Development of an acute myeloid leukemia murine model of invasive pulmonary aspergillosis to gain insights into the role of leukemia and its treatments in the pathobiology of aspergillosis

开发侵袭性肺曲霉病的急性髓系白血病小鼠模型，以深入了解白血病及其治疗在曲霉病病理学中的作用

• 批准号: 10622540
• 负责人: DIMITRIOS P KONTOYIANNIS
• 金额: $ 8.1万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622540
• 关键词: Acute Myelocytic Leukemia; Allergic Bronchopulmonary Aspergillosis; Antibodies; Antifungal Agents; Antifungal Therapy; Antigen-Antibody Complex; Applied Research; Area; Aspergillosis; Aspergillus; Aspergillus fumigatus; Azacitidine; Biological Markers; Blocking Antibodies; Cancer Patient; Cells; Chemotherapy-Oncologic Procedure; Clinical; Combined Modality Therapy; Communicable Diseases; Complication; Cytarabine; Cytotoxic Chemotherapy; Development; Frail Elderly; Fright; Future; Goals; Hematologic Neoplasms; Histopathology; Host Defense; Human; Immune; Immune System Diseases; Immune checkpoint inhibitor; Immune response; Immunity; Immunotherapeutic agent; Immunotherapy; Infection; Inflammatory; Leukocytes; Lung; Medical; Mission; Modeling; Molds; Mononuclear; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; New Agents; Oncology; Outcome; Outcome Study; PD-1 blockade; PD-1 pathway; PD-1/PD-L1; PD-L1 blockade; PDL1 inhibitors; Patients; Positioning Attribute; Pre-Clinical Model; Public Health; Regimen; Remission Induction; Remission Induction Therapy; Reporting; Research; Resources; Rodent Model; Role; Serum; Structure of parenchyma of lung; Study models; Testing; The science of Mycology; Therapeutic; Therapeutic Studies; Time; Voriconazole; adaptive immunity; antileukemic agent; chemotherapy; combat; comorbidity; comparative; cost efficient; cytokine; exhaustion; immunopathology; immunosuppressed; improved; improved outcome; inhibitor; innovation; insight; leukemia; leukemia treatment; mortality; mouse model; neutrophil; novel strategies; pharmacologic; pre-clinical; preclinical evaluation; preclinical study; prevent; programmed cell death ligand 1; programmed cell death protein 1; protective effect; recruit; response; stem

PROJECT SUMAMRY Invasive pulmonary aspergillosis (IPA) is a common and feared complication in patients with hematological malignancies, especially patients with acute myeloid leukemia (AML) undergoing remission-induction chemotherapy (RIC). As conven- tional antifungals have limited efficacy in the background of severe immune dysfunction, the long-term goal is to develop facile immunotherapeutic strategies to improve the outcomes of opportunistic invasive mold infections. The critical road- block for preclinical studies in this area, which contributes to the considerable bench/bedside disconnect of antifungal im- munotherapy, is the reliance on pharmacologically immunosuppressed but otherwise healthy rodent models that cannot recapitulate the complex immune alterations caused by an active hematological malignancy and chemotherapy. Moreover, the lack of pathophysiologically relevant IPA infection models in a leukemia background prevents a better understanding of potential “off-target benefits” of oncological immunotherapies on anti-mold immunity. Therefore, the primary objectives of this R03 project are to develop a murine IPA infection model in an AML background and to study, as a proof of principle, the previously proposed “double-hit hypothesis” that ICIs, when given as part of RIC in leukemia, might concomitantly enhance host defense against molds and thereby improve the outcomes of IPA complicating RIC. In Aim 1a, the simple and cost-efficient, syngeneic C1498 AML mouse model will be adapted and optimized for studies of IPA during RIC by com- paring morbidity, mortality, and fungal burden of leukemic mice infected with different Aspergillus fumigatus conidial inoculums during either conventional high-intensity chemotherapy with cytarabine or hypomethylating chemotherapy with 5-azacytidine. In Aim 1b, the model will be validated as a therapeutic platform by demonstrating protective activity of voriconazole, the first-line Aspergillus-active antifungal agent. In Aim 2, the newly developed model will be leveraged to compare morbidity/mortality of IPA and key immunological responses to A. fumigatus infection (e.g., cytokine profiles in serum and lung tissue, polarization of adaptive immunity, immune exhaustion markers, and pulmonary leukocyte recruit- ment) in mice developing IPA during hypomethylating RIC with or without concomitant PD-1/PD-L1 blockade. The pro- posed research is innovative as it introduces the conceptual novelty of using a leukemia model to study the impact of onco- logical therapies on the immunopathology of IPA. Once established, this preclinical platform will provide an invaluable resource for future studies of antifungal immunotherapy, new antifungal agents, and the impact of new classes of anti- leukemia agents on anti-mold immunity in an AML background. The significance of this project stems from its three major deliverables, (i) a pathophysiologically relevant IPA infection model in mice with AML that is positioned to set the new “gold standard” for preclinical studies of opportunistic mold infections during anti-leukemia therapy, (ii) a comparative determination of protective effects of PD-1 pathway inhibitors, given as part of anti-leukemia chemotherapy, against IPA in mice with underlying AML, and (iii) an assessment of immune features that correlate with favorable outcomes of IPA in mice with AML and could inform future human biomarker and immunotherapy studies.

