Thymic Lymphomas in a 6-Month rasH2-Tg Mouse Carcinogenicity Study With the RORγt Inverse Agonist, BMS-986251.

BMS-986251 is a retinoid-related orphan receptor γt (RORγt) inverse agonist that was in development for the treatment of autoimmune diseases. RORγt is a nuclear hormone receptor and transcription factor that is involved in the differentiation and function of T helper 17 cells. RORγt-deficient (constitutive or conditional) mice develop thymic lymphomas with >50% mortality at 4 months, whereas heterozygous mice are normal.

Decreased immune response in monkeys administered a human T-effector cell agonist (OX40) antibody.

The OX40 receptor plays a crucial co-stimulatory role in T effector cell survival, expansion, cytokine production, and cytotoxicity to tumor cells; therefore, OX40 agonists are being evaluated as anti-cancer immunotherapies, especially in combination with checkpoint inhibitors. To support clinical development of BMS-986178 (an OX40 agonist antibody), two repeat-dose toxicity studies were conducted in cynomolgus monkeys. In the first study, BMS-986178 was administered intravenously (IV) once weekly for one month at doses from 30 to 120 mg/kg.

Characterizing the Randot Preschool stereotest: Testability, norms, reliability, specificity and sensitivity in children aged 2-11 years.

Purpose: To comprehensively assess the Randot Preschool stereo test in young children, including testability, normative values, test/retest reliability and sensitivity and specificity for detecting binocular vision disorders.

Methods: We tested 1005 children aged 2-11 years with the Randot Preschool stereo test, plus a cover/uncover test to detect heterotropia. Monocular visual acuity was assessed in both eyes using Keeler Crowded LogMAR visual acuity test for children aged 4 and over.

ASTEROID: A New Clinical Stereotest on an Autostereo 3D Tablet.

Purpose: To describe a new stereotest in the form of a game on an autostereoscopic tablet computer designed to be suitable for use in the eye clinic and present data on its reliability and the distribution of stereo thresholds in adults.

Methods: Test stimuli were four dynamic random-dot stereograms, one of which contained a disparate target. Feedback was given after each trial presentation.

Bioavailability of protein therapeutics in rats following inhalation exposure: Relevance to occupational exposure limit calculations.

Protein therapeutics represent a rapidly growing proportion of new medicines being developed by the pharmaceutical industry. As with any new drug, an Occupational Exposure Limit (OEL) should be developed to ensure worker safety. Part of the OEL determination addresses bioavailability (BA) after inhalation, which is poorly understood for protein therapeutics.

Cancer Immunotherapy: Factors Important for the Evaluation of Safety in Nonclinical Studies.

The development of novel therapies that can harnass the immune system to eradicate cancer is an area of intensive research. Several new biopharmaceuticals that target the immune system rather than the tumor itself have recently been approved and fundamentally transformed treatment of many cancer diseases. This success has intensified the search for new targets and modalities that could be developed as even more effective therapeutic agents either as monotherapy or in combination.

Immunomodulation and lymphoma in humans.

Observational and clinical studies have associated increased cancer risks with primary or acquired immunodeficiencies, autoimmunity, and use of immunotherapies to treat chronic inflammation (e.g. autoimmunity) or support organ engraftment.

Methods: implementation of in vitro and ex vivo phagocytosis and respiratory burst function assessments in safety testing.

Functional innate immune assessments, including phagocytosis and respiratory burst, are at the forefront of immunotoxicology evaluation in pre-clinical animal species. Although in the clinic and in academic science, phagocytosis, and respiratory burst assessments have been reported for over two decades, the implementation of phagocytosis and respiratory burst analyses in toxicology safety programs is just recently gaining publicity. Discussed herein are general methods, both microtiter plate-based and flow cytometric-based, for assessing phagocytosis and respiratory burst in pre-clinical species including mouse, rat, dog, and monkey.

Chronic administration of belatacept, a T-cell costimulatory signal blocker, in cynomolgus monkeys.

The toxicokinetics and toxicity profile of belatacept (LEA29Y), which blocks the CD28 costimulation pathway to prevent T-cell activation, were evaluated in cynomolgus monkeys. In the current study, 30 monkeys (five monkeys per sex per group) received an intravenous dose of belatacept (10, 22, or 50 mg/kg) once weekly for 6 months. An additional five monkeys per sex received saline intravenously and served as controls.

