CD20 monoclonal antibodies for the treatment of multiple sclerosis: up-to-date

Introduction: Featuring demyelination and axonal degeneration, multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system representing a prominent cause of disability in young adults. The recently established therapeutic targeting of B cells in MS patients using CD20 monoclonal antibodies (CD20-mAbs) not only profoundly suppresses inflammatory disease activity but also materializes as the first treatment approach against disability accumulation in a subset of patients with primary progressive MS.

Areas covered: We will review current concepts regarding the immunopathology of B cells as well as results of clinical trials with CD20-mAbs in MS, from the murine-human chimeras rituximab and ublituximab to their increasingly humanized counterparts ocrelizumab and ofatumumab. We conducted a literature search using PubMed, clinicaltrials.gov, and clinicaltrialsregister.eu. We will focus on studies emphasizing the effectiveness of these mAbs in reducing MS disease activity and progression, long-term safety, optimal dosage and maintenance regimens. Lastly, we will turn to outstanding questions regarding anti-CD20 therapy in MS.

Expert opinion: CD20-mAbs could become first-line drugs in selected patients with highly active MS and already constitute an option for PPMS. Future studies could evaluate whether administration regimens currently in use can be optimized, while registry data could shed light on risk versus benefits on the long run, considering immunosenescence and a potentially increased risk of malignancies and infections in an aging population.     

Innovation in Chemistry,Manufacturing, and Controls—A Regulatory Perspective From Industry

This review describes the landscape of novel modalities such as cell and gene therapies, viruses, other novel biologics, oligomers, and emerging technologies, including modern analytics. We summarize the regulatory history and recent landmark developments in some major markets and examine specific chemistry, manufacturing, and controls (CMC) challenges, including suggestions for exploration of potential science-based approaches in support of regulatory strategy development from an industry perspective. In addition, we evaluate the economic factors contributing to patient access to innovation and discuss the impact of regulation. There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools. Although these tools are well described in current guidance documents, the specifics of applicability to complex novel modalities can still result in differing regulatory advice and outcomes. The future goals for efficiently regulating innovative modalities and technologies could be aided by more regulatory harmonization, regulatory education, and industry cooperation through consortia, enabling industry to supply key information to regulators in a transparent yet well-defined manner, and utilizing mutually understood risk-benefit analyses to produce drugs with appropriate safety, efficacy, and quality characteristics.     

Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.     

Concurrent mycosis fungoides and intravascular large B-cell lymphoma in a single patient

Mycosis fungoides (MF) is an indolent, uncommon, non-Hodgkin T-cell lymphoma of the skin. It classically presents with patches, plaques, and tumors and may rarely show spread to internal organs or bone marrow. Up to 7.5% of MF patients may be diagnosed with a second malignancy. Intravascular large B-cell lymphoma (IVLBCL) is an exceedingly rare non-Hodgkin B-cell lymphoma characterized by predominant growth of large neoplastic cells in the lumina of blood vessels. This case presents with an unusual confluence of two rare diagnoses, MF and IVLBCL, made more remarkable by the presence of both diagnoses on a single skin biopsy sample.     

Predicting progression to lymphoma in Sjögren's syndrome patients

Although the inherent complexity of the multifactorial nature of primary Sjögren's syndrome (pSS) renders the process of disease prognostication and prediction ambiguous, certain clinical and immunological characteristics have been described as lymphoma predictors in several studies. While the association between pSS and mucosa-associated lymphoid tissue lymphomas is indisputable, recent studies report a predominance of diffuse large B-cell lymphomas implying that pSS-lymphoma association is less subtype-specific than previously considered. The considerable differences in both disease severity and prognosis between patients with various types of lymphoma demand the identification of risk factors that can predict the development of the distinct subtypes. Additionally, a recently discovered diverse range of biological variables appears to influence clinical behavior and lymphoma outcome. In this review, we venture into the area of lymphoma prognostication in pSS, outlining long-established predictors, analyzing currently available prognostic models, and exploring the predictive potential of recent biological and molecular advances.     

Crossreaction of monoclonal Anti-T-cell antibodies: Implications for classifying B-cell leukemias

Summary Cell samples from 62 patients with B-cell leukemias (33 CLL, 8 IC, 6 PLL, 4 HCL, 2 ALL and 9 other NHL) were tested with a series of monoclonal antibodies (A50, T101, Lyt2, Leu1, M203) directed against T cells and shown to crossreact with B-CLL. The results demonstrate a heterogeneity of B-cell leukemias as all typical cases of CLL were reactive whereas most other cases were negative. Using the fluorescence-activated cell sorter, a somewhat stronger reaction was seen in early or benign cases of CLL, compared to advanced cases. All B-cell leukemias tested expressed the Ia antigen.     

肝细胞肝癌组织中B细胞淋巴瘤因子9的表达及临床意义

目的 :探讨B细胞淋巴瘤因子9(B-cell lymphoma 9,BCL9)在肝细胞肝癌(hepatocellular carcinoma,HCC)组织中的表达情况及临床意义。方法:采用Western Blot法检测8对新鲜冰冻HCC和对应癌旁组织中BCL9的蛋白表达;采用免疫组织化学法检测100例HCC和对应癌旁组织石蜡切片中BCL9的表达情况,并分析HCC中BCL9的表达与临床病理参数之间的关系。结果:Western Blot结果显示BCL9在HCC中的表达显著高于对应癌旁组织;免疫组化结果显示BCL9在HCC中主要定位于细胞核和细胞质,呈高表达,而在对应癌旁组织中主要定位于细胞质,表达较低或缺失;BCL9在HCC中的表达与肿瘤的分化程度和淋巴侵犯相关(P<0.05),与患者的性别、年龄、肿瘤直径、包膜完整、门静脉癌栓、血清HBs Ag、甲胎蛋白及肝硬化无关(P>0.05)。结论:BCL9在HCC中高表达,可能参与了HCC的发生、发展及转移。