Discovery Category Highlights

Novel Approaches and Mechanisms in Hematopoietic Stem Cell Gene Therapy

Abstract: Hematopoietic stem cell gene therapy is one of the most exciting clinical tools to emerge from the gene therapy stable. This technology combines the expansion capability of hematopoietic stem cells, capable of replacing the entire blood and immune system of an individual, with the capacity for long-term replacement of one or more gene copies using integrating gene therapy vectors. Hematopoietic stem cell gene therapy benefits significantly from the pre-existing experience of standard blood and marrow transplantation, whilst at the same time having the capacity to deliver a safer and more effective therapy to a wider range of diseases. In this review we summarize the potential of hematopoietic stem cell gene therapy to expand the scope of hematopoietic stem cell transplantation, including the evolution of vector delivery systems and the success and failures of current clinical experience with this treatment. In particular we deal with the incidence of vector mediated transformation in patients and the steps that have been taken to minimize this risk. Finally we discuss the innovations in preclinical development that are likely to drive the future of this field, including the expansion to many more genetic diseases, particularly those affecting the brain. ... Read more

Immunotherapy in Sarcoma: A New Frontier

Abstract: Sarcomas are rare cancers of soft tissue and bone, and remain incurable when refractory to standard multimodality treatments. With the recent advances in immunotherapy for other solid tumors, there is heightened interest in the potential link of the immune system with sarcoma physiology. This review aims to summarize the ongoing laboratory and clinical research investigating the applications of immunotherapy in the treatment of sarcomas. With ongoing opportunities in vaccine therapy, adoptive transfer of immune cells, biochemotherapy, and immune checkpoint inhibitors, enrollment in immunotherapy clinical trials is an appealing option for sarcoma patients either in conjunction with traditional treatment modalities, or for those with few standard treatment options. ... Read more

All Eyes on the Next Generation of HIV Vaccines: Strategies for Inducing a Broadly Neutralizing Antibody Response

Abstract: HIV-1 broadly neutralizing antibodies (BNAbs) develop after several years of infection through a recursive process of memory B cell adaptation and maturation against co-evolving virus quasispecies. Advances in single-cell sorting and memory B cell antibody cloning methods have identified many new HIV BNAbs targeting conserved epitopes on the HIV envelope (env) protein. 3D crystal structures and biophysical analyses of BNAbs bound to invariant virus structures expressed on monomeric gp120, epitope scaffolds, core structures, and native trimers have helped us to visualize unique binding interactions and paratope orientations that have been instrumental in guiding vaccine design. A paradigm shift in the approach to structure-based design of HIV-1 envelope immunogens came recently after several laboratories discovered that native viral envelopes or "env-structures" reverse-engineered to bind with high affinity to a handful of broadly neutralizing antibodies did not in fact bind the predicted germline precursors of these broadly neutralizing antibodies. A major challenge for HIV-1 B cell vaccine development moving forward is the design of new envelope immunogens that can trigger the selection and expansion of germline precursor and intermediate memory B cells to recapitulate B cell ontogenies associated with the maturation of a broadly neutralizing antibody response. Equally important for vaccine development is the identification of delivery systems, prime-boost strategies, and synergistic adjuvant combinations that can induce the magnitude and quality of antigen-specific T follicular helper (TFH) cell responses needed to drive somatic hypermutation (SHM) and B cell maturation against heterologous primary virus envelopes. Finding the combination of multi-protein envelope immunogens and immunization strategies that can evolve a potent broadly neutralizing antibody response portends to require a complex vaccine regimen that might be difficult to implement on any scale. This perspective strives to integrate recent insights into mechanisms associated with the evolution of an HIV-1 broadly neutralizing antibody response with current immunogen design and proffers a novel immunization strategy for skewing TH17/TFH cell responses that can drive B cell adaptation and affinity maturation associated with a broadly neutralizing antibody response. ... Read more

Novel Biological Radiochemotherapy Approaches in Locally Advanced-stage Cervical Cancer Management

