Immune Checkpoint Blockade in Advanced Cutaneous Squamous Cell Carcinoma: What Do We Currently Know in 2020?

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer that predominantly arises in chronically sun-damaged skin. Immunosuppression, genetic disorders such as xeroderma pigmentosum (XP), exposure to certain drugs and environmental noxae have been identified as major risk factors. Surgical removal of cSCC is the therapy of choice and mostly curative in early stages. However, a minority of patients develop locally advanced tumors or distant metastases that are still challenging to treat. Immune checkpoint blockade (ICB) targeting CTLA-4, PD-L1 and PD-1 has tremendously changed the field of oncological therapy and especially the treatment of skin cancers as tumors with a high mutational burden. In this review, we focus on the differences between cSCC and cutaneous melanoma (CM) and their implications on therapy, summarize the current evidence on ICB for the treatment of advanced cSCC and discuss the chances and pitfalls of this therapy option for this cancer entity. Furthermore, we focus on special subgroups of interest such as organ transplant recipients, patients with hematologic malignancies, XP and field cancerization.     

The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

Immunotherapy has improved patient survival in many types of cancer, but for prostate cancer, initial results with immunotherapy have been disappointing. Prostate cancer is considered an immunologically excluded or cold tumor, unable to generate an effective T-cell response against cancer cells. However, a small but significant percentage of patients do respond to immunotherapy, suggesting that some specific molecular subtypes of this tumor may have a better response to checkpoint inhibitors. Recent findings suggest that, in addition to their function as cancer genes, somatic mutations of PTEN, TP53, RB1, CDK12, and DNA repair, or specific activation of regulatory pathways, such as ETS or MYC, may also facilitate immune evasion of the host response against cancer. This review presents an update of recent discoveries about the role that the common somatic mutations can play in changing the tumor microenvironment and immune response against prostate cancer. We describe how detailed molecular genetic analyses of the tumor microenvironment of prostate cancer using mouse models and human tumors are providing new insights into the cell types and pathways mediating immune responses. These analyses are helping researchers to design drug combinations that are more likely to target the molecular and immunological pathways that underlie treatment failure.     

TMB in NSCLC: A Broken Dream?

Although immune checkpoint inhibitors have changed the treatment paradigm of a variety of cancers, including non-small-cell lung cancer, not all patients respond to immunotherapy in the same way. Predictive biomarkers for patient selection are thus needed. Tumor mutation burden (TMB), defined as the total number of somatic/acquired mutations per coding area of a tumor genome (Mut/Mb), has emerged as a potential predictive biomarker of response to immune checkpoint inhibitors. We found that the limited use of TMB in clinical practice is due to the difficulty in its detection and compounded by several different biological, methodological and economic issues. The incorporation of both TMB and PD-L1 expression or other biomarkers into multivariable predictive models could result in greater predictive power.     

免疫检查点抑制剂相关甲状腺毒症

免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)是近年来恶性肿瘤治疗领域的一项重大突破。其通过针对T细胞的调节作用,增强抗肿瘤免疫反应,改善恶性肿瘤患者的预后,延长患者生存期,现已获批用于治疗多种肿瘤,但ICIs在应用过程中产生的甲状腺毒症是不容忽视的临床问题。本文对ICIs相关甲状腺毒症的发生机制、临床表现、处理对策等进行综述。     

Immune Aging and Immunotherapy in Cancer

Immune functions decline as we age, while the incidence of cancer rises. The advent of immune checkpoint blockade (ICB) has not only revolutionized cancer therapy, but also spawned great interest in identifying predictive biomarkers, since only one third of patients show treatment response. The aging process extensively affects the adaptive immune system and thus T cells, which are the main target of ICB. In this review, we address age-related changes regarding the adaptive immune system with a focus on T cells and their implication on carcinogenesis and ICB. Differences between senescence, exhaustion, and anergy are defined and current knowledge, treatment strategies, and studies exploring T cell aging as a biomarker for ICB are discussed. Finally, novel approaches to improve immunotherapies and to identify biomarkers of response to ICB are presented and their potential is assessed in a comparative analysis.     

Neurological Immunotoxicity from Cancer Treatment

The emergence of immune-based treatments for cancer has led to a growing field dedicated to understanding and managing iatrogenic immunotoxicities that arise from these agents. Immune-related adverse events (irAEs) can develop as isolated events or as toxicities affecting multiple body systems. In particular, this review details the neurological irAEs from immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell immunotherapies. The recognition and treatment of neurological irAEs has variable success, depending on the severity and nature of the neurological involvement. Understanding the involved mechanisms, predicting those at higher risk for irAEs, and establishing safety parameters for resuming cancer immunotherapies after irAEs are all important fields of ongoing research.     

Unified model for assessing checkpointing protocols at extreme‐scale

In this paper, we present a unified model for several well‐known checkpoint/restart protocols. The proposed model is generic enough to encompass both extremes of the checkpoint/restart space, from coordinated approaches to a variety of uncoordinated checkpoint strategies (with message logging). We identify a set of crucial parameters, instantiate them, and compare the expected efficiency of the fault tolerant protocols, for a given application/platform pair. We then propose a detailed analysis of several scenarios, including some of the most powerful currently available high performance computing platforms, as well as anticipated Exascale designs. The results of this analytical comparison are corroborated by a comprehensive set of simulations. Altogether, they outline comparative behaviors of checkpoint strategies at very large scale, thereby providing insight that is hardly accessible to direct experimentation. Copyright © 2013 John Wiley & Sons, Ltd.     

基于拜占庭容错的Checkpoint协议

根据Web服务的特点,设计一个拜占庭容错Checkpoint协议。Checkpoint协议在复制品中定期创建检查点,将复制品都认可的稳定状态保存,这些检查点可以在复制品进行状态转换和前摄恢复时提供历史数据。与其他的拜占庭容错Checkpoint协议相比,该协议最大的改进在于允许Web服务改变自身的状态,这一点对于Web服务,尤其是组合服务尤其重要。通过实验分析,结果显示了算法的有效性。     

A Low-Cost Checkpointing Technique for Distributed Databases

For distributed databases, checkpointing is used to ensure an efficient way to perform global reconstruction. However, the need for global reconstruction is infrequent. Most current checkpointing approaches for distributed databases are too expensive during run time. Some of them allow the checkpointing process to run in parallel with normal transactions at the cost of more data and resource contention, which in turn causes longer response time for normal transactions. Thus, an efficient way to checkpoint distributed databases is needed to avoid degrading the system performance. This paper presents a low-cost solution, called Loosely Synchronized Local Fuzzy Checkpointing (LSLFC), to these problems. LSLFC supports global reconstruction, and our performance study shows that LSLFC has little overhead during run time.     

基于检测点设置依赖图和属性表的卷回恢复算法

为了解决检测点设置过程中的Domino效应问题及卷回恢复过程中的活锁问题,并最大限度地减小时间开销,提出了基于检测点设置依赖图和属性表的卷回恢复算法。同以前的算法相比较,该算法一方面节省了用于进程之间同步的时间开销,另一方面检测点设置及卷回过程中涉及少量的相关进程。对该算法的正确性进行了证明。