Development of Gleevec for TB and TB/HIV

 描述(由申请人提供)：在现有的抗结核疗法下，耐多药和广泛耐药结核病(耐多药结核病、广泛耐药结核病)的治疗成功率令人沮丧，突显了对新药的迫切需要。格列卫(甲磺酸伊马替尼)是一种用于人类治疗慢性粒细胞白血病(CML)和胃肠道间质瘤(GIST)的抗癌药物，是一种潜在的用于耐药结核病感染和HIV/TB混合感染的“宿主导向治疗(HDT)”。格列卫可抑制c-Abl酪氨酸激酶(TK)及其相关的TKs(如c-Kit)。格列卫耐受性良好，严重不良反应很少，毒性很小，特别是在低剂量时。在动物模型中，格列卫通过破坏结核分枝杆菌(Mtb)进入宿主细胞并在宿主细胞中生存的细胞机制，促进结核分枝杆菌(Mtb)的清除，并刺激“紧急造血”，这是一种宿主对感染的免疫反应，动员髓系细胞群体，但Mtb抑制这种反应。格列卫与抗生素具有协同作用，对耐药分支杆菌有效，与抗生素相比，可能不太可能产生耐药性。最后，格列卫对HIV-1等其他共病感染也有效。我们的建议旨在：(1)在模拟人类感染艾滋病毒/结核病的非人灵长类动物(NHP)感染模型中开发格列卫疗效的临床前数据；(2)确定在低剂量下对美国正常人以及以前治疗过的肺结核患者(包括那些感染艾滋病毒的患者)的安全性和免疫学反应；(3)确定格列卫对经过优化背景MDR-TB方案治疗的成年人(包括接受ART治疗的艾滋病毒感染患者)2个月以上的安全性和微生物学疗效。我们将测量痰培养转换时间、与骨髓生成相关的免疫学参数和病原体特异性免疫功能。Deepak Kaushal(杜兰)将评估UH2部分的结核病和结核病/SIV感染。对于UH3，丹尼尔·卡尔曼(Emory)和埃德蒙·沃勒(Edmund Waller)将在美国受试者中评估低剂量格列卫的安全性和免疫学效果(增加骨髓生成)；格列卫是治疗包括结核病在内的传染病的HDT的先驱，埃德蒙·沃勒(Emory)是血液学家，专门从事造血祖细胞移植和免疫治疗；在博茨瓦纳领导一个临床转化研究单位的结核病免疫学家格雷戈里·P·比森(U·Penn)将在成人接受治疗的肺结核患者中进行剂量和安全性研究，并在患有多药耐药结核病(包括艾滋病毒患者)的成人中进行格列卫的试验；药物计量学家Tawanda Gumbo(贝勒)将在美国和博茨瓦纳的正常和感染患者群体中评估和建模PK/PD参数，以指导剂量。我们的实验设计将评估免疫疗效、毒性以及药理学和药物相互作用，并将评估活动性耐多药结核病患者的微生物学疗效。更广泛地说，这些数据将提供一个范例，用来进一步评估格列卫或其他免疫调节性HDTS作为治疗结核病感染和艾滋病毒/结核病合并感染的药物。

 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.