Human Immunology News Volume 5.09 | Mar 7 2017

TOP STORY

Target Expression, Generation, Preclinical Activity, and Pharmacokinetics of the BCMA-T Cell Bispecific Antibody EM801 for Multiple Myeloma Treatment

Researchers identified B cell maturation antigen (BCMA) as a potential therapeutic target in 778 newly diagnosed and relapsed myeloma patients. They constructed an IgG-based BCMA-T cell bispecific antibody (EM801) and showed that it increased CD3⁺ T cell/myeloma cell crosslinking, followed by CD4⁺/CD8⁺ T cell activation, and secretion of interferon-γ, granzyme B, and perforin. [Cancer Cell] Abstract | Graphical Abstract

(Ranked by impact factor of the journal)

Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing

The authors demonstrated that T cell-dependent bispecific antibodies (TDBs) trigger T cell receptor activation by inducing target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule played a key role in the efficiency of the synapse formation. The anti-FcRH5/CD3 TDB killed human plasma cells and patient-derived myeloma cells at picomolar concentrations and resulted in complete depletion of B cells and bone marrow plasma cells in cynomolgus monkeys. [Cancer Cell] Full Article

Clonal Selection in the Human vδ1 T Cell Repertoire Indicates γδ TCR-Dependent Adaptive Immune Surveillance

γδ T cells are considered to be innate-like lymphocytes that respond rapidly to stress without clonal selection and differentiation. Scientists used next-generation sequencing to probe how this paradigm relates to human Vδ2^neg T cells, implicated in responses to viral infection and cancer. [Nat Commun] Full Article

Potassium Channels Kv1.3 and KCa3.1 Cooperatively and Compensatorily Regulate Antigen-Specific Memory T Cell Functions

Investigators showed using Kv1.3-deficient rats, that Kv1.3 is involved in the development of chronically activated antigen-specific T cells. Experiments with Kv1.3 knockout rats and Kv1.3 siRNA knockdown or channel-specific inhibition of human T cells showed that maximal T-cell responses against autoantigen or repeated tetanus toxoid stimulations require both Kv1.3 and KCa3.1. [Nat Commun] Full Article

Targeting CD38 Suppresses Induction and Function of T Regulatory Cells to Mitigate Immunosuppression in Multiple Myeloma

The authors studied CD38 levels in immunosuppressive CD4⁺CD25^highFoxp3⁺ Tregs and further defined immune modulating effects of a therapeutic CD38 monoclonal antibody Isatuximab/SAR650984 in multiple myeloma. [Clin Cancer Res] Abstract

In Situ Activation of Pituitary-Infiltrating T Lymphocytes in Autoimmune Hypophysitis

Using a mouse model of autoimmune hypophysitis scientists assessed whether T lymphocytes undergo activation in the pituitary gland. Infiltrating T cells co-localized with dendritic cells in the pituitary and produced increased levels of interferon-γ and interleukin-17 upon stimulation in vitro. [Sci Rep] Full Article

The Role of Indoleamine 2,3-Dioxygenase-Aryl Hydrocarbon Receptor Pathway in the TLR4-Induced Tolerogenic Phenotype in Human DCs

Researchers investigated the role of indoleamine 2,3-dioxygenase (IDO) in shaping dendritic cells (DCs) phenotype and function under endotoxin tolerance conditions. Their data showed that TLR4 ligation in LPS-primed DCs, induced higher levels of both IDO isoforms together with the transcription factor aryl-hydrocarbon receptor, compared to unprimed controls. [Sci Rep] Full Article

Dimethyl Fumarate Selectively Reduces Memory T Cells and Shifts the Balance between Th1/Th17 and Th2 in Multiple Sclerosis Patients

To better understand the therapeutic effects of Tecfidera and its rare side effect of progressive multifocal leukoencephalopathy, scientists conducted cross-sectional and longitudinal studies by immunophenotyping cells from peripheral blood derived from untreated and 4–6 and 18–26 months Tecfidera-treated stable relapsing-remitting multiple sclerosis patients using multiparametric flow cytometry. [J Immunol] Abstract

Interleukin 21 Inhibits Cancer-Mediated FOXP3 Induction in Naïve Human CD4 T Cells

Investigators showed that in the context of a number of cancers, naïve CD₄₅RA⁺ CD4 T cells are induced to express high levels of FOXP3, and that FOXP3 expression correlates with inhibition of T cell proliferation. FOXP3 expression was most potently induced by tumors secreting higher levels of total and active TGFβ1 and this induction could be potently counteracted with IL-21, restoring T cell proliferation. [Cancer Immunol Immunother] Full Article

Age-Related Changes in CD4⁺CD25⁺FOXP3⁺ Regulatory T Cells and Their Relationship with Lung Cancer

Although studies have demonstrated that the number and suppressive activity of regulatory T cells (Treg) increases with age, it is not clear whether these changes correlate with a higher incidence of tumors in the elderly. Researchers explored the relationship between an increase in CD4⁺CD25⁺FOXP3⁺ Treg and the higher risk of lung cancer in the elderly. [PLoS One] Full Article

