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: 10524878
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524878
• 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; Cancer Patient; Cells; Chemotherapy-Oncologic Procedure; Clinical; Combined Modality Therapy; Communicable Diseases; Complication; Cytarabine; Cytotoxic Chemotherapy; Development; Frail Elderly; Fright; Future; Goals; Gold; Hematologic Neoplasms; Histopathology; Host Defense; Human; Immune; Immune System Diseases; Immune checkpoint inhibitor; Immune response; Immunity; Immunologics; Immunotherapeutic agent; Immunotherapy; Infection; Leukocytes; Lung; Medical; Mission; Modeling; Molds; Mononuclear; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; New Agents; Outcome; Outcome Study; PD-1 blockade; PD-1 pathway; PD-1/PD-L1; PD-L1 blockade; PDL1 inhibitors; Patients; Pharmacology; Physiological; 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; bench to bedside; 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; 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 侵袭性肺曲霉病（IPA）是血液系统恶性肿瘤患者常见且令人担忧的并发症， 特别是接受诱导缓解化疗（RIC）的急性髓系白血病（AML）患者。 在严重免疫功能障碍的背景下，传统抗真菌药物的疗效有限，长期目标是开发 简便的免疫治疗策略可改善机会性侵袭性霉菌感染的结果。 该领域的临床前研究受到阻碍，这导致了抗真菌药物的实验室/床边相当大的脱节。 免疫疗法是对药物免疫抑制但其他方面健康的啮齿动物模型的依赖，这些模型不能 概括了由活动性血液恶性肿瘤和化疗引起的复杂的免疫改变。 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 因此，肿瘤免疫疗法对抗霉菌免疫的潜在“脱靶益处”。 该 R03 项目的目标是在 AML 背景下开发小鼠 IPA 感染模型，并研究作为原理证明， 先前提出的“双重打击假设”，即当 ICI 作为白血病 RIC 的一部分给予时，可能会同时出现 增强宿主对霉菌的防御并改善 IPA 的结果，从而使 RIC 复杂化 在目标 1a 中，简单且有效。 经济高效的同基因 C1498 AML 小鼠模型将通过 com- 在 RIC 期间进行 IPA 研究进行调整和优化 降低感染不同烟曲霉分生孢子的白血病小鼠的发病率、死亡率和真菌负荷 在使用阿糖胞苷的传统高强度化疗或使用阿糖胞苷的低甲基化化疗期间接种 在目标 1b 中，将通过证明 5-氮杂胞苷的保护活性来验证模型作为治疗平台的效果。 伏立康唑，一线曲霉活性抗真菌剂。在目标 2 中，新开发的模型将用于 比较 IPA 的发病率/死亡率和对烟曲霉感染的关键免疫反应（例如，烟曲霉中的细胞因子谱） 血清和肺组织、适应性免疫的极化、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 阻断的情况下，在 RIC 低甲基化过程中产生 IPA 的小鼠中。 所提出的研究具有创新性，因为它引入了使用白血病模型来研究肿瘤的影响的概念新颖性。 IPA 免疫病理学的逻辑疗法一旦建立，该临床前平台将提供宝贵的价值。 抗真菌免疫疗法、新型抗真菌药物以及新型抗真菌药物的影响的未来研究资源 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个主要方面。 可交付成果，(i) AML 小鼠中病理生理学相关的 IPA 感染模型，旨在设定新的 抗白血病治疗期间机会性霉菌感染的临床前研究的“金标准”，(ii) 比较 确定 PD-1 通路抑制剂（作为抗白血病化疗的一部分）对 IPA 的保护作用 在患有潜在 AML 的小鼠中，以及 (iii) 对与 IPA 的有利结果相关的免疫特征进行评估 患有 AML 的小鼠，可以为未来的人类生物标志物和免疫治疗研究提供信息。