Abstract: Biological anticancer agents that enhance radiochemotherapeutic effect are appealing in the modern medical treatment of uterine cervix cancer. In this concise review, the focus is on three classes of biological anticancer agents. The first class is ribonucleotide reductase inhibitors. These biological anticancer agents impede deoxyribonucleotide payout and stop new synthesis of DNA molecule building blocks. By disrupting deoxyribonucleotide supply and demand economics, ribonucleotide reductase inhibitors disrupt the repair of radiation- and chemotherapy-induced DNA damage and enhance cancer cell death. Angiogenesis inhibitors represent a second class of biological anticancer agents. Angiogenesis inhibitors are conceptually thought to normalize cancer tumor vasculature and modulate vascular endothelial growth factor signals. Consequences of normalized tumor vessel permeability are better oxygen supply for radiosensitization and improved tumor fluid dynamics imparting chemosensitization. A third class, cytolytic T-cell immune modulators, edits human immune system responses to cancer cell antigens. These biological anticancer agents exploit molecular signaling involved in immune detection and in immune eradication. Completed and planned clinical trials utilizing these agents are discussed relative to the future radiochemotherapeutic management of uterine cervix cancer. ... Read more

Bimodal Plasma Metabolomics Strategy Identifies Novel Inflammatory Metabolites in Inflammatory Bowel Diseases

Abstract: Introduction: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by variable phenotypes. Metabolites are signatures of biochemical activity that can reveal unknown pathogenic pathways. We employed untargeted mass spectrometry (MS) based metabolomics to identify novel inflammatory mechanisms in IBD and a targeted assay to quantify metabolites of the auto-immunomodulating kynurenine pathway (KP) in IBDs and health. Materials and Methods: Metabolome analysis of CD, UC, and control plasmas was performed on a Liquid Chromatography (LC)-MS/MS system. KP metabolites quinolinic acid (QA) and picolinic acid (PA) were quantified by gas chromatography/MS. Results: Nineteen UC, 25 CD, and 9 control plasmas were analyzed: 34 metabolites exhibited abundance profiles associated with CD by global metabolome analysis (P≤0.05, false discovery rate q≤0.01). Notably, inflammatory-implicated metabolites angiotensin IV (4439 ion intensity score ± 0.56) (P=0.049, q<0.001), diphthamide (278.9 ± 43.2) (P=0.018, q<0.001), and GM3 gangliosides (mean 2175.6 ± 89.5) (P<0.001, q<0.001) were increased in CD. On the kynurenine metabolites assay, QA (0.44 pmol/ml ± 0.14 SD) and combined kynurenine metabolites (CKM) were increased in CD (0.82 ± 0.17) compared to controls (QA 0.30 ± 0.09; P<0.01; CKM 0.65 ± 0.16; P<0.01). CD QA positively correlated with CDAI (r=0.85; P<0.01), CRP (r=0.46; P=0.01), and ESR (r=0.42; P=0.03), while CKMs correlated with CDAI (r=0.615; P<0.01) and CRP (r=0.615; P=0.02). Conclusions: Associations of angiotensin IV, diphthamide, and GM3 gangliosides with CD implicate novel pathways in activating a Th1/Th17 inflammatory profile. Increased QA concentrations in CD may indicate a defective auto-immunomodulation mechanism. ... Read more

Epigenetic Silencing of RASSF10 Promotes Tumor Growth in Esophageal Squamous Cell Carcinoma

Abstract: Esophageal squamous cell carcinoma (ESCC) is one of the most malignant diseases and the five year survival rate remains less than 10%. RASSF10 is a newly identified member of the Ras-association family, but the regulation and the function of RASSF10 in ESCC remain unclear. Research methodologies such as methylation specific PCR (MSP), semi-quantitative RT-PCR, immunohistochemistry, Sodium bisulfite sequencing, and colony formation assay were utilized in this investigation. Loss of RASSF10 expression was found in KYSE150 cells and reduced expression was found in KYSE70 and KYSE180 cells. Expression of RASSF10 was found in KYSE140, KYSE450, KYSE510, TE1, TE3, and TE8 cell lines. Complete methylation was found in KYSE30 and KYSE150 cells, partial methylation was found in KYSE70, KYSE180, KYSE510, and TE1, and unmethylation was found in KYSE140, KYSE450, TE3, and TE8. Re-expression or increased expression was induced by 5-Aza-dC treatment. RASSF10 was methylated in 44.3% primary esophageal squamous cell carcinoma. RASSF10 inhibits cell proliferation and induces G2/M phase arrest in esophageal cancer cells. In conclusion: RASSF10 was frequently methylated in human esophageal squamous cell carcinoma and expression of RASSF10 was regulated by promoter region hypermethylation. RASSF10 may serve as a tumor suppressor of esophageal cancer. ... Read more

