Use of natalizumab in multiple sclerosis: current perspectives

ABSTRACT

Introduction: Natalizumab is an efficacious monoclonal antibody approved for use in relapsing-remitting multiple sclerosis (RRMS). Multiple studies have demonstrated reduced relapse rate, decreased disability progression and prolonged disease-free intervals with natalizumab use. However, natalizumab is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), thus restricting its widespread use with populations at high risk for developing PML. Recently, the effect of natalizumab in secondary-progressive (SPMS) population has been explored.

Areas covered: This review highlights the pathophysiology behind disease progression in MS and summarizes various attributes of natalizumab including: its pharmacological properties and global economic impact, results of clinical efficacy studies, its role in SPMS, pregnancy and its adverse events profile including PML and discontinuation protocols.

Expert opinion: Despite an established role in reducing RRMS disease activity, natalizumab has found limited use in SPMS due to insufficient evidence of efficacy. Current disease-modifying therapies exert modest overall benefit in SPMS owing to its complex pathophysiology, higher prevalence of comorbidities and increased PML risk with age and lack of reliable outcome measures. Finding more appropriate MRI and clinical outcome measures is quintessential for designing future randomized trials and possibly exploring primary neuroprotective agents for treating SPMS.     

Immune-based therapeutics for pediatric cancer

Importance of the field: Although most children with cancer are cured, there remain significant limitations of standard treatment, most notably chemotherapy resistance and non-specific toxicities. Novel immune-based therapies that target pediatric malignancies offer attractive adjuncts and/or alternatives to commonly employed cytotoxic regimens of chemotherapy or radiotherapy. Elucidation of the principles of tumor biology and the development of novel laboratory technologies over the last decade have led to substantial progress in bringing immunotherapies to the bedside.

Areas covered in this review: Current immunotherapeutic clinical trials in pediatric oncology and the science behind their development are reviewed.

What the reader will gain: Most of the immune-based therapies studied to date have been well tolerated, and some have shown promise in the setting of refractory or high-risk malignancies, demonstrating that immunotherapy has the potential to overcome resistance to conventional chemotherapy.

Take home message: Some immune-based therapies, such as ch14.18 and MTP-PE, have already been proven effective in phase III randomized trials. Further studies are needed to optimize and integrate other therapies into standard regimens, and to test them in randomized trials for patients with childhood cancer.     

Blood stem cell transplantation for breast cancer: new approaches using pre- peri- post-transplant immunotherapy

Autologous peripheral blood stem cell transplantation (auto-PBSCT) after high dose chemotherapy is usually offered to breast cancer patients carrying a high risk of relapse or having chemosensitive metastatic disease. Whether progression free and overall survival of such patients is improved after auto-PBSCT compared to conventional chemotherapy is a matter of debate. Currently available results of randomised trials could not uniformly prove or disprove auto-PBSCT being advantageous. Yet such studies have not employed any manipulation of the stem cell graft or any post-transplant immunomodulation exploiting the unique immunological environment for tumour eradication which exists only after auto-PBSCT. Preliminary data have discussed the ex vivo and in vivo generation of cytotoxic effector cells employing IL-2 and/or IFN-α/γ in the auto-PBSCT setting. Other cytokines such as IL-12, IL-15 and prolactin have likewise been considered . Several anticancer vaccine protocols after auto-PBSCT are ongoing using monovalent vaccines or anti-idiotypic antibodies. Polyvalent anticancer vaccines, cytokine secreting tumour cells, tumour pulsed or hybridised dendritic cells (DC) enhanced with cytokines are studied. Monoclonal antibodies (mAb) could assist: unlabelled for pretransplant ex vivo purging, post-transplant for enhancing antibody-dependent cell mediated cytotoxicity (ADCC) or radioimmunoconjugated as an additive cytotoxic part of the conditioning regimen. Autologous graft versus host induction and allogeneic stem cell transplantation (probably with non-myeloablative conditioning followed by donor lymphocyte infusions) are other approaches. Evaluation of successful combinations, optimal dosages and appropriate timing schedules is the subject of future investigations. Since breast cancer patients belong to countless subgroups, a large number of protocols need to be addressed in order to avoid over treatment and prevent relapse.     

