Human Immunology News Volume 5.21 | May 30 2017

TOP STORY

Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma

Investigators performed a proof-of-concept Phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R). In 18 primary CNS lymphoma (PCNSL) patients, 94% showed tumor reductions with ibrutinib alone, including patients having PCNSL with CD79B and/or MYD88 mutations, and 86% of evaluable patients achieved complete remission with DA-TEDDi-R. [Cancer Cell] Abstract

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The A946T Variant of the RNA Sensor IFIH1 Mediates an Interferon Program that Limits Viral Infection but Increases the Risk for Autoimmunity

The single-nucleotide polymorphism rs1990760 in the gene encoding the cytosolic viral sensor IFIH1 results in an amino-acid change (A946T; IFIH1^T946) that is associated with multiple autoimmune diseases. The authors found that human peripheral blood mononuclear cells and cell lines expressing the risk variant IFIH1^T946 exhibited heightened basal and ligand-triggered production of type I interferons. [Nat Immunol] Abstract

Replicating Viral Vector Platform Exploits Alarmin Signals for Potent CD8⁺ T Cell-Mediated Tumor Immunotherapy

Scientists showed that lymphocytic choriomeningitis virus can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumor-associated antigens to dendritic cells for efficient cytotoxic effector T lymphocyte priming. Unlike replication-deficient vectors, artLCMV also targets lymphoid tissue stroma cells expressing the alarmin interleukin-33. [Nat Commun] Full Article | Press Release

The Long Noncoding RNA Lnc-EGFR Stimulates T-Regulatory Cells Differentiation Thus Promoting Hepatocellular Carcinoma Immune Evasion

Investigators showed that long noncoding (lnc)-epidermal growth factor receptor (EGFR) upregulation in Tregs correlates positively with the tumor size and expression of EGFR/Foxp3, but negatively with IFN-γ expression in patients and xenografted mouse models. [Nat Commun] Full Article

A Disease-Linked ULBP6 Polymorphism Inhibits NKG2D-Mediated Target Cell Killing by Enhancing the Stability of NKG2D Ligand Binding

Scientists studied the molecular and functional consequences of the two major alleles of ULBP6, the most polymorphic ULBP gene, which are associated with autoimmunity and relapse after stem cell transplantation. Surface plasmon resonance and crystallography studies revealed that the arginine-to-leucine polymorphism within ULBP0602 affected the natural killer (NK)G2D-ULBP6 interaction by generating an energetic hotspot. [Sci Signal] Full Article | Press Release

Antigen-Specific T Cell Analysis Reveals that Active Immune Responses to β Cell Antigens Are Focused on a Unique Set of Epitopes

Researchers showed that CD45RO⁺CD38⁺ β cell Ag-specific CD4⁺ T cells were present at higher frequencies in type 1 diabetes subjects compared with those in healthy subjects. These results imply an ongoing β cell immunity years after onset of diabetes and suggest that these activated T cells have an active role in the disease process. [J Immunol] Abstract

Human IgG2- and IgG4-Expressing Memory B Cells Display Enhanced Molecular and Phenotypic Signs of Maturity and Accumulate with Age

Sequential immunoglobulin class switching is linked to higher levels of somatic hypermutation in vivo, but it remains unclear if these are generated temporally during an immune response or upon activation in a secondary response. The authors aimed to uncouple these processes and to distinguish memory B cells from primary and secondary immune responses. [Immunol Cell Biol] Full Article

Altered Regulatory T-Cell Fractions and Helios Expression in Clinically Isolated Syndrome: Clues to the Development of Multiple Sclerosis

Researchers analyzed peripheral blood mononuclear cells from 18 treatment-naive individuals with recently diagnosed clinically isolated syndrome for disturbances in the phenotype of T regulatory, follicular T regulatory, T helper, follicular T helper and B cells. [Clin Exp Immunol] Full Article

