RESUMO
Two decades ago, we discovered 'superagonistic' monoclonal antibodies specific for the CD28 molecule which are able to polyclonally activate T cells, in particular regulatory T cells, and are therapeutically active in many rodent models of autoimmunity, inflammation, transplantation, and tissue repair. A phase I trial of the human CD28 superagonist TGN1412 failed in 2006 due to an unexpected cytokine release syndrome, but after it became clear that dose-reduction allows to preferentially address regulatory T cells also in humans, clinical development was resumed under the name TAB08. Here, I recount the story of CD28 superagonist development from a personal perspective with an emphasis on the dramatic events during and after the 2006 phase I trial, the reasons for the failure of preclinical research to warn of the impending cytokine storm, and on the research which allowed resumption of clinical development.
Assuntos
Anticorpos Monoclonais Humanizados/história , Antígenos CD28/agonistas , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/toxicidade , Antígenos CD28/história , Ensaios Clínicos Fase I como Assunto/história , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos/história , Alemanha , Voluntários Saudáveis , História do Século XX , História do Século XXI , Humanos , Londres , Ativação Linfocitária , Meios de Comunicação de Massa/história , Camundongos , Ratos , Linfócitos T Reguladores/imunologia , Falha de TratamentoRESUMO
Radiochemotherapy is undergoing a complete expansion. Currently, possibilities of treatment combination are skyrocketting, with different anticancer and targeted molecules, different radiotherapy techniques, and dose escalation with each therapy. The development of a modern phase I radiochemotherapy trial becomes more and more complex and should be fully investigated. In the literature, there are no exhaustive reviews describing the necessity of their characteristics. The present article explores historical and current phase I clinical trials involving a combination of radiation therapy and anticancer therapies. Selected trials were identified by searching in PubMed databases. A total of 228 studies were identified in the last three decades, and a portrait of their characteristics is presented. As expected, most frequently studied malignancies were head and neck cancers, followed by non-small cell lung cancer and brain cancer. Toxicity is reported in more than 90% of the studies. Most studies were published since 2010, at the area of targeted therapies, but mainly concerned classical chemotherapies (cisplatin and 5-fluorouracil). The present review highlights some limits. Indeed, methodology seems not optimised and could be based on more accurate methods of dose-escalation. The present portrait of phase I radiochemotherapy trials suggests that radiochemotherapy notion must be reinvented and trials should be adapted to its complexity. Step by step method does not sound like an option anymore. Let us build the future of radiochemotherapy on past evidences.
Assuntos
Quimiorradioterapia , Ensaios Clínicos Fase I como Assunto , Neoplasias/terapia , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/história , Quimiorradioterapia/tendências , Ensaios Clínicos Fase I como Assunto/história , História do Século XX , História do Século XXI , Humanos , Neoplasias/mortalidade , Neoplasias/patologia , Doses de Radiação , Resultado do TratamentoRESUMO
The Great East Japan Earthquake of 2011 seriously jeopardized our collaborative research with Professor Masashi Aoki (Tohoku University School of Medicine) on the development of new therapies for amyotrophic lateral sclerosis (ALS) using hepatocyte growth factor. After the earthquake struck, Professor Aoki made a tremendous contribution to saving patients' lives and to recovering from the disastrous situation. Thanks to his strong leadership and support from many reliable colleagues, we could finally start new clinical trials for ALS patients. In this article, I wish to introduce Professor Aoki's heroic efforts.
Assuntos
Ensaios Clínicos Fase I como Assunto/história , Desastres/história , Terremotos/história , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/história , História do Século XXI , Hospitais Universitários/história , Humanos , Japão , Socorro em Desastres/históriaRESUMO
OBJECTIVE: To evaluate the safety and efficacy of a chimeric monoclonal antibody to tumor necrosis factor alpha (TNF alpha) in the treatment of patients with rheumatoid arthritis (RA). METHODS: Twenty patients with active RA were treated with 20 mg/kg of anti-TNF alpha in an open phase I/II trial lasting 8 weeks. RESULTS: The treatment was well tolerated, with no serious adverse events. Significant improvements were seen in the Ritchie Articular Index, which fell from a median of 28 at study entry to a median of 6 by week 6 (P < 0.001), the swollen joint count, which fell from 18 to 5 (P < 0.001) over the same period, and in the other major clinical assessments. Serum C-reactive protein levels fell from a median of 39.5 mg/liter at study entry to 8 mg/liter at week 6 (P < 0.001), and significant decreases were also seen in serum amyloid A and interleukin-6 levels. CONCLUSION: Treatment with anti-TNF alpha was safe and well tolerated and resulted in significant clinical and laboratory improvements. These preliminary results support the hypothesis that TNF alpha is an important regulator in RA, and suggest that it may be a useful new therapeutic target in this disease.