Summary of roundtable discussion meeting: non-human primates to assess risk for EBV-related lymphomas in humans.

Epstein-Barr virus (EBV)-associated lymphomas are a known risk for immunosuppressed individuals. Non-clinical methods to determine the potential of new immunomodulatory compounds to produce EBV-associated lymphomas (hazard identification) have not been developed. Since lymphocryptovirus (LCV) in non-human primates (NHP) has similar characteristics to EBV in humans, a Roundtable meeting was held in October 2010 to explore how the potential for EBV-related lymphomas in humans can be assessed by using surrogate biomarkers for lymphoma risk in NHP toxicity studies.

Immunotoxicity testing in non-rodent species.

Evaluation of the immunotoxicity potential of some pharmaceuticals, including immunomodulatory chemicals and biologics, cannot be limited to testing in rodents. Thus, immune function tests have also been applied in studies with non-human primates and more recently dogs that assess various components of the immune system. These assays include TDAR responses with various immunogens, lymphocyte phenotyping, natural-killer cell activity, delayed-type hypersensitivity, and macrophage function assays.

Meeting Report Immune-Mediated Drug Hypersensitivity Reactions (IDHR) Workshop.

Immune-mediated drug hypersensitivity reactions (IDHR) are relatively rare reactions to drugs that can be observed in a limited population of patients, yet these reactions can have significant impacts on public health, clinical practice, and drug development. Despite the potentially significant impact of IDHR, research into the causes and mechanisms of action of these reactions has been limited. In order to identify and enhance potential research opportunities in IDHR, the Health and Environmental Sciences Institute (HESI) hosted a two-day workshop involving stakeholders from government, academia, and industry.

Evaluation of immunogenicity of the T cell costimulation modulator abatacept in patients treated for rheumatoid arthritis.

Objective: The immunogenicity of abatacept, a selective costimulation modulator, administered intravenously, was assessed across Phase II and III trials in patients with rheumatoid arthritis (RA).

Methods: Two direct-format enzyme-linked immunosorbent assays evaluated antibody responses [whole abatacept molecule (CTLA-4 and Ig portion) and CTLA-4 portion only (Assay A)] in the Phase II trials. During the Phase III trials and 2-year open-label periods, a similar, but more sensitive, Assay B was employed.

Abatacept treatment does not exacerbate chronic Mycobacterium tuberculosis infection in mice.

Objective: Treatment of rheumatoid arthritis and other autoimmune disorders with anti-tumor necrosis factor (anti-TNF) agents is associated with an increased risk of reactivation of latent Mycobacterium tuberculosis. While the mechanism of action of abatacept is fundamentally different from that of anti-TNF therapies, its effect on the protective response to latent tuberculosis is not known. We undertook this study to determine the effect of abatacept treatment in a murine model of chronic M tuberculosis infection.

The use of the Newcastle Control Score in the management of intermittent exotropia.

Aim: To evaluate the use of the Newcastle Control Score (NCS) in the management of intermittent exotropia (X(T)).

Participants And Methods: Children aged <11 years with X(T) had an assessment of NCS as part of routine management. Other data collected included visual acuity, near and distance alignment with alternating prism cover test and near (Frisby test) and distance stereoacuity (Frisby Davis Distance Stereotest (FD2TM)).

A modified method for measuring uniocular fields of fixation: reliability in healthy subjects and in patients with Graves orbitopathy.

Objective: To assess the intraobserver and interobserver reliability of recording uniocular fields of fixation using a modified perimeter technique in healthy subjects and patients with Graves orbitopathy (GO). Patients with restrictive myopathies, particularly GO, require accurate measurement of monocular excursions. These ductions are recorded in 4 to 12 directions of gaze using a perimeter, producing a plot known as a uniocular field of fixation.

Task force report: future research needs for the prevention and management of immune-mediated drug hypersensitivity reactions.

Immune-mediated drug hypersensitivity reactions (IDHR) have a significant impact on clinical practice, drug development, and public health. However, research to understand IDHR mechanisms and to develop diagnostic and predictive tests has been limited. To stimulate more research, a task force with representatives from the key stakeholders (research clinicians, regulatory scientists, and immunotoxicologists from the pharmaceutical industry) was assembled to identify critical data gaps and opportunities and to make recommendations on how to overcome some of the barriers to IDHR research and address research needs.