项目总结 侵袭性肺曲霉菌病（IPA）是恶性血液病患者常见且令人担忧的并发症， 尤其是正在接受缓解诱导化疗（RIC）的急性髓性白血病（AML）患者。作为惯例- 传统的抗真菌药物在严重免疫功能障碍的背景下疗效有限，长期目标是开发 简单的免疫策略，以改善机会性侵袭性霉菌感染的结果。关键的道路- 这一领域的临床前研究的障碍，这有助于相当大的实验室/床边分离的抗真菌药物， 免疫疗法，是依赖于免疫抑制，但在其他方面健康的啮齿动物模型， 概括了由活动性恶性血液病和化疗引起的复杂免疫改变。此外，委员会认为， 在白血病背景下缺乏病理生理学相关的IPA感染模型阻碍了更好的理解 肿瘤免疫疗法对抗霉菌免疫的潜在“脱靶益处”。因此，主要目标 该R 03项目的目的是在AML背景下建立小鼠IPA感染模型，并研究，作为原理证明， 先前提出的“双重打击假说”，即ICIs作为RIC的一部分给予白血病时， 增强宿主对霉菌的防御，从而改善IPA并发RIC的结果。在目标1a中， 成本效益，同源C1498 AML小鼠模型将被调整和优化，用于RIC期间的IPA研究， 不同烟曲霉孢子感染白血病小鼠的发病率、死亡率和真菌负荷 在使用阿糖胞苷的常规高强度化疗或使用 5-氮杂胞苷。在目标1b中，将通过证明以下物质的保护活性来验证该模型作为治疗平台： 伏立康唑，一线抗真菌药。在目标2中，将利用新开发的模型， 比较IPA的发病率/死亡率和对A.烟曲霉感染（例如，细胞因子谱 血清和肺组织、获得性免疫极化、免疫耗竭标记物和肺白细胞募集- 在有或没有伴随PD-1/PD-L1阻断的低甲基化RIC过程中，亲- 提出的研究是创新的，因为它引入了使用白血病模型研究肿瘤影响的概念新奇， 对IPA免疫病理学的逻辑治疗。一旦建立，这个临床前平台将提供一个宝贵的 资源为未来的研究抗真菌免疫治疗，新的抗真菌药物，和新的类别的抗真菌药物的影响， 白血病药物对AML背景下抗霉菌免疫的影响。该项目的意义源于其三大 可交付成果，（i）AML小鼠中的病理生理学相关IPA感染模型，该模型被定位为建立新的 抗白血病治疗期间机会性霉菌感染临床前研究的“金标准”，（ii） 作为抗白血病化疗的一部分给予的PD-1通路抑制剂对IPA的保护作用的测定 在患有基础AML的小鼠中，以及（iii）评估与IPA的有利结果相关的免疫特征， 这可能为未来的人类生物标志物和免疫治疗研究提供信息。