Invasive Mykosen – Innovative Therapien

Invasive Pilzerkrankungen sind schwer zu behandeln und stellen eine erhebliche Bedrohung für immungeschwächte Menschen dar. Die derzeitigen antimykotischen Wirkstoffe stoßen an ihre Grenzen, einschließlich zunehmender Resistenzen gegen Antimykotika und unerwünschter Wirkungen. Diese Übersicht soll einen umfassenden Überblick über neue Behandlungsstrategien geben.

Abstract

Invasive fungal diseases (IFD) are difficult to treat and pose a significant threat to immunocompromised individuals. Current antifungal agents face limitations, including antifungal resistance and adverse effects. This review aims to give a comprehensive overview of emerging treatment strategies.

Novel drugs in development are Ibrexafungerp, an orally available triterpenoid inhibiting glucan synthesis, and Rezafungin representing the echinocandins with extended half-life and improved tissue penetration, both recently licensed for certain indications. Fosmanogepix targets glycosylphosphatidylinositol biosynthesis, while Olorofim, an orotomide, inhibits fungal nucleic acid synthesis, both currently assessed in advanced clinical trials.

Immunotherapeutic approaches include immune checkpoint inhibitors to enhance immune response in immunosuppressed individuals and fungal-specific allogeneic CAR-T cell therapy. For prophylactic purpose in high-risk populations to develop IFD, monoclonal antibodies against different virulence factors of Candida spp. have been discovered but are not yet seen in clinical trials. Vaccines against distinct fungal antigens as well as pan fungal vaccines to prevent IFD are under development in preclinical stages, notably for Candida spp., Cryptococcus spp., and Aspergillus spp., however, their clinical value is still discussed.

In summary, major advances to treat IFD have been observed, but challenges for their establishment in the clinical routine persist.

Kernaussagen

• Vier neue Antimykotika befinden sich in der fortgeschrittenen Entwicklung.

• Hiervon sind Ibrexafungerp (ein oral verfügbarer Glucan-Synthase-Inhibitor) und Rezafungin (ein Echinocandin mit sehr langer Halbwertszeit) bereits für einzelne Indikationen zugelassen.

• Dagegen befinden sich Olorofim (ein Dihydroorotat-Synthase-Inhibitor) und Fosmanogepix (ein Glycosylphosphatidylinositol-Inhibitor) in Phase-II/III-Studien.

• Immuncheckpoint-Inhibitoren wurden bereits bei ausgewählten immunsupprimierten Patient*innen mit invasiven Mykosen im Rahmen eines individuellen Heilversuchs als adjuvante, immunstimulierende Therapie angewendet.

• Experimentelle und überwiegend präklinische Ansätze existieren zur Entwicklung von „Off-the-Shelf“-CAR-T-Zell-Konstrukten gegen Infektionen mit A. fumigatus sowie zur prophylaktischen Anwendung von monoklonalen Antikörpern gegen Virulenzfaktoren von Candida spp. und Aspergillus spp. bei Hochrisikopatient*innen und von Vakzinen gegen C. albicans, Cryptococcus neoformans und der chronisch pulmonalen Aspergillose.

Schlüsselwörter

invasive Pilzinfektion - Immuntherapie - monoklonale Antikörper - CAR-T-Zelltherapie

Keywords

invasive fungal diseases - immunotherapy - monoclonal antibodies - CAR-T cell therapy

Publication History

Article published online:
24 April 2024

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