F Stevenson

..Clearly, mechanisms of attack vary with the malignancy, the target molecule, and the antibody design, offering opportunities for optimizing this promising strategy...

..These twin problems of engagement of T-cell help and delivery of adequate antigen can now be addressed by applying immunological logic to cancer vaccines...

..Continuing regulatory activity, mediated via autoantigen, could suppress Ig production and lead to disease-associated hypogammaglobulinemia...

..We also have modern assays using surrogate markers of performance to correlate with clinical effects. It is timely to select significant relevant papers to illustrate the growing potential for patients with cancer...

..This induces fast cytotoxic T-cell attack on peptide-expressing tumor cells. Injection of DNA appears safe and clinical trials will test the efficacy of this approach, and probably lead to improvements in these flexible vaccines...

..Vaccination strategies against cancer and against microbes are sharing knowledge and technology for mutual benefit...

..Physical methods including electroporation provide increased expression without introducing additional competing antigens. A wide range of cancers can be targeted, and objective assays of response will determine efficacy...

..Prolongation of remission is the goal and an activated immune system should achieve this...

..There is no evidence so far of toxicity due to injection of DNA, but for antigens which are expressed by normal cells, the line between attack on tumour and autoimmunity will have to be carefully drawn...

..It also has a clear clinical relevance in tracking tumor cells, measuring residual disease, and finally in offering the opportunity of developing vaccines for treatment...

..The critical clinical requirement, however, will be to treat the presenting tumour with maintenance or restoration of immune capacity. We await results of the preliminary clinical trials with great interest...

..Clinical trials of patients with cancer are showing induction of responses, with preliminary indications of suppression of tumor growth and evidence for clinically manageable concomitant autoimmunity...

..The ease of manipulation of gene sequences, together with the increasing knowledge of the operation of the immune system, means that we now have the tools to take vaccines into the next exciting stage of development...

..New inhibitors of BCR signaling appear to have clinical activity. In this Perspective, we discuss the functional significance of the BCR in CLL, and we describe strategies to target BCR signaling as an emerging therapeutic approach...

..The 9G4 antibody therefore provides a simple tool for discrimination between these autoanti-red cell antibodies, which should be of use in red cell serology...

..The principles revealed by using a DNA vaccine have implications for all cancer vaccines designed to induce and maintain antibody responses against weak autologous tumor antigens...

..They also suggest that the elimination of dormant tumor may represent a greater challenge than the elimination of primary tumors...

..These findings relate to the maintenance of memory and have consequences for assessments of specific T-cell responses to vaccination...

..In this chapter, we focus on the analysis of V genes in follicular lymphomas based on the experience in our laboratory and provide a detailed guide for this analysis...

..This chapter describes in detail the methodology for determining V gene usage in CLL, from acquisition of patient sample to generating the V-gene readout...

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..These scFv.FrC DNA vaccines provide protection in myeloma models and are currently in clinical trials. The vaccines are patient specific and can be rapidly assembled for clinical use...

..These safe epitope-specific vaccines offer a potential strategy to prime HA-1- or HA-2-specific CTL in transplant donors before adoptive transfer...

..These results demonstrate a simple strategy to engage anti-microbial T cell help to activate epitope-specific polyclonal CD8(+) T cell responses from a residual tolerized repertoire...

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..Recently, novel delivery systems, especially electroporation, have overcome this translational block. Here, we assess the development, current performance and potential of DNA vaccines for the treatment of cancer...

..Our findings reveal strategies for activating T cells against low-affinity peptides, of potential importance for patients with repertoires narrowed by deletional tolerance...

..Therefore, the establishment and maintenance of public beta-chains in the periphery is predominantly controlled by post-thymic events through modification of the primary, thymus-derived TCR repertoire...

..Transient expression at priming therefore led to a net higher secondary response. In terms of vaccine design, we propose that the most effective DNA-based CD8+ T cell vaccines will be those that deliver a short burst of Ag...

..The remarkable selective glycosylation within the heavy chain V region gene of FL apparently permits only limited processing to oligomannose at somatically mutated motifs, creating a feature exploitable by GC lymphomas...

