RESUMO
The efficacy of immune checkpoint inhibitors has been shown to depend on preexisting antitumor immunity; thus, their combination with cancer vaccines is an attractive therapeutic approach. Plasmacytoid dendritic cells (PDC) are strong inducers of antitumor responses and represent promising vaccine candidates. We developed a cancer vaccine approach based on an allogeneic PDC line that functioned as a very potent antigen-presenting cell in pre-clinical studies. In this phase Ib clinical trial, nine patients with metastatic stage IV melanoma received up to 60 million irradiated PDC line cells loaded with 4 melanoma antigens, injected subcutaneously at weekly intervals. The primary endpoints were safety and tolerability. The vaccine was well tolerated and no serious vaccine-induced side effects were recorded. Strikingly, there was no allogeneic response toward the vaccine, but a significant increase in the frequency of circulating anti-tumor specific T lymphocytes was observed in two patients, accompanied by a switch from a naïve to memory phenotype, thus demonstrating priming of antigen-specific T-cells. Signs of clinical activity were observed, including four stable diseases according to IrRC and vitiligoïd lesions. Four patients were still alive at week 48. We also demonstrate the in vitro enhancement of specific T cell expansion induced by the synergistic combination of peptide-loaded PDC line with anti-PD-1, as compared to peptide-loaded PDC line alone. Taken together, these clinical observations demonstrate the ability of the PDC line based-vaccine to prime and expand antitumor CD8+ responses in cancer patients. Further trials should test the combination of this vaccine with immune checkpoint inhibitors.
Assuntos
Vacinas Anticâncer , Melanoma , Células Dendríticas , Humanos , Imunidade , Melanoma/terapia , Linfócitos TRESUMO
INTRODUCTION: Islet transplantation may be an appropriate treatment option for patients with severely unstable type 1 diabetes experiencing major glucose variability with severe hypoglycaemia despite intensive insulin therapy. Few data are available on the costs associated with islet transplantation in relation to its benefits. The STABILOT study proposes to assess the economic impact of islet transplantation in comparison with the current best medical treatment defined as sensor-augmented pump (SAP) therapy. METHODS: The trial will adopt an open-label, randomised, multicentred design. The study will include 30 patients with severely unstable type 1 diabetes. Eligible participants will be 18-65â years old, with type 1 diabetes duration >5â years, a negative basal or stimulated C-peptide, and severe instability defined by persistent, recurrent and disabling severe hypoglycaemia, despite optimised medical treatment. Participants will be randomised into two groups: one group with immediate registration for islet transplantation, and one group with delayed registration for 1â year while patients receive SAP therapy. The primary endpoint will be the incremental cost-utility ratio at 1â year between islet transplantation and SAP therapy. Perspectives of both the French Health Insurance System and the hospitals will be retained. ETHICS AND DISSEMINATION: Ethical approval has been obtained at all sites. The trial has been approved by ClinicalTrials.gov (Trial registration ID NCT02854696). All participants will sign a free and informed consent form before randomisation. Results of the study will be communicated during national and international meetings in the field of diabetes and transplantation. A publication will be sought in journals usually read by physicians involved in diabetes care, transplantation and internal medicine. TRIAL REGISTRATION NUMBER: NCT02854696; Pre-results.
Assuntos
Diabetes Mellitus Tipo 1/terapia , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina , Transplante das Ilhotas Pancreáticas/economia , Transplante das Ilhotas Pancreáticas/métodos , Adolescente , Adulto , Idoso , Técnicas Biossensoriais , Análise Custo-Benefício , Diabetes Mellitus Tipo 1/complicações , Feminino , França , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Regressão , Projetos de Pesquisa , Resultado do Tratamento , Adulto JovemRESUMO
Advances in lung transplantation allow the women of childbearing age to consider becoming mothers. When planning to become pregnant, a therapeutic drug management of immunosuppressive drugs and associated therapies is required. It must take into account teratogenic and fetotoxic drugs, as well as pharmacokinetic changes encountered during pregnancy. Increasingly data are currently available on the management of immunosuppressive drugs and associated therapies during pregnancy. We report the case management of drug therapy before and during pregnancy in two patients after a lung or heart-lung transplantation. To prevent the emergence of complications for mother and child, a literature review has been necessary to manage drug therapies of each patient.
Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Imunossupressores/uso terapêutico , Transplante de Pulmão , Complicações na Gravidez/tratamento farmacológico , Anormalidades Induzidas por Medicamentos/prevenção & controle , Cesárea , Contraindicações , Fibrose Cística/complicações , Feminino , Retardo do Crescimento Fetal/etiologia , Feto/efeitos dos fármacos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Pravastatina/farmacocinética , Pravastatina/uso terapêutico , Pré-Eclâmpsia/cirurgia , Gravidez , Complicações na Gravidez/metabolismo , Gravidez em Diabéticas/tratamento farmacológico , Adulto JovemRESUMO
Advances in lung transplantation allow the women of childbearing age to consider becoming mothers. When planning to become pregnant, a therapeutic drug management of immunosuppressive drugs and associated therapies is required. It must take into account teratogenic and fetotoxic drugs, as well as pharmacokinetic changes encountered during pregnancy. Increasingly data are currently available on the management of immunosuppressive drugs and associated therapies during pregnancy. We report the case management of drug therapy before and during pregnancy in two patients after a lung or heart-lung transplantation. To prevent the emergence of complications for mother and child, a literature review has been necessary to manage drug therapies of each patient.
RESUMO
Gefitinib and erlotinib are selective epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor. They are approved for the treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating mutations of EGFR-TK. We report the case of a hepatitis cytolytic during gefitinib treatment with a positive rechallenge. A relay by erlotinib has been initiated and doesn't give recurrence of hepatotoxicity. From a literature review and this observation, arguments have been provided to justify erlotinib as a safe and well-tolered alternative for patients who have to stop gefitinib after a severe hepatotoxicity.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/efeitos adversos , Quinazolinas/uso terapêutico , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Doença Hepática Induzida por Substâncias e Drogas/terapia , Substituição de Medicamentos , Cloridrato de Erlotinib , Gefitinibe , Humanos , Neoplasias Pulmonares/patologia , MasculinoRESUMO
BACKGROUND: The potential interest of antifungal treatment of non-immunocompromized patients with sepsis, extra-digestive Candida colonization and multiple organ failure is unknown. It represents three-quarters of antifungals prescribed in Intensive Care Units. It may allow early treatment of invasive fungal infection in the incubation phase but expose patients to unnecessary antifungal treatments with subsequent cost and fungal selection pressure. As early diagnostic tests for invasive candidiasis are still considered to be insufficient, the potential interest in this strategy needs to be demonstrated. METHODS: This prospective multicenter, double blind, randomized-controlled trial is conducted in 23 French Intensive Care Units. All adult patients, mechanically ventilated for more than four days with sepsis of unknown origin and with at least one extradigestive fungal colonization site and multiple organ failure are eligible for randomization. Patients with proven invasive candidiasis are not included. After a complete mycological screening, patients are allocated to receive micafungin 100 mg intravenously once a day or placebo for 14 days. We plan to enroll 260 patients. The main objective is to demonstrate that micafungin increases survival of patients without invasive candidiasis at day 28 as compared to placebo. Other outcomes include day 28 and 90 survival and organ failure evolution. Additionally, pharmacokinetics of micafungin in enrolled patients will be measured and evolution of fungal biomarkers and susceptibility profiles of infecting fungi will also be followed. DISCUSSION: This study will help to provide guidelines for treating non-immunocompromized patients with fungal colonization multiple organ failure and sepsis of unknown origin. TRIAL REGISTRATION: Clinicaltrials.gov number NCT01773876.