Assuntos
Anticorpos Monoclonais/história , Antirreumáticos/história , Artrite Reumatoide/história , Fator de Necrose Tumoral alfa/história , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/terapia , Ensaios Clínicos Fase I como Assunto/história , Ensaios Clínicos Fase II como Assunto/história , História do Século XX , Humanos , Fator de Necrose Tumoral alfa/imunologiaAssuntos
Distinções e Prêmios , Transplante de Medula Óssea , Efeito Enxerto vs Leucemia , Leucemia Mieloide Aguda/cirurgia , Ensaios Clínicos Fase I como Assunto/história , Ensaios Clínicos Fase II como Assunto/história , Georgia , Efeito Enxerto vs Leucemia/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , História do Século XXI , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Proteínas Recombinantes , Indução de Remissão , Reoperação , Transplante Homólogo , Estados UnidosRESUMO
This review presents a short overview of 25-years of clinical trials by the GHSG for the treatment of primary Hodgkin's Lymphoma. The trials HD1-HD12 that have been conducted between 1978-2002 are reviewed and major results are discussed. Furthermore, the development of the strategies concerning chemo- and radiotherapy for the treatment of Hodgkin's Lymphoma is characterized.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Doença de Hodgkin/terapia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/história , Estudos de Casos e Controles , Ensaios Clínicos Fase I como Assunto/história , Ensaios Clínicos Fase II como Assunto/história , Terapia Combinada/história , Feminino , História do Século XX , História do Século XXI , Doença de Hodgkin/história , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-IdadeAssuntos
Criança , Ensaios Clínicos Fase I como Assunto/ética , Neoplasias/tratamento farmacológico , Experimentação Humana não Terapêutica/ética , Medição de Risco , Ensaios Clínicos Fase I como Assunto/história , Objetivos , História do Século XX , Humanos , Consentimento Livre e Esclarecido , Consentimento dos Pais , Má Conduta CientíficaAssuntos
Antineoplásicos/história , Comitês de Monitoramento de Dados de Ensaios Clínicos/história , Ensaios Clínicos Fase I como Assunto/história , Ensaios Clínicos Fase II como Assunto/história , Neoplasias/história , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Financiamento Governamental/história , Política de Saúde/história , História do Século XX , Humanos , Cooperação Internacional/história , Neoplasias/tratamento farmacológico , Projetos de Pesquisa , Reino UnidoAssuntos
Terapia Genética/história , Experimentação Humana/história , Talassemia beta/história , Animais , Ensaios Clínicos Fase I como Assunto/história , Ensaios Clínicos Fase I como Assunto/normas , Ética Médica/história , Terapia Genética/normas , Globinas/genética , Globinas/uso terapêutico , História do Século XX , Humanos , Camundongos , Modelos Animais , Simplexvirus/enzimologia , Simplexvirus/genética , Tetra-Hidrofolato Desidrogenase/genética , Timidina Quinase/genética , Timidina Quinase/uso terapêutico , Estados Unidos , Talassemia beta/genética , Talassemia beta/terapiaRESUMO
The author provides a historical context for the difficult ethical and clinical issues associated with the inclusion of women and members of minority groups in clinical research. He cites as a point of departure the Nuremberg Code of the late 1940s, which declared the fundamental dignity of human beings involved as research subjects, a principle that was quickly endorsed worldwide. From the period following World War II through the 1970s, the prevailing attitude--not always practiced--toward research subjects in the United States was that they should be protected from exploitation. That attitude was reflected in the first broad federal policy on research subjects, created in 1966. During those years, research was widely regarded by the public as dangerous and of little value to individual participants; it is remarkable that so many men and women consented to participate in clinical studies at that time. Furthermore, during the 1970s, for reasons explained by the author, various events--the abortion debate, disclosures from the infamous Tuskegee syphilis study, Nixon's "war on cancer," new federal regulations in 1974 and 1975 (the latter providing additional protection for pregnant women in research), the broad interpretation of the FDA's 1977 policy excluding pregnant or potentially pregnant women from clinical trials, and the tendency of blacks and persons from other minority groups to shun participation in research--tended to deter participation of women and members of minority groups in clinical research.(ABSTRACT TRUNCATED AT 250 WORDS)