Development of Gleevec for TB and TB/HIV

开发治疗结核病和结核病/艾滋病毒的格列卫

基本信息

批准号：
9040684
负责人：
GREGORY P. BISSON
金额：
$ 60万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040684
关键词：
ABL1 gene Adult Africa South of the Sahara African Animal Model Animals Antibiotic Resistance Antibiotics Antigen Presentation Antineoplastic Agents Autophagocytosis Blood Blood Flow Cytometry Botswana Cell Count Cells Chronic Myeloid Leukemia Clinical Clinical Trials Communicable Diseases Country Data Dependence Development Disease Dose Drug Interactions Drug Kinetics Drug Monitoring Drug resistance in tuberculosis Drug usage Drug-sensitive Emergency Situation Emergency response Epidemic European Evaluation Experimental Designs Extreme drug resistant tuberculosis FDA approved Fibrosis Funding Gastrointestinal Stromal Tumors Genus Mycobacterium Gleevec Goals HIV HIV Infections HIV-1 Hand Hematologist Hematopoiesis Hematopoietic Hematopoietic stem cells Human Imatinib mesylate Immune Immune response Immunologics Immunologist Immunosuppressive Agents Immunotherapy Individual Infection Lung Macaca Macaca mulatta Malignant Neoplasms Measures Modeling Monitor Multi-Drug Resistance Multiple drug resistant Mycobacteria Tuberculosis Mus Mycobacterium Infections Mycobacterium tuberculosis Myelogenous Myeloid Cells Myelopoiesis Outcome Pathology Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Population Property Protein Tyrosine Kinase Proto-Oncogene Protein c-kit Publishing Pulmonary Tuberculosis Recording of previous events Regimen Resistance SIV Safety Serum Severe Adverse Event Sputum Stem cell transplant Testing Therapeutic Therapeutic Agents Time Toxic effect Translational Research Tuberculosis United States University Hospitals Vulnerable Populations aerosolized antiretroviral therapy base c-abl Proto-Oncogenes co-infection cohort combat design dosage drug metabolism healthy volunteer immune function improved in vivo interest killings macrophage nonhuman primate pathogen patient population pharmacokinetic model pre-clinical public health relevance research study response safety study success trafficking tuberculosis treatment volunteer

项目摘要

DESCRIPTION (provided by applicant): With existing anti-tubercular therapies, treatment success rates for multi- and extensively-drug resistant tuberculosis (MDR-TB, XDR-TB) are dismal, highlighting the urgent need for new drugs. Gleevec (imatinib mesylate), a cancer drug used in humans for chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GISTs), is a potential "host- directed therapeutic (HDT)" for drug resistant TB infections and HIV/TB co-infections. Gleevec inhibits c-Abl tyrosine kinase (TK), which is dys-regulated in CML, as well as related TKs (e.g. c-Kit). Gleevec is well tolerated, with few severe adverse events and little toxicity, especially at low doses. In animal models, Gleevec facilitates clearanc of Mycobacterium tuberculosis (Mtb), by disrupting the cellular mechanisms that Mtb uses for entry and survival in host cells, and stimulates "emergency hematopoiesis," a host immune response to infection that mobilizes myeloid cell populations, but which is suppressed by Mtb. Gleevec acts synergistically with antibiotics, is effective against antibiotic-resistant mycobacteria, and may be less likely to engender resistance compared to antibiotics. Finally, Gleevec is also effective against other co-morbid infections such as HIV-1. Our proposal seeks to: (1) develop preclinical data on efficacy of Gleevec in a non-human primate (NHP) model of infection with TB and TB/SIV that mimic poorly controlled HIV/TB in humans; (2) determine safety and immunological responses at low doses in normal individuals in the United States, and in patients with previously treated pulmonary TB, including those infected with HIV; (3) determine the safety and microbiologic efficacy of Gleevec administered over 2 months to adults treated with optimized background MDR-TB regimens, including HIV-infected patients on ART. We will measure the time to sputum culture conversion, immunological parameters associated with myelopoeisis and pathogen-specific immune function. Deepak Kaushal (Tulane) will evaluate TB and TB/SIV infection for the UH2 portion. For the UH3, Daniel Kalman, (Emory), who has pioneered Gleevec as an HDT for infectious diseases including TB, and Edmund Waller (Emory), a hematologist, specializing in hematopoietic progenitor cell transplantation and immunotherapy, will evaluate the safety and immunologic effects (increased myelopoiesis) of low dose Gleevec in US subjects; Gregory P. Bisson (U. Penn), a TB immunologist who directs a clinical translational research unit in Botswana, will conduct dosing and safety studies in adults with treated pulmonary TB and a trial of Gleevec in adults with active MDR-TB, including those with HIV; and Tawanda Gumbo (Baylor), a pharmacometrician, will evaluate and model PK/PD parameters in normal and infected patient populations in the US and Botswana to guide dosing. Our experimental design will assess immunologic efficacy, toxicity, as well as pharmacology and drug interactions, and will evaluate microbiologic efficacy in patients with active MDR-TB. More broadly, these data will provide a paradigm with which to further evaluate Gleevec or other immunomodulatory HDTs as therapeutics for TB infection and HIV/TB co-infection.

