. Companies with application purpose of “maintain stockholders’ equities and corporate credit” have considerably bigger average CAR than companies with application purpose of “transferring stocks to employees”. In industries other than electrics, companies with application purpose of “maintain stockholders’ equities and corporate credit” have bigger accumulated abnormal return response than companies with application purpose of “transferring stocks to employees”. In case of “maintain stockholders’ equities and corporate credit” as the application purpose of stock repurchase, companies from industries other than electrics have relatively higher average CAR response. The empirical study results can serve as a reference for the listed company management and to related academic studies.     

一种实现控件与多语言文本动态绑定的方法

现代应用中大多已有进行多语言切换的需求,但对于控件本身文本显示信息,要实现多语言实时切换还有一些难度,文中提出一种能够根据用户的选择将控件与显示文本进行动态绑定显示的方法,通过对控件文本信息的多语言实时切换.该方法具有执行效率较高、定制选择灵活方便、性能稳定可靠、适用范围较为广泛的特点.该方法已在基于CAR构件的Elastos操作系统上实现并运用于智能手机应用.     

基于CAR构件编程的自动生成Singleton模式的实现

设计模式是一种对设计过程中经常遇到的一些问题的总结及其通用的解决方法,使人们可更加简单方便地复用成功的设计和体系结构.Singleton模式属于设计模式中的一种方法.文中通过基于CAR构件编程的方法,设计了一种基于CAR构件编程中实现自动生成Singkton模式的方法,并通过具体实例来证明此方法的可行性与有效性.用户只需要在类设计时指定类属性为Singleton,就可以自动生成Singleton模式的相关实现代码,从而降低了用户编程的复杂度.