Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: results of a phase II, randomized, placebo-controlled, dose-finding trial.

OBJECTIVE: To assess the efficacy, safety, and biologic activity of atacicept in patients with rheumatoid arthritis (RA) in whom the response to treatment with tumor necrosis factor antagonists was inadequate. METHODS: The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial (AUGUST I) was a multicenter, phase II, double-blind, placebo-controlled dose-finding study involving 256 patients randomized 1:1:1:1 to receive atacicept (25 mg, 75 mg, or 150 mg) or placebo twice weekly for 4 weeks, then weekly for 21 weeks, with a 13-week treatment-free followup period (week 38). The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20% improvement in disease severity, using the C-reactive protein level. RESULTS: No statistically significant differences were observed in the efficacy end points at week 26 (P = 0.410 for overall treatment effect). However, atacicept significantly reduced immunoglobulin and rheumatoid factor (RF) levels, but not anti-citrullinated protein antibody levels, in a dose-dependent manner, with levels returning toward baseline values during followup. The effects of treatment on IgG-RF and IgA-RF were more pronounced than the effects on total IgG and IgA. Adverse events (AEs), including serious AEs, leading to withdrawal were more common among patients treated with atacicept compared with placebo. AEs were variable in nature, and no dose-dependent trends were observed. The frequency of infection-related AEs was similar across treatments. No notable effect of treatment on immunization status (protective versus nonprotective titer) was observed after initiation of treatment. CONCLUSION: This study did not meet the primary efficacy end point. However, clear biologic activity consistent with the proposed mechanism of action was observed. The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA. The safety of atacicept was considered acceptable in this patient population.

Clinical trial: a multicentre, randomized, double-blind, placebo-controlled, dose-finding, phase II study of subcutaneous interferon-beta-la in moderately active ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) pathophysiology is characterized by an imbalance between pro- and anti-inflammatory cytokines. Interferon (IFN)-beta-1a has potent immunoregulatory properties, including stimulation of host defence mechanisms and thus represents a potential treatment. AIM: To extend pilot data and identify a suitable dose of IFN-beta-1a to achieve endoscopically confirmed remission (ECR) in patients with moderately active UC and to evaluate safety. METHODS: In this multicentre, double-blind, placebo-controlled trial, adults with moderately active UC were randomized to IFN-beta-1a 44 or 66 microg, or placebo, subcutaneously three times weekly for 8 weeks, with a 4-week follow-up. RESULTS: Endoscopically-confirmed remission was observed in 23.4% [95% confidence interval (CI): 13.8-35.7] of placebo patients, 29.2% (95% CI: 18.6-41.8) of the IFN-beta-la 44 microg group and 20.0% (950% CI: 11.1-31.8) of the 66 microg group (P = 0.45). Improvements with IFN-beta-1a 44 microg were greater than with placebo for most secondary efficacy outcomes, although significance was not achieved. Placebo response rates were higher than expected from previous trials. Adverse events were similar to the known safety profile of IFN treatment. CONCLUSIONS: Interferon-beta-1a was generally well tolerated at the doses tested, but a significant therapeutic benefit in patients with UC was not observed.

Recombinant yellow fever viruses are effective therapeutic vaccines for treatment of murine experimental solid tumors and pulmonary metastases.

We have genetically engineered an attenuated yellow fever (YF) virus to carry and express foreign antigenic sequences and evaluated the potential of this type of recombinant virus to serve as a safe and effective tumor vaccine. Live-attenuated YF vaccine is one of the most effective viral vaccines available today. Important advantages include its ability to induce long-lasting immunity, its safety, its affordability, and its documented efficacy. In this study, recombinant live-attenuated (strain 17D) YF viruses were constructed to express a cytotoxic T-lymphocyte epitope derived from chicken ovalbumin (SIINFEKL). These recombinant viruses replicated comparably to the 17D vaccine strain in cell culture and stably expressed the ovalbumin antigen, and infected cells presented the antigen in the context of major histocompatibility complex class I. Inoculation of mice with recombinant YF virus elicited SIINFEKL-specific CD8(+) lymphocytes and induced protective immunity against challenge with lethal doses of malignant melanoma cells expressing ovalbumin. Furthermore, active immunotherapy with recombinant YF viruses induced regression of established solid tumors and pulmonary metastases. Thus, recombinant YF viruses are attractive viral vaccine vector candidates for the development of therapeutic anticancer vaccines.

Robust B cell immunity but impaired T cell proliferation in the absence of CD134 (OX40).

CD134 (OX40) is a member of the TNF receptor family that is expressed on activated T lymphocytes. T cells from mice that lack expression of CD134 made strong responses to a range of challenges, but they showed impaired proliferation in response to direct stimulation through the TCR with monoclonal anti-CD3epsilon Ab. CD134-deficient mice controlled infection with Leishmania major, Nippostrongylus brasiliensis, and Theiler's murine encephalomyelitis virus, and they made overtly normal Ab responses to a variety of antigens. Thus, CD134 is not essential for many T cell responses in vivo, nor is it required for the provision of help to B cells. Nonetheless, a subtle role in the regulation of T cell reactivity is suggested by the effect of CD134 deficiency on in vitro T cell responses.

Theiler's virus infection induces a specific cytotoxic T lymphocyte response.

Theiler's virus, a murine picornavirus, persists in the central nervous system of susceptible mouse strains and causes chronic inflammation and primary demyelination. One of the current hypotheses is that demyelination is, at least in part, mediated by virus-specific cytotoxic T lymphocytes (CTL). However, it is generally assumed that picornaviruses do not induce CTL. In point of fact, their existence has only been demonstrated for Coxsackievirus B-3. To determine whether Theiler's virus induces a CTL response, we generated a murine mastocytoma cell line stably transfected with the coding region of the genome of Theiler's virus strain DA. Using these cells as targets we showed that infected DBA/2 mice, a susceptible strain, produce cytotoxic T lymphocytes. The cytotoxic activity was Theiler's-virus specific. It was for the most part mediated by CD8+ T lymphocytes and H-2 restricted. This is the first demonstration that a specific CTL response is generated during Theiler's virus infection.

Major histocompatibility complex-linked and T cell-dependent selection of antibody repertoires. Quantitation of I-E-related specificities in normal mice.

Autoreactive B cell repertoires with major histocompatibility complex (MHC) class II (I-E)-related specificities were investigated by quantitating frequencies of specific B lymphocyte clonal precursors in unmanipulated normal and athymic BALB/c mice and in I-E-negative, MHC-congenic BALB.B10 mice. Clonal culture supernatants containing anti-I-E antibodies were identified by their selective binding to I-Ek alpha Ed beta-transfected fibroblasts, and those containing anti-anti-I-E antibodies were detected by their selective binding to anti-I-E monoclonal antibodies. Analysis of splenic B lymphocytes from BALB/c mice revealed high frequencies of both specificities in the compartment of large, naturally activated cells, but not among small, resting lymphocytes. The selection of such clones was found to be MHC linked because of their absence in BALB.B10 mice, and T cell dependent because of their reduced frequency in athymic BALB/c mice. The positive selection of V regions representing complementarities and mimicries of self-class II antigens may suggest a set of mechanisms participating in the maintenance of natural tolerance.