Agammaglobulinaemia Despite Terminal B-Cell Differentiation in a Patient with a Novel LRBA Mutation

Scientists report a novel homozygous mutation in lipopolysaccharide-responsive vesicle trafficking, beach and anchor-containing protein (LRBA) allele in seven-year-old Omani boy, born to consanguineous parents. He presented with type 1 diabetes, autoimmune hematological cytopenia, recurrent chest infections and lymphocytic interstitial lung disease. The patient was treated with CTLA4-Ig (abatacept) with good outcome every two weeks for a period of three months. He developed complete IgG deficiency, but remarkably, histological examination revealed germinal centers and plasma cells in lymphoid and inflamed lung tissue. Further charatecterization showed these cells to express IgM but not IgG. [Clin Transl Immunology] Full Article

Differential Cytokine Withdrawal-Induced Death Sensitivity of Effector T Cells Derived from Distinct Human CD8⁺ Memory Subsets

Researchers demonstrated that primary human effector T cells derived from the CD8⁺ effector memory subset exhibit significantly higher sensitivity to cytokine withdrawal-induced cell death, a critical intrinsic apoptosis program responsible for culling cells once an infection is cleared and interleukin-2 (IL-2) levels diminish. They found no differences in the expression of IL-2 or IL-2 receptor components in cells originating from either subset. [Cell Death Discov] Full Article

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Chemokines in the Cancer Microenvironment and Their Relevance in Cancer Immunotherapy

The authors focus on the main chemokines that are found in the human tumor microenvironment; they elaborate on their patterns of expression, their regulation and their roles in immune cell recruitment and in cancer and stromal cell biology, and they consider how they affect cancer immunity and tumorigenesis. They also discuss the potential of targeting chemokine networks, in combination with other immunotherapies, for the treatment of cancer. [Nat Rev Immunol] Abstract

Therapeutic T Cell Engineering

Scientists discuss how engineered T cells are applicable in principle to many cancers, pending further progress to identify suitable target antigens, overcome immunosuppressive tumor microenvironments, reduce toxicities, and prevent antigen escape. Advances in the selection of optimal T cells, genetic engineering, and cell manufacturing are poised to broaden T-cell-based therapies and foster new applications in infectious diseases and autoimmunity. [Nature] Abstract

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Abramson Cancer Center Studies Show Hope for Multiple Cancers with Pembrolizumab Combination Therapies

The combination of pembrolizumab and the checkpoint inhibitor known as epacadostat has lead to promising responses and has been generally well tolerated in patients with triple-negative breast cancer, non-small cell lung cancer, squamous cell cancer of the head and neck, and several other cancers. [Press release from Penn Medicine discussing research to be presented at the 2017 American Society of Clinical Oncology Annual Meeting, Chicago] Press Release

AstraZeneca Delivers New Data on Expanding Portfolio of Cancer Medicines

AstraZeneca, along with its global biologics research and development arm, MedImmune, will demonstrate how it is rapidly delivering on the company’s science-led strategy for transformational cancer medicine development. [Press release from AstraZeneca discussing research to be presented at the 2017 American Society for Clinical Oncology Annual (ASCO) Meeting, Chicago] Press Release

Array BioPharma and Bristol-Myers Squibb Announce Strategic Collaboration

Array BioPharma and Bristol-Myers Squibb announced the companies have entered into a clinical research collaboration to investigate the safety, tolerability and efficacy of Array’s investigational MEK inhibitor, binimetinib in combination with Bristol-Myers Squibb’s Opdivo and Opdivo + Yervoy regimen as a potential treatment for metastatic colorectal cancer in patients with microsatellite stable tumors. [Array BioPharma] Press Release

Celyad Obtains Additional US Patent for Cancer Treatment Based on TCR-Deficient Allogeneic CAR-T Cells