描述（由适用提供）：对于现有的抗结核疗法，多种抗药性结核病（MDR-TB，XDR-TB）的治疗成功率令人沮丧，突显了对新药的迫切需求。 Gleevec（伊马替尼梅赛酸盐）是一种用于人类的癌症药物，用于慢性粒细胞性白血病（CML）和胃肠道间质肿瘤（GISTS），是一种潜在的“宿主指导治疗（HDT）”，用于药物抗药性TB感染和HIV/TB联合感染。 Gleevec抑制在CML中调节的C-Abl酪氨酸激酶（TK）以及相关的TK（例如C-KIT）。 Gleevec的耐受性很好，严重的不良事件和毒性很少，尤其是在低剂量下。在动物模型中，Gleevec通过破坏MTB用于进入和生存的细胞机制来促进结核分枝杆菌（MTB）的清晰度，并刺激“紧急造血症”，并刺激了一种宿主免疫，以感染了感染的骨液细胞群体，但受到骨髓细胞群体的抑制，但已被MTB抑制。 Gleevec与抗生素协同作用，有效地抵抗抗生素耐药性分枝杆菌，与抗生素相比，可能会产生耐药性。最后，Gleevec还有效地针对其他合并症感染（例如HIV-1）。我们的提议试图：（1）在非人类灵长类动物（NHP）中使用TB和TB/SIV感染的临床前数据，以模仿人类中控制不良的HIV/TB；（2）确定美国正常个体的低剂量的安全性和免疫反应，以及先前治疗的肺结核患者，包括感染HIV的患者；（3）确定Gleevec在2个月内对接受优化背景MDR-TB治疗的成年人（包括HIV感染的ART患者）进行的2个月内服用的Gleevec的安全性和微生物学有效性。我们将测量痰培养转化的时间，与骨髓病和病原体特异性免疫功能相关的免疫学参数。 Deepak Kaushal（Tulane）将评估UH2部分的TB和TB/SIV感染。对于UH3，丹尼尔·卡尔曼（Daniel Kalman）（Emory），他将Gleevec作为传染病的HDT开创性，包括结核病（TB）和血液学家Edmund Waller（Emory），专门从事造血祖细胞细胞移植和免疫疗法的专门研究，将评估Myelololopic效应（较低的plowe sose inseelopoies and Myelopoies and Isesies and），并及时;指挥博茨瓦纳临床翻译研究单元的结核病学家格雷戈里·贝森（Gregory P.药剂师师Tawanda Gumbo（Baylor）将在美国和博茨瓦纳正常和感染的患者人群中评估和模型PK/PD参数，以指导剂量。我们的实验设计将评估免疫效率，毒性以及药理和药物相互作用，并评估活性MDR-TB患者的微生物效率。更广泛地说，这些数据将提供一个范式，以进一步评估Gleevec或其他免疫调节HDTS作为结核病感染和HIV/TB共感染的治疗。