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Dysbiosis and the Immune System

The authors categorize dysbiosis in conceptual terms and provide an overview of immunological associations; the causes and consequences of bacterial dysbiosis, and their involvement in the molecular etiology of common diseases; and implications for the rational design of new therapeutic approaches. [Nat Rev Immunol] Abstract

Amino-Acid Transporters in T-Cell Activation and Differentiation

Scientists present current information on amino-acid transporters, such as l-leucine transporter, l-glutamine transporter and γ-aminobutyric acid transporter-1, which are critically important for mediating peripheral naive T-cell homeostasis, activation and differentiation, especially for Th1 and Th17 cells, and even memory T cells. [Cell Death Dis] Full Article

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New Results from Second Phase III Study Show Significant Efficacy of Guselkumab and Superiority Versus Humira^® in Treatment of Moderate to Severe Plaque Psoriasis

Janssen Research & Development, LLC announced new findings from two pivotal Phase III studies reporting the efficacy and safety of guselkumab in the treatment of adults with moderate to severe plaque psoriasis. Data from the VOYAGE 2 study showed that patients treated with guselkumab experienced significant improvements in skin clearance and other measures of disease activity compared with placebo, and significantly greater improvements compared with the anti-tumor necrosis factor-alpha treatment Humira^®. [Press release from Janssen Research & Development, LLC discussing research presented at the 2017 American Academy of Dermatology (AAD) Annual Meeting, Orlando] Press Release

Regen BioPharma, Inc. Licenses NR2F6 Technology for Cancer Treatment and Autoimmune Disorders to CheckPoint Immunology Inc.

Regen BioPharma Inc. has granted CheckPoint Immunology Inc. an exclusive worldwide license to develop and commercialize Regen’s NR2F6 technology for human therapeutic use. The objective of the license grant is the separation of Regen’s small molecule technology from its other intellectual property in order to facilitate any future transactions involving small molecule therapies focused on the NR2F6 checkpoint. [Regen BioPharma Inc. (PR Newswire Association LLC.)] Press Release

John Theurer Cancer Center Part of Multi-Center Study with National Cancer Institute and Kite Pharma for CAR-T Cell Therapy Study Showing Very Impressive Results in Aggressive Lymphoma Refractory to Chemotherapy

John Theurer Cancer Center (JTCC) at Hackensack University Medical Center was part of a critical large multi-center study which confirmed the activity of a groundbreaking approach. For almost a decade JTCC has been involved in novel cellular therapies to improve the outcome of patients with blood cancers, working with the NCI and Kite Pharma, which is seeking FDA approval for the therapy. [Hackensack Meridian Health (PR Newswire Association LLC.)] Press Release

Prominent British Geneticist Offers Defense in Long-Running Misconduct Investigation

A leading UK academic has spoken publicly for the first time about a byzantine saga involving allegations of research misconduct in papers that stemmed from his research group at University College London. Geneticist David Latchman told Nature that although he did not scrutinize some of the papers sufficiently to detect errors, he also did not produce or directly supervise any of the images at the heart of the allegations. [Nature News] Editorial

Government of Canada Celebrates Cutting-Edge Infrastructure for Researchers at Ryerson University

The Honorable Bill Morneau, Minister of Finance, on behalf of the Honorable Kirsty Duncan, Minister of Science celebrated $128,000 in funding for Ryerson University. [Government of Canada] Editorial

NEW Keystone Symposium: Aging & Mechanisms of Aging-Related Disease
May 15-19, 2017
Yokohama, Japan

NEW 1^st International Congress of Micro-Immunotherapy (ICoMI)
May 18-20, 2017
Palma de Mallorca, Spain

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NEW Postdoc Positions – HIV Cure Research (Aarhus University)

Research Technologist – Cell Separation & Immunology (STEMCELL Technologies, Inc.)

Postdoctoral Fellow – Stromal Tissue Imprinting of Immune Cell Function (AstraZeneca)

Postdoctoral Researcher – Development of Immune System (Lund University)

Research Investigator – Immuno-Oncology (Bristol-Meyers Squibb)

Postdoctoral Position – Interaction between the Immune System and Pancreatic Cancer (Cold Spring Harbor Laboratory)

Postdoctoral Fellow – Immune Regulation and Human Diseases (The Wistar Institute)

Bioinformatician – Immunology (KOTAI Biotechnologies, Inc.)

Scientist – Immunology (Moderna Therapeutics)

Research Scientist – CAR-T Start-Up (Leucid Bio)

Postdoctoral Fellow – Immunology (Institute of Molecular and Cell Biology)

Postdoctoral Fellow – Immunology (The University of Texas Medical School at Houston)

Postdoctoral Fellow – Molecular Immunology (University of California San Diego School of Medicine)

Assistant Associate – Cancer Immunology (Fred Hutchinson Cancer Research Center)

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