Celyad announced the issuance of United States (US) Patent No. 9,663,763 relating to Celyad’s method of treating cancer by administering allogeneic primary human T cells that are engineered to be T-cell receptor (TCR)-deficient and to express a chimeric antigen receptor (CAR). [Celyad] Press Release

Progenitor Life Sciences, Developer of Technologies for ‘Off-the-Shelf’ Cellular Immunotherapies, Announces Its Proprietary Stealth™ Immune-Compatibility Platform

Progenitor announces Stealth™ platform enabling sourcing of cells from a wide range of healthy donors, without donor-recipient HLA-matching. Stealth™-engineered cells also reduce immune-mediated adverse events caused by unintended activation of the recipient’s immune system following infusion of engineered cell therapies. [Progenitor Life Sciences (Business Wire, Inc.)] Press Release

Intensity Therapeutics, Inc. Successfully Administers INT230-6 to First Patient in a Phase I/II Trial

Intensity Therapeutics, Inc. announced that the first patient successfully received treatment with the company’s lead product, INT230-6, as part of a Phase I/II international clinical study. [Intensity Therapeutics Inc.] Press Release

U of T Research Helps Pave the Way for an Off-the-Shelf Supply of Cells for Immunotherapy

Two U of T students have developed new technologies that clear some of the barriers to having a limitless source of cells to target cancer and other diseases. These breakthroughs, described in two recent papers published in Nature Communications and Nature Methods and funded by Medicine by Design and the Ontario Institute for Regenerative Medicine, could lead to new cell therapies for boosting patients’ immune systems against disease, and for cancer immunotherapy, in which immune cells can be engineered to attack tumors. [University of Toronto] Press Release

Texas on Track to Become First State to Explicitly Back Stem Cell Therapies

Lawmakers in Austin have approved a bill authorizing unapproved stem cell therapies, putting Texas on track to become the first state to explicitly recognize the experimental treatments. [STAT News] Editorial

NIH Scales Back Plan to Curb Support for Big Labs after Hearing Concerns

Faced with a barrage of criticism, the National Institutes of Health (NIH) has scaled back a plan to cap its support for individual labs in order to free up funds for more scientists. The changes did not appease scientists who gave NIH a tongue-lashing at a meeting of NIH’s Council of Councils. [ScienceInsider] Editorial

House Science Panel Joins Trump in Questioning Research Overhead Payments

A hearing on how the U.S. government defrays the cost of doing federally funded research on college campuses might put most people to sleep. But when budgets are tight, the billions of dollars being spent each year on so-called overhead become an irresistible target for lawmakers. [ScienceInsider] Editorial

NEW Tumor Immunology and Immunotherapy
October 1-4, 2017
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NEW Metabolism in Action – Lifetime Influence of Genes and Environment
October 1-5, 2017
Hillerød, Denmark

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NEW Postdoctoral Research Fellow – Innate Immunity (Fred Hutchinson Cancer Research Center)

Scientific Sales Representative – Cell Separation (STEMCELL Technologies Inc.)

PhD Research Fellowship – Neuroimmunology (University of Oslo)

Postdoctoral Fellow – Innate and Adaptive Immunity (Stanford University)

Postdoctoral Position – Cancer Immunology and Immunotherapy (Weill Cornell Medicine)

Scientist – Analytical Development (KBI Biopharma)

Postdoctoral Research Associate – Molecular Microbiology and Immunology (University of Southern California)

Senior Scientific Researcher – Personalized Cancer Vaccines (Genentech)

Tenure-Track Faculty Position(s) – Immunology (Cornell University)

Faculty Position – Cancer Immunology (Mayo Clinic)

Postdoctoral Fellow – Innate Immunity and Neurodegeneration (Mount Sinai Health System)

Postdoctoral Associate Position – Immunometabolism and Myeloid Cell Regulation within the Tumor Microenvironment (University of Louisville Health Science Center)

Postdoctoral Scholar – Multiple Sclerosis (University of Washington)

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

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