1,720,981 research outputs found
The therapeutic use of antibodies for malignancy
No full textThe idea of using the specificity of antibodies to target malignant cells was put forward very soon after the discovery of techniques to generate monoclonal reagents. The responses seen with mouse anti-idiotype in patients with B-cell lymphomas indicated the potential of this approach, but it was some years before key technical obstacles were overcome and the more widespread application of these therapies became possible. Whilst they were originally conceived as having an immunotherapeutic effect, it has become clear that recruitment of immune effectors is only one component of successful antibody therapy, and their action upon the cellular target, either blocking or agonistic, is also critical. The development of immunoconjugates to deliver toxins or radiation is a further extension of the approach, and here again the intracellular effect of antibody ligation appears to be crucial. This presentation will address the central theme of antibody treatments for malignancy that are now reaching the clinic, and will use these examples to highlight ways in which antibodies may be acting in vivo
Differential regulation of cell survival by CD40
No full textThe CD40 cell surface receptor is required for normal function of the immune system and is a positive regulator of cell survival for normal B-lymphocytes. However, there is evidence to support both pro- and anti-apoptotic functions for CD40 in malignant B-cells and epithelial cancers. There is increasing interest in the potential of CD40 activating agents as novel therapies for cancer and it is essential to understand the differential response of malignant cells, to inform the design of trials. Here we review the current understanding of differential responses to CD40 activation and apoptosis controlling proteins regulated by CD40 that might account for these effects
Therapeutic potential of immunostimulatory monoclonal antibodies
No full textThe aim of cancer immunotherapy is to employ the specificity of the immune system to provide a more effective, less toxic, treatment compared with conventional therapies. Although many strategies have been used to try to generate effective anticancer immune responses, very few have reached mainstream clinical use. A new approach introduced over the last few years is to use immunostimulatory mAbs (monoclonal antibodies) to boost weak endogenous antitumour immune responses to levels which are therapeutic. Such agonistic or antagonistic mAbs bind to key receptors in the immune system acting to enhance antigen presentation, provide co-stimulation or to counteract immunoregulation. In animal models, this approach has been shown to promote powerful tumour-specific T-cell responses capable of clearing established tumour and leaving the animal with long-term immunity. In addition to this impressive therapy seen in tumour models, these same mAbs also have the potential to be therapeutically useful in autoimmune and infectious diseases. This review discusses the use of these mAbs as therapeutic agents, their advantages and disadvantages and the challenges that need to be overcome to use them clinicall
Initial dose intensity has limited impact on the outcome of ABVD chemotherapy for advanced Hodgkin's Lymphoma (HL): Data from UKLG LY09 (ISRCTN97144519)
No full textBackground. Response-adjusted therapy is attractive in the treatment
of HL, to avoid over-treatment of patients with a good prognosis and to
maximise the chance of cure. However, it is not clear whether the intensity
of initial therapy prior to early response assessment is critical to the
outcome, or whether subsequent intensification may compensate for
less intense initial treatment. We investigated whether dose intensity in
the first two cycles of standard ABVD chemotherapy is predictive of progression-
free survival (PFS).Methods. Data for 379 eligible patients allocated to receive ABVD in
the UKLG LY09 trial and who received at least two cycles of chemotherapy
were included. All patients were planned to have 6 cycles of
chemotherapy, extended to 8 where there was evidence of continuing
response at 6. Growth factor support was permitted following delays or
reductions in treatment. Radiotherapy was recommended for residual
masses or at the sites of prior bulk disease. Patients were recruited
between 1998 and 2002 with median follow-up of 52 months. Observed
dose was standardised by dividing by expected dose for the first two
cycles. Dose intensity was defined as standardised dose divided by
[observed duration for two cycles divided by expected duration for two
cycles]. These were calculated separately for doxorubicin, bleomycin,
dacarbazine and vinblastine and averaged. Landmark analyses were
timed from the start of cycle 3. The analyses include 96 PFS events: disease
progression or death from HL.Results. 93/397 (25%) of patients received treatment at >97% intended
DI (averaged across all 4 drugs) for cycles 1-2, whilst 137 (37%)
received 86-97% and 147 (39%) less than 86%. Dose and dose intensity
in cycles 1-2 correlated well with dose and dose intensity in the
remaining cycles 3-6 for all drugs. There was no good evidence from
unadjusted univariate analyses of the four drugs individually and their
average, that higher dose intensity in the first two cycles was associated
with better PFS. Adjusting for baseline IPI score, the strongest effect of a 10% increase in DI in cycles 1-2 was from Doxorubicin. This was associated
with a hazard ratio of 0.90 (95%CI 0.78, 1.02); bleomycin HR=0.90
(95%CI 0.78, 1.05), dacarbazine HR=0.92 (95%CI 0.79, 1.06), vinblastine
HR=0.94 (95%CI 0.81, 1.09). Among 82 patients who had cycles 3-6
delivered at over 97% DI on average, patients who received average DI
below 86% in cycles 1-2 had the same long-term PFS as those patients
who received average DI over 97% in cycles 1-2. Poorer DI in cycles 1-2
was associated with increased use of G-CSF during subsequent cycles.Discussion. We have found no evidence of improved PFS with higher
dose intensity in the first two cycles of ABVD. This is a non-randomised
comparison and caution is needed in the interpretation of such retrospective
data. However, the data comes from a large cohort of patients following
a standard treatment regimen, ABVD, in the context of a randomised
controlled trial. It is possible that following initial low dose
intensity, growth factors were effectively used to restore the efficacy of
treatment and/or chemotherapy was continued for more cycles and/or
consolidation radiotherapy used. This does not appear to support the
introduction of a policy of maximising initial dose intensity without
testing in a further prospective study
Intestinal strictures: a new complication of treatment for primary gastrointestinal diffuse large B-cell lymphoma
No full text
Will histone deacetylase inhibitors require combination with other agents to fulfil their therapeutic potential?
No full textHistone deacetylase inhibitors have progressed rapidly from the laboratory to clinical testing. This review highlights the promising data for their combination with a wide range of established and novel anticancer agents and discusses the mechanisms that underpin these interactions
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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