Development of Gleevec for TB and TB/HIV

 描述（由申请人提供）：使用现有的抗结核治疗方法，多重和广泛耐药结核病（MDR-TB，XDR-TB）的治疗成功率令人沮丧，突出了对新药的迫切需求。格列卫（甲磺酸伊马替尼）是一种用于人类慢性髓性白血病（CML）和胃肠道间质瘤（GIST）的癌症药物，是一种潜在的耐药TB感染和HIV/TB合并感染的“宿主导向治疗（HDT）”药物。Gleevec抑制c-Abl酪氨酸激酶（TK），其在CML中失调，以及相关TK（例如c-Kit）。格列卫耐受性良好，几乎没有严重的不良反应，毒性也很小，特别是在低剂量下。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存活的细胞机制，促进结核分枝杆菌（Mtb）的清除，并刺激“紧急造血”，这是一种动员骨髓细胞群的宿主对感染的免疫反应，但被Mtb抑制。格列卫与抗生素协同作用，对耐药分枝杆菌有效，与抗生素相比，可能不太可能产生耐药性。最后，格列卫也对其他合并症感染如HIV-1有效。我们的建议旨在：（1）开发关于格列卫在感染TB和TB/SIV的非人灵长类动物（NHP）模型中的疗效的临床前数据，该模型模拟人类中控制不佳的HIV/TB;（2）确定在美国正常个体和先前治疗过的肺TB患者（包括感染HIV的患者）中低剂量的安全性和免疫应答;（3）确定接受优化背景耐多药结核治疗方案治疗的成人（包括接受抗逆转录病毒治疗的HIV感染患者）接受格列卫治疗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化的时间，与骨髓增生相关的免疫学参数和病原体特异性免疫功能。Deepak Kaushal（Tulane）将评价UH 2部分的TB和TB/SIV感染。对于UH 3，丹尼尔卡尔曼，（埃默里大学），谁率先格列卫作为一种HDT的感染性疾病，包括结核病，和埃德蒙沃勒（埃默里大学），血液学家，专门从事造血祖细胞移植和免疫治疗，将评估安全性和免疫效果（增加骨髓）的低剂量格列卫在美国受试者;格雷戈里P。Penn）是一名结核病免疫学家，负责博茨瓦纳的一个临床转化研究单位，他将在接受治疗的肺结核患者中进行剂量和安全性研究，并在活动性耐多药结核患者（包括艾滋病毒感染者）中进行Gleevec试验;药物计量学家Tawanda Gumbo（Baylor）将在美国和博茨瓦纳的正常和感染患者人群中评估和建模PK/PD参数，以指导剂量。我们的实验设计将评估免疫学疗效、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，进一步评估格列卫或其他免疫调节性HDTs作为TB感染和HIV/TB合并感染的治疗剂。

 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.