..These data provide proof of principle for a DNA fusion plasmid strategy as a novel approach to preparing vaccines based on defined, protective epitopes...

..Downstream signaling pathways, therefore, appear intact in CLL, locating anergy to sIgM, mainly in M-CLL. Integration of differential isotype-specific effects mediated by (auto)antigen may determine tumor behavior...

..These findings suggest a potential contribution to lymphoma pathogenesis involving antigen-independent interaction of surface immunoglobulin of the B-cell receptor with mannose-binding molecules of innate immunity in the germinal center...

..Taken together, these results demonstrate that vaccination protocols involving different modes of Ag presentation at prime and boost can significantly improve the effectiveness of immunization...

..Therefore, boosting may not require viral vectors, but simply a physical change in delivery, facilitating application to the cancer clinic...

..The differential properties of the newly described subsets of CLL are also highlighted...

..In contrast, IgM-secreting multiple myeloma arises at a later stage in differentiation, when isotype switch mechanisms have been engaged...

..Patients with MALT lymphoma had a low frequency (9%) of novel sites, comparable to normal B cells. These findings distinguish glycosylation sites from ongoing mutation and may reflect different environmental influences on these tumours...

..These findings support the concept that CLL arises from B cells driven by antigen/superantigen and is not a stochastic event in the elderly B-cell population...

..They may have relevance for escape of human virus-associated malignancies, and raise the question of whether analogous molecules might contribute to the failure of CTL to eliminate tumors...

..These data demonstrate the power of epitope-specific CTL against tumor cells and illustrate a strategy for priming immunity via a dual component DNA vaccine...

..This interaction could leave most of the conventional binding site available for binding other Ags...

..The findings underpin the approach of DNA idiotypic fusion vaccination for patients with B-cell tumours...

..These data support the concept that typical WM is derived from a B cell that has undergone somatic mutation prior to transformation, at a point where isotype switch events have not been initiated. (Blood. 2002;100:1505-1507)..

..This is the first report of a DNA vaccine able to induce anti-idiotypic immunity against TCL, and it presents a simple strategy for selectively eliminating T-cell clones in vivo...

..One possibility is that the added carbohydrate in the variable region contributes to interaction with elements in the germinal center environment. This common feature of FL may be critical for tumor behavior...

..These strategies are particularly important for cancer vaccines to increase their immunogenicity and to overcome tolerance...

..UM MCLs implicate origins from pre-GC B cells and reveal switch events at ectopic sites...

..Both mutational and switching events may be influenced by environmental factors at extrafollicular sites...

..For patients, vaccination could activate a potentially less tolerized repertoire against similar Ags that may be overexpressed by tumor cells, for focused immune attack...

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..In contrast, human eBL development occurs in a GC or post-GC site with a likely contribution to pathogenesis from Epstein-Barr virus (EBV) and other epigenetic factors...

..These data suggest that amplification of the immune response may occur via mechanisms other than VP22-mediated intercellular spread of antigen...

..Additional prospective studies are required for comparing CD38 expression with other prognostic factors and for taking sequential measurements during the course of the disease...

..The results presented show that proteomic analysis can complement other approaches in identifying proteins that may have potential value in the biological and diagnostic distinction between important clinical subtypes of CLL...

..Thus, Mcl-1 insertions are not acquired during leukemogenesis and are unlikely to play an important role in this disease...

..Importantly, because several replacement mutations were located within or close to the complementarity-determining regions (CDRs), it raises the question of a role for antigen in driving tumor growth...

..If so, censoring is bypassed following EBV infection, after which equilibrium is restored. Continuing high serum levels in SLE may arise either by disordered regulation, or by subclinical reactivation of endogenous virus...

..Transformation can occur at either MGUS stage, but it involves a single cell in which somatic mutation is then silent...

..Constitutive AID activation in malignant epithelial cells further raises a potential for inducing aberrant mutational activity...

..Junctional sequences indicate translocation origins from earlier BCL-6 mutations and switch recombinase events...