Rapid generation of maturationally synchronized human dendritic cells: contribution to the clinical efficacy of extracorporeal photochemotherapy.

Extracorporeal photochemotherapy (ECP) is widely used to treat cutaneous T-cell lymphoma, graft-versus-host disease, and allografted organ rejection. Its clinical and experimental efficacy in cancer immunotherapy and autoreactive disorders suggests a novel mechanism. This study reveals that ECP induces a high percentage of processed monocytes to enter the antigen-presenting dendritic cell (DC) differentiation pathway, within a single day, without added cytokines, as determined by enhanced expression of relevant genes. The resulting DCs are capable of processing and presentation of exogenous and endogenous antigen and are largely maturationally synchronized, as assessed by the level of expression of costimulatory surface molecules. Principal component analysis of the ECP-induced monocyte transcriptome reveals that activation or suppression of more than 1100 genes produces a reproducible distinctive molecular signature, common to ECP-processed monocytes from normal subjects, and those from patients. Because ECP induces normal monocytes to enter the DC differentiation pathway, this phenomenon is independent of disease state. The efficiency with which ECP stimulates new functional DCs supports the possibility that these cells participate prominently in the clinical successes of the treatment. Appropriately modified by future advances, ECP may potentially offer a general source of therapeutic DCs.

Novel glucagon receptor antagonists with improved selectivity over the glucose-dependent insulinotropic polypeptide receptor.

Optimization of a new series of small molecule human glucagon receptor (hGluR) antagonists is described. In the process of optimizing glucagon receptor antagonists, we counter-screened against the closely related human gastric inhibitory polypeptide receptor (hGIPR), and through structure activity analysis, we obtained compounds with low nanomolar affinities toward the hGluR, which were selective against the hGIPR and the human glucagon-like peptide-1 receptor (hGLP-1R). In the best cases, we obtained a >50 fold selectivity for the hGluR over the hGIPR and a >1000 fold selectivity over the hGLP-1R. A potent and selective glucagon receptor antagonist was demonstrated to inhibit glucagon-induced glycogenolysis in primary rat hepatocytes as well as to lower glucagon-induced hyperglycemia in Sprague-Dawley rats. Furthermore, the compound was shown to lower blood glucose in the ob/ob mouse after oral dosing.

FDG-PET/CT for the evaluation of response to therapy of cutaneous T-cell lymphoma to vorinostat (suberoylanilide hydroxamic acid, SAHA) in a phase II trial.

INTRODUCTION: Harnessing the power of molecular imaging in particular positron emission tomography (PET) to assess response to therapy in early clinical trials has the potential to yield crucial data on efficacy and streamline drug development. Vorinostat (also known as SAHA, suberoylanilide hydroxamic acid) is a histone deacetylase (HDAC) inhibitor which alters gene transcription to inhibit proliferation and promote apoptosis. METHODS: In a phase II trial of vorinostat for cutaneous T cell lymphoma (CTCL), 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-PET/computed tomography (CT) was performed on patients with both cutaneous and nodal disease. FDG-PET/CT fuses the power of metabolic imaging from FDG-PET with the anatomic detail of CT. Scans were conducted on subjects pre-therapy and during therapy. RESULTS: Changes in the values of FDG uptake and measurements of nodal dimensions and thickness of cutaneous lesions were tabulated. FDG-PET/CT provided an objective measure of the response (or lack thereof) of both cutaneous and nodal disease to therapy with vorinostat. The results of this study are encouraging for the potential utility of FDG-PET/CT in future trials with HDAC inhibitors for other diseases and for CTCL with other therapies. CONCLUSION: Further study will be required to determine the prognostic value of the initial PET/CT scan and response on follow-up scans.

[Quality of pharma rep meetings in general practice]. / Kvaliteten på legemiddelkonsulentbesøk i allmennpraksis.

BACKGROUND: For many general practitioners (GPs), visits from pharmaceutical representatives (reps) are common settings for receiving updated drug information. We here aim to describe the content and assess the quality of information provided by reps visiting Norwegian GPs. MATERIAL AND METHOD: Medical students filled in a questionnaire addressing one pharma rep visit they had experienced during their 6-week general practice period in their fifth year at medical school in Oslo (2001 and 2002). RESULTS: Students from three classes participated and 144/241 (60 %) of them returned completed questionnaires. The 144 pharma rep meetings addressed 64 different and mostly new drugs, most commonly cardiovascular and pulmonary preparations. The visit was most commonly conducted during a free lunch (90 %) for the entire practice staff (81 %). The representatives offered the GPs free drug samples (41 %), and small presents (44 %). Four of five visits were characterized by incomplete or lacking information about side effects, interactions, contraindications or precautions for using the drug. The students scored their educational benefit from the session on a visual analogue scale from 0 (poor) to 10 (excellent), which revealed a mean score of less than neutral, 4.2. INTERPRETATION: The systematic omittance of important safety information, emphasizes the need for industry unbiased continuing medical drug education in general practice.

Transimmunization for cutaneous T cell lymphoma: a Phase I study.

Extracorporeal photochemotherapy (ECP) is a widely used immunotherapy for cutaneous T cell lymphoma (CTCL). It involves four sequential steps: conversion of blood monocytes into dendritic antigen presenting cells (DC) by repetitive adherence and disadherence to plastic surface; reinfusion of the new DC; presumed in vivo loading of the new DC with apoptotic malignant leukocytes; and expansion of the anti-tumor CD8 T cell pool. To assess the safety of a methodology designed to increase ex vivo contact between the apoptotic malignant cells and new DC prior to reinfusion, a single-center, open-label Phase I clinical study of a revised procedure--referred to as "Transimmunization"--was conducted in CTCL patients. Twenty-seven subjects were treated monthly for 3 to 5 months, alone or in combination with electron beam therapy. For those receiving Transimmunization alone, there was an overall diminution in infiltrative lesions in eleven (55%) of twenty patients. In the twelve leukemic CTCL patients, there was a significant mean reduction of 50.1% in the circulating malignant cells, as determined with family-specific anti-T cell receptor Vbeta monoclonal antibodies (P

The growth of cutaneous T-cell lymphoma is stimulated by immature dendritic cells.

In the initial stage of cutaneous T-cell lymphoma (CTCL), proliferating CTCL cells are concentrated in the epidermis in close association with an immature dendritic cell (DC), the Langerhans cell. Because long-term in vitro culture of CTCL cells has proven difficult, the in vivo association with the major antigen-presenting cell (APC) of the epidermis has been postulated to play a role in directly stimulating the clonal T-cell proliferation. We report that CTCL cells can be reproducibly grown in culture for 3 months when cocultured with immature DCs. CTCL cells retain the phenotype and genotype of the initial malignant clone, whereas the APCs are a mixture of immature and mature DCs. CTCL cell and DC survival was dependent on direct membrane contact. Growth was inhibited by antibodies that bound to the T-cell receptor (TCR) or interfered with the interaction of CD40 with its ligand on the CTCL cell. Addition of antibody to CD3 or the clonotypic TCR caused rapid CTCL cell apoptosis followed by engulfment by avidly phagocytic immature DCs and subsequent DC maturation. The opportunity to study CTCL cells and immature DCs for prolonged periods will facilitate studies of tumor cell biology and will allow investigation of the intriguing hypothesis that CTCL cell growth is driven through TCR recognition of class II-presented self-peptides. In addition, the culture of CTCL cells will permit evaluation of therapies in vitro before clinical intervention, thereby improving safety and efficacy.