Invasive Mykosen – Innovative Therapien

Zusammenfassung

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:
29 July 2024

• Literatur

• 1 Patterson TF, Thompson 3rd GR, Denning DW. et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 63: e1-e60 DOI: 10.1093/cid/ciw326. (PMID: 27365388)
• 2 Hoenigl M, Seidel D, Sprute R. et al. COVID-19-associated fungal infections. Nat Microbiol 2022; 7: 1127-1140 DOI: 10.1038/s41564-022-01172-2. (PMID: 35918423)
• 3 Mazi PB, Sahrmann JM, Olsen MA. et al. The Geographic Distribution of Dimorphic Mycoses in the United States for the Modern Era. Clin Infect Dis 2023; 76: 1295-1301 DOI: 10.1093/cid/ciac882. (PMID: 36366776)
• 4 Cornely OA, Bassetti M, Calandra T. et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect 2012; 18 (Suppl. 07) 19-37 DOI: 10.1111/1469-0691.12039. (PMID: 23137135)
• 5 Cornely OA, Leguay T, Maertens J. et al. Randomized comparison of liposomal amphotericin B versus placebo to prevent invasive mycoses in acute lymphoblastic leukaemia. J Antimicrob Chemother 2017; 72: 2359-2367 DOI: 10.1093/jac/dkx133. (PMID: 28575414)
• 6 Koehler P, Tacke D, Cornely OA. Bone and joint infections by Mucorales, Scedosporium, Fusarium and even rarer fungi. Crit Rev Microbiol 2016; 42: 158-171 DOI: 10.3109/1040841X.2014.910749. (PMID: 24809926)
• 7 Rodriguez CJ, Tribble DR, Malone DL. et al. Treatment of Suspected Invasive Fungal Infection in War Wounds. Mil Med 2018; 183 (Suppl. 02) 142-146 DOI: 10.1093/milmed/usy079. (PMID: 30189071)
• 8 Stemler J, Mellinghoff SC, Khodamoradi Y. et al. Primary prophylaxis of invasive fungal diseases in patients with haematological malignancies: 2022 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). J Antimicrob Chemother 2023; 78: 1813-1826
• 9 Friedman DZP, Schwartz IS. Emerging Fungal Infections: New Patients, New Patterns, and New Pathogens. J Fungi (Basel) 2019; 5: 67 DOI: 10.3390/jof5030067. (PMID: 31330862)
• 10 Marty FM, Ostrosky-Zeichner L, Cornely OA. et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis 2016; 16: 828-837 DOI: 10.1016/S1473-3099(16)00071-2. (PMID: 26969258)
• 11 Hoenigl M, Sprute R, Egger M. et al. The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin. Drugs 2021; 81: 1703-1729 DOI: 10.1007/s40265-021-01611-0. (PMID: 34626339)
• 12 Hoenigl M, Sprute R, Arastehfar A. et al. Invasive candidiasis: investigational drugs in the clinical development pipeline and mechanisms of action. Expert Opin Investig Drugs 2022; 31: 795-812 DOI: 10.1080/13543784.2022.2086120. (PMID: 35657026)
• 13 Thompson GR 3rd GR, Soriano A, Cornely OA. et al. Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial. Lancet 2023; 401: 49-59 DOI: 10.1016/S0140-6736(22)02324-8. (PMID: 36442484)
• 14 Vazquez JA, Pappas PG, Boffard K. et al. Clinical Efficacy and Safety of a Novel Antifungal, Fosmanogepix, in Patients with Candidemia Caused by Candida auris: Results from a Phase 2 Trial. Antimicrob Agents Chemother 2023; 67: e0141922
• 15 Grimaldi D, Pradier O, Hotchkiss RS. et al. Nivolumab plus interferon-γ in the treatment of intractable mucormycosis. Lancet Infect Dis 2017; 17: 18 DOI: 10.1016/S1473-3099(16)30541-2. (PMID: 27998559)
• 16 Spec A, Shindo Y, Burnham CA. et al. T cells from patients with Candida sepsis display a suppressive immunophenotype. Crit Care 2016; 20: 15
• 17 Keir ME, Butte MJ, Freeman GJ. et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: 677-704 DOI: 10.1146/annurev.immunol.26.021607.090331. (PMID: 18173375)
• 18 Patil NK, Guo Y, Luan L. et al. Targeting Immune Cell Checkpoints during Sepsis. Int J Mol Sci 2017; 18: 2413
• 19 Chang K, Svabek C, Vazquez-Guillamet C. et al. Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis. Crit Care 2014; 18: R3
• 20 Banck JC, Mueller N, Mellinghoff SC. et al. Immune Checkpoint Blockade for Aspergillosis and Mucormycosis Coinfection. Hemasphere 2021; 5: e530 DOI: 10.1097/HS9.0000000000000530. (PMID: 33604513)
• 21 Khatamzas E, Mellinghoff SC, Thelen M. et al. Nivolumab induces long-term remission in a patient with fusariosis. Eur J Cancer 2022; 173: 91-94
• 22 Lukaszewicz AC, Venet F, Boibieux A. et al. Nivolumab and interferon-γ rescue therapy to control mixed mould and bacterial superinfection after necrotizing fasciitis and septic shock. Med Mycol Case Rep 2022; 37: 19-22 DOI: 10.1016/j.mmcr.2022.06.003. (PMID: 35770129)
