Project 3

Lundquist Institute For Biomedical Innovation At Harbor-Ucla Medical Center, Torrance CA

Investigators

Abstract

PROJECT SUMMARY Because immune recovery is a crucial determinant of outcome in severely immunocompromised patients with invasive mucormycosis (MCM), the development of facile immune enhancement strategies remains a major unmet need to potentiate the efficacy of antifungal pharmacotherapy and improve MCM outcomes. Specifically, there is a strong interest in readily available and FDA-approved non-cellular immune agents, including immune checkpoint inhibitors, immuno-polarizing cytokines (e.g., interferon-gamma), and hematopoietic growth factors (e.g., GM-CSF). Using a combination of three distinct MCM mouse models (diabetic ketoacidosis, chemother- apy-induced neutropenia, and acute myeloid leukemia) and analyses of clinical samples from cancer patients with MCM (provided by the Clinical Core), Project 3 of MUCOR-ADVANCE seeks to address important con- ceptual gaps of knowledge about MCM-induced immune paralysis and immunotherapy of MCM. To that end, Aim 1 will characterize immune dynamics and the prognostic significance of immune paralysis in cancer patients with MCM compared to high-risk patients without infection and those with invasive aspergillosis (in collaboration with Project 2 and the Gen/Tr Core). These finding will be essential to understand the mechanisms of immune paralysis in MCM patients, cross-validate immune dynamics and markers of immune paralysis uncovered in murine models, prioritize targets for future clinical immunotherapy studies, and identify prognostic immune mark- ers that can be studied with rapid immunoassays. Aim 2 will elucidate synergies of non-cellular immune enhanc- ers with first-line antifungals (liposomal amphotericin B and isavuconazole) in murine MCM models. Combined with comprehensive transcriptomic and immunologic analyses (in collaboration with Project 2 and the Gen/Tr Core), these studies will characterize the mechanisms of pulmonary and systemic immune enhancement, define synergies between immune enhancers and antifungals, compare the efficacy of immunotherapy in mice infected with different Mucorales species, inform biomarkers of therapeutic responses assayable in peripheral blood, and unveil potential off-target toxicities. Aim 3 will then combine the most effective immune enhancers, anti-virulence agents developed by Project 1 (e.g., monoclonal antibodies against Mucoralean toxins), and antifungal therapy for multimodal management of MCM. In-depth studies of both augmented host defense and fungal adaptation to multimodal therapy will provide rich preclinical data to understand and maximize synergies between host- and pathogen-targeted interventions. Building on strong preliminary data, this conceptually innovative and highly collaborative project is expected to yield three significant translational advances: (i) systematic preclinical eval- uation of multimodal MCM therapy, (ii) identification of candidate biomarkers to monitor early responses to mul- timodal therapy, and (iii) thorough characterization of immune paralysis in cancer patients with MCM to inform risk-based targeted application of anti-MCM immunotherapy. Altogether, these pivotal deliverables hold major promise to advance anti-MCM immunotherapy from a “last resort” option toward a mainstream therapy.