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

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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.