Understanding Autoimmunity in the Eye: From Animal Models to Novel Therapies

Abstract: In recent years considerable headway has been made on understanding the mechanisms underlying inflammatory diseases of the eye. This includes the role of the innate vs. adaptive arms of the immune systems in disease, the concept that distinct immune pathways can drive end-organ pathology, and the role as well as limitations of immune privilege in controlling the innate and adaptive effector responses that lead to eye pathology and loss of vision. These insights have largely been derived from basic studies in established and in newly developed animal models of uveitis. The increased understanding of disease mechanisms has the potential to guide development of rational therapies for human uveitis. Many novel biologics currently in use or being evaluated have been developed, or validated, in animal models of autoimmune and inflammatory disease, including experimental uveitis. Paradoxically, and fueled in part by dwindling research budgets, a campaign has been gathering momentum against use of animal models in preclinical research, as being poorly representative of responses in humans. Given the extensive genetic similarity between humans and laboratory rodents as revealed by the Human, Mouse and Rat Genome Projects, and the finding that almost all known disease-associated genes have orthologs in mice and rats, perhaps the problem is our still-insufficient understanding of mechanisms and inadequate knowledge of species differences, resulting in poor choice of models, rather than in an inherent unsuitability of animal models to represent human disease. ... Read more

Novel Approaches and Mechanisms of Immunotherapy for Glioblastoma

Abstract: Glioblastoma (GBM) is the most aggressive primary brain tumor. Combination therapy with surgery, radiation, and chemotherapy is not curative at present and carries a significant risk of toxicity. Advancements in the knowledge of tumor biology and tumor microenvironment have led to the development of novel targeted therapies for glioblastoma. In the past 15 years, a vast amount of pre-clinical data has been generated for glioblastoma immunotherapy. Translating these promising results into the clinic is, however, still an evolving process. Early clinical trials have demonstrated the feasibility and safety of several such approaches in patients with recurrent as well as newly diagnosed glioblastoma. Both passive as well as active immunotherapeutic modalities have also shown potential clinical benefit in at least a subset of these patients. This brief review discusses 'why' and 'how' various types of immunotherapies are being employed to treat glioblastoma. ... Read more

Mesenchymal Stem Cell-Based Therapy for Type 1 Diabetes

Abstract: Diabetes has increasingly become a worldwide health problem, causing huge burden on healthcare system and economy. Type 1 diabetes (T1D), traditionally termed "juvenile diabetes" because of an early onset age, is affecting 5~10% of total diabetic population. Insulin injection, the predominant treatment for T1D, is effective to ameliorate the hyperglycemia but incompetent to relieve the autoimmunity and to regenerate lost islets. Islet transplantation, an experimental treatment for T1D, also suffers from limited supply of human islets and poor immunosuppression. The recent progress in regenerative medicine, especially stem cell therapy, has suggested several novel and potential cures for T1D. Mesenchymal stem cell (MSC) based cell therapy is among one of them. MSCs are a type of adult stem cells residing in bone marrow, adipose tissue, umbilical cord blood, and many other tissues. MSCs, with self-renewal potential and transdifferentiation capability, can be expanded in vitro and directed to various cell lineages with relatively less efforts. MSCs have well-characterized hypoimmunogenicity and immunomodulatory effect. All these features make MSCs attractive for treating T1D. Here, we review the properties of MSCs and some of the recent progress using MSCs as a new therapeutic in the treatment of T1D. We also discuss the strength and limitations of using MSC therapy in human trials. ... Read more

Treating IgA Nephropathy: Quid Novi?

Abstract: IgA nephropathy is a common autoimmune renal disease resulting in kidney failure for patients with significant proteinuria. The therapeutic options are limited including non-specific treatment to reduce proteinuria accomplished by renin-angiotensin blockade. Strategies to control intrarenal inflammation include the administration of fish oil and for severe disease the use of immunosuppressive agents such as cyclophosphamide, glucocorticosteroids, and mycophenolate mofetil. In light of the limited option, there is an unmet need for novel therapeutic intervention in patients with progressive disease. Herein, we review the evidence for existing treatment choices and explore new immunopharmacologic agents being investigated for IgA nephropathy. ... Read more

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