• 23 Serris A, Ouedrani A, Uhel F. et al. Case Report: Immune Checkpoint Blockade Plus Interferon-Γ Add-On Antifungal Therapy in the Treatment of Refractory Covid-Associated Pulmonary Aspergillosis and Cerebral Mucormycosis. Front Immunol 2022; 13: 900522 DOI: 10.3389/fimmu.2022.900522. (PMID: 35720319)
• 24 Steinbach A, Cornely OA, Wisplinghoff H. et al. Mould-reactive T cells for the diagnosis of invasive mould infection-A prospective study. Mycoses 2019; 62: 562-569 DOI: 10.1111/myc.12919. (PMID: 31034691)
• 25 Kumaresan PR, da Silva TA, Kontoyiannis DP. Methods of Controlling Invasive Fungal Infections Using CD8+ T Cells. Front Immunol 2018; 8: 1939 DOI: 10.3389/fimmu.2017.01939. (PMID: 29358941)
• 26 Oh BLZ, Chan LWY, Chai LYA. Manipulating NK cellular therapy from cancer to invasive fungal infection: promises and challenges. Front Immunol 2022; 13: 1044946 DOI: 10.3389/fimmu.2022.1044946. (PMID: 36969979)
• 27 Kumaresan PR, Manuri PR, Albert ND. et al. Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection. Proc Natl Acad Sci U S A 2014; 111: 10660-10665 DOI: 10.1073/pnas.1312789111. (PMID: 25002471)
• 28 Seif M, Kakoschke TK, Ebel F. et al. CAR T cells targeting Aspergillus fumigatus are effective at treating invasive pulmonary aspergillosis in preclinical models. Sci Transl Med 2022; 14: eabh1209 DOI: 10.1126/scitranslmed.abh1209. (PMID: 36170447)
• 29 Prommersberger S, Reiser M, Beckmann J. et al. CARAMBA: a first-in-human clinical trial with SLAMF7 CAR-T cells prepared by virus-free Sleeping Beauty gene transfer to treat multiple myeloma. Gene Ther 2021; 28: 560-571
• 30 Gruell H, Schommers P. Advancing bnAb combinations for HIV prevention. Lancet HIV 2023; 10: e625-e626 DOI: 10.1016/S2352-3018(23)00172-8. (PMID: 37802563)
• 31 Rudkin FM, Raziunaite I. et al. Single human B cell-derived monoclonal anti-Candida antibodies enhance phagocytosis and protect against disseminated candidiasis. Nat Commun 2018; 9: 5288 DOI: 10.1038/s41467-019-08392-x. (PMID: 30659194)
• 32 Lian X, Scott-Thomas A, Lewis JG. et al. Monoclonal Antibodies and Invasive Aspergillosis: Diagnostic and Therapeutic Perspectives. Int J Mol Sci 2022; 23: 5563 DOI: 10.3390/ijms23105563. (PMID: 35628374)
• 33 Mogavero S, Höfs S, Lauer AN. et al. Candidalysin Is the Hemolytic Factor of Candida albicans. Toxins 2022; 14: 874 DOI: 10.3390/toxins14120874. (PMID: 36548771)
• 34 De Bernardis F, Graziani S, Tirelli F. et al. Candida vaginitis: virulence, host response and vaccine prospects. Med Mycol 2018; 56 (Suppl. 01) 26-31 DOI: 10.1093/mmy/myx139. (PMID: 29538739)
• 35 Edwards Jr JE, Schwartz MM, Schmidt CS. et al. A Fungal Immunotherapeutic Vaccine (NDV-3A) for Treatment of Recurrent Vulvovaginal Candidiasis-A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial. Clin Infect Dis 2018; 66: 1928-1936 DOI: 10.1093/cid/ciy185. (PMID: 29697768)
• 36 Oliveira LVN, Wang R, Specht CA. et al. Vaccines for human fungal diseases: close but still a long way to go. NPJ Vaccines 2021; 6: 33 DOI: 10.1038/s41541-021-00294-8. (PMID: 33658522)
• 37 Upadhya R, Lam WC, Maybruck B. et al. Induction of Protective Immunity to Cryptococcal Infection in Mice by a Heat-Killed, Chitosan-Deficient Strain of Cryptococcus neoformans. mBio 2016; 7: e00547-16 DOI: 10.1128/mBio.00547-16. (PMID: 27165801)
• 38 Hole CR, Wager CML, Castro-Lopez N. et al. Induction of memory-like dendritic cell responses in vivo. Nat Commun 2019; 10: 2955 DOI: 10.1038/s41467-019-10486-5. (PMID: 31273203)
• 39 van de Veerdonk FL, Gresnigt MS, Romani L. et al. Aspergillus fumigatus morphology and dynamic host interactions. Nat Rev Microbiol 2017; 15: 661-674 DOI: 10.1038/nrmicro.2017.90. (PMID: 28919635)
• 40 Clemons KV, Danielson ME, Michel KS. et al. Whole glucan particles as a vaccine against murine aspergillosis. J Med Microbiol 2014; 63: 1750-1759 DOI: 10.1099/jmm.0.079681-0. (PMID: 25288643)
• 41 Wang Y, Wang K, Masso-Silva JA. et al. A Heat-Killed Cryptococcus Mutant Strain Induces Host Protection against Multiple Invasive Mycoses in a Murine Vaccine Model. mBio 2019; 10: e02145-19 DOI: 10.1128/mBio.02145-19. (PMID: 31772051)
• 42 Wüthrich M, Brandhorst TT, Sullivan TD. et al. Calnexin induces expansion of antigen-specific CD4(+) T cells that confer immunity to fungal ascomycetes via conserved epitopes. Cell Host Microbe 2015; 17: 452-465