Antifungal chemotherapies and immunotherapies for the future.

Abstract

Human fungal pathogens cause a broad plethora of infections, spanning cutaneous dermatophytoses to invasive infections in immunocompromised hosts. As eukaryotic pathogens are capable of morphotype switching, they present unique challenges both for drug development and the immunological response. Whilst current antifungal therapies are limited to the orally available triazoles, intravenous echonocandins and polyenes, and flucytosine and terbinafine, there has been recent significant progress in the antifungal armamentorium with ibrexafungerp, a novel orally available terpanoid that inhibits 1,3-beta-D-glucan-approved by Food and Drug Administration in 2021, and fosmanogepix, an orally available pro-drug of manogepix, which targets glycosylphosphatidylinositol-anchored protein maturation entering Phase 3 studies for candidaemia. A number of further candidates are in development. There has been significant use of existing immunotherapies such as recombinant interferon-γ and G-CSF for fungal disease in immunocompromised patients, and there are emerging opportunities for monoclonal antibodies targeting TH2 inflammation. Omalizumab, an anti-IgE monoclonal antibody in asthma, is now used routinely for the treatment of allergic bronchopulmonary aspergillosis, and further agents targeting IL-4 and IL-5 are being evaluated. In addition, T-cell CAR therapy is showing early promise for fungal disease. Thus, we are likely to see rapid advances to our approach to the management of fungal disease in the near future.