The use of an antibody drug conjugate,glembatumumab vedotin (CDX-011), for the treatment of breast cancer

Introduction: Breast cancer (BC) is the most common malignancy in women in the USA. Despite the multi-modality treatments that are currently available, advanced BC has a persistent and unacceptable mortality rate. The need for new therapeutic strategies is extremely high. Experimental approaches with targeted therapies such as antibody drug conjugates provide hope for future treatment possibilities.

Areas covered: The development status and the possible role of antibody-mediated cytotoxic therapy are discussed in the setting of advanced BC. An overview of, mechanism of action, preclinical and Phase I/II results of glembatumumab vedotin (CDX-011) are discussed.

Expert opinion: The evidence that the glycoprotein NBM (GPNMB) target is a relevant target in BC, along with data showing that CDX-011 is safe and active in patients with advanced BC, provide a strong rationale to continue to explore this drug in patients with GPNMB-expressing breast tumors.     

RANK ligand inhibition with denosumab for the management of osteoporosis

Receptor activator of nuclear factor-κB ligand (RANKL) is a cytokine member of the tumour necrosis factor family that is the principal final mediator of osteoclastic bone resorption. It plays a major role in the pathogenesis of postmenopausal osteoporosis, as well bone loss associated with rheumatoid arthritis, metastatic cancer, multiple myeloma, aromatase inhibitor therapy and androgen deprivation therapy. Denosumab (AMG 162) is an investigational fully human monoclonal antibody with a high affinity and specificity for RANKL. By inhibiting the action of RANKL, denosumab reduces the differentiation, activity and survival of osteoclasts, thereby slowing the rate of bone resorption. Denosumab has been shown to increase bone mineral density (BMD) and reduce bone turnover in postmenopausal women with low BMD. Denosumab is a potential treatment for osteoporosis and other skeletal disorders.     

Thymic hormones in cancer diagnostics and treatment

The thymus is an endocrine organ. A unified, physiological concept of humoral regulation of the immune response emerged in the last three decades. The thymus is the primary major site of production of immunocompetent T-lymphocytes from their haematopoietic stem cells. The thymus provides a superior humoral microenvironment for the development of immunocompetent T-lymphocytes. Although yolk sac derived pre-T stem cells enter the thymus using a homing receptor, the immigration process requires also secretion of a peptide, called thymotaxin by the cells of the reticulo-epithelial (RE) network. This complex process requires direct cell to cell, receptor based interactions, as well as in situ paracrine information via the numerous cytokines and thymic hormones produced by the RE cells of thymic microenvironment. Thymic hormones induce in situ T-lymphocyte marker differentiation, expression and functions. These polypeptide hormones have also been shown by means of immunocytochemistry to localise in the RE cells of the thymic cellular microenvironment. Based on the complexity of the intrathymic maturation sequence of T-lymphocytes and the increasing numbers of T-lymphocyte subpopulations that are being identified, it would be surprising if a single thymic humoral factor could control all of the molecular steps and cell populations involved. Rather, it would appear that the control of intrathymic T-lymphocyte maturation and functional maturation involves a complex number of thymic-specific factors and other molecules that rigidly control the intermediary steps in the differentiation process. Thymosin fraction 5 (TF5) and its component polypeptides influence a variety of lymphocyte properties including cyclic nucleotide levels, migration inhibitory factor production, T-dependent antibody production and expression of certain surface maturation/differentiation markers. Recently, thymic hormones, mostly thymosins have been employed not only in neoplasms’ early detection but also in clinical trials to strengthen the effects of immunomodulators in immunodeficiencies, autoimmune diseases and neoplastic malignancies. Combined chemoimmunotherapeutical antineoplastic treatment seems to be useful. Generally, haematopoietic toxicity of every chemotherapeutical clinical trial can be reduced significantly by the immunotherapy, compared to 50% in patients treated with chemotherapy alone.     

Cetuximab: still an option in the treatment of pancreatic cancer?

Introduction: In this review, we analyzed the current literature about cetuximab to clarify its role in the treatment of pancreatic cancer. Using single-agent gemcitabine has been the standard treatment for more than 15 years for advanced pancreatic cancer. The attempts at improving the results by combining it with several other drugs, such as fluorouracil, cisplatin, irinotecan, oxaliplatin, or pemetrexed produced no clear survival benefit. Recently, however, new combination chemotherapy regimens (e.g., FOLFIRINOX, nab-paclitaxel plus gemcitabine) achieved a significant survival benefit compared to gemcitabine alone.

