Immuno-protection and adjunctive therapeutic efficacy of nebulized pattern recognition receptor agonists in immunosuppressed mice with mold pneumonia

About This Grant

PROJECT SUMMARY Despite significant improvements in early diagnosis and expansion of the anti-infective armamentarium, pneu- monia remains the most common and most lethal infection in highly immunosuppressed patients. In particular, pneumonias due to opportunistic molds such as Aspergillus and Mucorales species are major causes of mor- bidity and mortality, with death rates up to 50% at 6 weeks post diagnosis in high-risk patients. As outcomes are mainly host-driven, delivering effective, safe, and timely immunomodulatory interventions to address im- mune deficits has become the “Holy Grail” of modern medical mycology. Specifically, deployment of locally de- livered (inhaled) immunomodulators with broad activity against multiple classes of pathogenic molds and even bacterial and viral co-infections would present a unique, pathogen-agnostic opportunity for prophylactic and therapeutic immunomodulation. Extensive preclinical and clinical studies have demonstrated the remarkable efficacy of nebulized Pam2/ODN, an innovative dyad of synergistic pattern recognition receptor agonists, to protect against a wide array of known and novel respiratory pathogens in both healthy and vulnerable host conditions with excellent safety and tolerability profiles. Its broad activity and predominantly epithelium-targeted mechanism that reduces reli- ance on leukocyte-driven immunity position Pam2/ODN as an ideal candidate to protect severely immunocom- promised hosts from opportunistic molds and pulmonary co-pathogens. This R21/R33 project will provide comprehensive preclinical data on the largely unexplored potential of nebu- lized adjunctive immunomodulatory interventions against mold pneumonias and polymicrobial lung infections. The R21 phase will focus on proof-of-concept experiments in immunosuppressed mice with invasive pulmo- nary aspergillosis and mucormycosis to define the benefit of adjunct Pam2/ODN in clinically relevant prophy- lactic (Aim 1) and therapeutic (Aim 2) scenarios, with and without concomitant posaconazole. The R33 phase will expand these studies through optimization of Pam2/ODN dosing regimens and characterization of time- lines and mechanisms of immune protection (Aim 3), validation of immuno-protective activity against additional mold isolates including rare recalcitrant molds that are frequently resistant to antifungals (Aim 4), and testing of Pam/2ODN in mice with mixed fungal & bacterial or fungal & viral pneumonia (Aim 5). This project will rigorously integrate several preclinical scenarios that uniquely represent critical real-world clini- cal challenges to advance prophylactic and therapeutic immunomodulation with nebulized Pam2/ODN in medi- cal mycology. Given the readily available clinical-grade formulation of Pam2/ODN (PUL-042), existing safety data in cancer patients, and potent clinical trial infrastructure at MD Anderson Cancer Center, this novel ap- proach holds significant promise for rapid clinical translation upon completion of R21/R33 funding.