RESUMO
Cancer vaccines are aimed at stimulating an immune response to tumor tissue. There is a high level of clinical activity in this rapidly advancing field with over 1,400 trials registered on Clincaltrials.gov. The recent approval of Sipuleucel-T which is the first cancer vaccine approved in the US and EU has encouraged developers in this field. In contrast to more established approaches for treating cancer such as chemotherapy, regulatory guidelines have been developed relatively recently for cancer vaccines. These guidelines advise on general clinical requirements. As there is an increase in innovative strategies with novel products, a 2-way dialog with regulators is recommended on a case-by-case basis to justify the clinical development plan, taking into account specific quality issues related to the product(s) in development. It is important that the rationale, background and justification for the planned development is convincing when interacting with the regulatory authorities, to enable drug developers and regulators to reach agreement.
Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Ensaios Clínicos como Assunto/normas , Guias como Assunto/normas , Neoplasias/terapia , União Europeia , Humanos , Estados Unidos , United States Food and Drug Administration/normasRESUMO
Although atopic dermatitis generally responds to topical therapy, small numbers of patients have severe resistant disease despite second-line therapies. High-dose intravenous immunoglobulin has been suggested to be of benefit in a small number of reports. We have conducted an open, single-centre study of adjunctive high-dose intravenous immunoglobulin (Flebogamma 5%). Six patients received treatment at 2 g kg(-1) month(-1) for 6 cycles, with a 3-month follow-up period. Skin scores, lymphocyte phenotypes and intracellular cytokine analysis were performed. Four of six patients had major improvements in skin scores and the overall reduction was significant (p = 0.035). CD4+ T-cell numbers fell following high-dose intravenous immunoglobulin infusions, recovering by the next cycle. T-cell CD69 expression decreased to 60% of baseline values. Reductions in the proinflammatory cytokines IFN-gamma and TNF-alpha were non-significant. Adjunctive high-dose intravenous immunoglobulin may be a useful therapeutic approach in adults with severe treatment-resistant atopic dermatitis, but it will require further assessment in randomized controlled trials to establish this.
Assuntos
Citocinas/efeitos dos fármacos , Dermatite Atópica/terapia , Imunoglobulinas Intravenosas/administração & dosagem , Adolescente , Adulto , Contagem de Linfócito CD4 , Citocinas/análise , Dermatite Atópica/diagnóstico , Dermatite Atópica/imunologia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Medição de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: Given the prognostic relevance that the identification of mutated and germline subgroups of chronic lymphocytic leukemia (CLL) has recently acquired we set out to analyze in depth individual VH gene usage rearrangements in patients with mutated and germline CLL. DESIGN AND METHODS: Using sequence analysis of FR1/JH polymerase chain reaction products, the VH immunoglobulin gene configuration was analyzed in 159 rearranged IgH alleles from 154 CLL patients. Having previously identified a spatial relationship between VH gene usage and JH proximity in patients with acute lymphocytic leukemia (ALL), we performed linear and Poisson regression analysis on patients with germline and mutated CLL against VH rearrangements from normal peripheral blood. RESULTS: Sequence analysis showed that 102 patients (64%) had mutated sequences (>2% DNA base pair changes) while 57 (36%) had germline sequences. The germline CLL group showed JH proximal overusage similar to that reported in ALL patients, while the mutated CLL group showed a pattern comparable to that of the control group (peripheral blood rearranged VH sequences). The CDR3 region was statistically longer in the patients with germline CLL than in those with mutated CLL. INTERPRETATION AND CONCLUSIONS: This study highlights differences in the VDJ profile in mutated and germline CLL, consistent with the suggestion that CLL comprises two subgroups. The interpretation of these differences is that the B-cell of CLL, particularly in the germline group, may derive from a pool that has been unable to follow or complete the normal pathway of B-cell differentiation.
Assuntos
Rearranjo Gênico de Cadeia Pesada de Linfócito B , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/genética , Proteínas de Neoplasias/genética , Alelos , Linfócitos B/química , Diferenciação Celular , Estudos de Coortes , Regiões Determinantes de Complementaridade/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Genes de Imunoglobulinas , Humanos , Região de Junção de Imunoglobulinas/genética , Células-Tronco Neoplásicas/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMO
Fas (CD95) plays an important role in apoptosis. Patients with defects in Fas have an autoimmune lymphoproliferative syndrome (ALPS) characterized by lymphadenopathy, autoimmune cytopenias and an increased incidence of lymphomas. There are approximately 70 known cases described worldwide. The autoimmune cytopenias are difficult to treat in this group. We describe a patient with a defect in the death domain of the FAS molecule who had autoimmune thrombocytopenia resistant to conventional therapy but which responded to a combination of rituximab and vincristine.