Areas covered: Epidermal growth factor receptor (EGFR) transmembrane glycoprotein has been demonstrated to be overexpressed in pancreatic cancer, and it correlates with more advanced disease, poor survival, and the presence of metastases. Therefore, inhibition of the EGFR signaling pathway could be an attractive therapeutic target in this tumor. Although several combinations of EGFR inhibitors with chemotherapy demonstrate inhibition of tumor-induced angiogenesis, tumor cell apoptosis, and regression in xenograft models, these benefits remain to be confirmed.

Expert opinion: The encouraging results from preclinical and early clinical studies with cetuximab in pancreatic cancer were not confirmed in a Phase III trial. Cetuximab failed to demonstrate improved patient outcome when paired with various chemotherapeutic regimens and/or other biological agents.     

From the Cover: Dominant suppression of inflammation by glycan-hydrolyzed IgG

A unique anti-inflammatory property of IgG, independent of antigen specificity, is described. IgG with modification of the heavy-chain glycan on asparagine 297 by the streptococcal enzyme endo-β-N-acetylglucosaminidase (EndoS) induced a dominant suppression of immune complex (IC)-mediated inflammation, such as arthritis, through destabilization of local ICs by fragment crystallizable–fragment crystallizable (Fc-Fc) interactions. Small amounts (250 µg) of EndoS-hydrolyzed IgG were sufficient to inhibit arthritis in mice and most effective during the formation of ICs in the target tissue. The presence of EndoS-hydrolyzed IgG disrupted larger IC lattice formation both in vitro and in vivo, as visualized with anti-C3b staining. Neither complement binding in vitro nor antigen–antibody binding per se was affected.     

Primary autoimmune haemolytic anaemia and coeliac disease

Background: Irritable bowel syndrome is a common cause of abdominal pain and discomfort and may be related to disordered gastrointestinal motility. Our aim was to assess the effects of long-term treatment with a prokinetic agent, cisapride, on postprandial jejunal motility and symptoms in the irritable bowel syndrome (IBS). Methods: Thirty-eight patients with IBS (constipation-predominant, n = 17; diarrhoea-predominant, n = 21) underwent 24-h ambulatory jejunal manometry before and after 12 week's treatment {cisapride, 5mg three times daily (n = 19) or placebo (n = 19)}. Results     

4-1BB单克隆抗体及激素对刀豆蛋白A诱导免疫性肝损伤治疗作用的研究

目的 探讨4-1BB单克隆抗体(4-1BBmAb)及激素对免疫性肝损伤的治疗作用及对CD4+CD25+T细胞的影响.方法 建立刀豆蛋白A(ConA)诱导免疫性肝损伤小鼠模型,激素治疗组ConA注射2h后腹腔内注射甲泼尼龙(3 mg/kg),4-1BBmAb治疗组尾静脉注射4-1BBmAb(100 μg/只),联合治疗组同时使用甲泼尼龙(3 mg/kg)及4-1BBmAb(100 μg/只),健康对照组仅注射相同体积的0.9％氯化钠注射液.分别通过肝脏组织学、肝功能进行治疗效果的验证.分别抽取各组小鼠血液,流式细胞仪观察CD4+CD25+T细胞表达的变化.采用方差分析及t检验进行统计分析.结果 健康对照组丙氨酸转氨酶(ALT)(140±22) U/L,天冬氨酸转氨酶(AST)(131±16) U/L;激素治疗组ALT(76±11)U/L,AST (71±10) U/L;4-1BBmAb治疗组ALT(98±14) U/L,AST (89±11) U/L;联合治疗组ALT (61±8) U/L,AST (55±7) U/L;联合治疗组与4-1BBmAb组、激素治疗组、健康对照组比较,差异均具有统计学意义(P＜0.01).健康对照组、激素治疗组及4-1BBmAb组CD4+CD25+T细胞分别为(3.0±0.8)％,(8.5±2.9)％及(8.4±3.5)％,而联合治疗组为(11.2±3.5)％,联合治疗组与其他3组比较,差异均有统计学意义(P＜0.05).结论 4-1BBmAb对免疫性肝损伤具有一定的治疗作用.4-1BBmAb联合激素治疗效果比单独使用激素或4-1BBmAb治疗效果更好.4-1BBmAb及激素对CD4+CD25+T细胞表达的影响可能是其治疗作用机制之一.