Immunomodulation as a Therapy for Aspergillus Infection: Current Status and Future Perspectives

Abstract

Invasive aspergillosis (IA) is the most serious life-threatening infectious complication of intensive remission induction chemotherapy and allogeneic stem cell transplantation in patients with a variety of hematological malignancies. Aspergillus fumigatus is the most commonly isolated species from cases of IA. Despite the various improvements that have been made with preventative strategies and the development of antifungal drugs, there is an urgent need for new therapeutic approaches that focus on strategies to boost the host’s immune response, since immunological recovery is recognized as being the major determinant of the outcome of IA. Here, we aim to summarize current knowledge about a broad variety of immunotherapeutic approaches against IA, including therapies based on the transfer of distinct immune cell populations, and the administration of cytokines and antibodies.

Aspergillus fumigatus and Aspergillosis in 2019

“…Similar immunotherapeutic strategies have been successfully implemented in the clinical management of immunocompromised patients with viral infections (e.g., CMV) (701). Many preclinical studies over the past 30 years have successfully employed different immunotherapeutic approaches, with the use of (i) cytokines, (ii) myeloid hemopoietic growth factors (M-CSF) (iii) phagocyte transfusions, (iv) generation of Aspergillus-specific T cells, (v) engineered CAR T cells targeting ␤ glucan, (vi) checkpoint inhibitors, (vii) NK cells, and (viii) vaccines that enhance Aspergillus-specific immune responses (702)(703)(704)(705)(706)(707)(708)(709)(710)(711). Other investigators implemented anti-inflammatory therapies to restrict detrimental inflammatory immunopathology induced by the fungus (712).…”

Immunomodulation for the Treatment of Fungal Infections: Opportunities and Challenges

“…Adoptive T-cell therapy Stimulation of T-cells with antigen and infusion into the patient (Tramsen et al, 2014) Generation of an adequate number of fungal-specific T cells with sufficient purity is challenging (Papadopoulou et al, 2016) Monoclonal antibodies Avoid toxicity risks because they are directed specifically to pathogen epitopes, reduce durations of antifungal drug treatment (Casadevall et al, 2004;Cassone, 2008) Highly specific, high production costs (Chames et al, 2009) CAR T-cell therapies T-cells are genetically modified to express CAR and provide MHC unrestricted antigen recognition (Meiliana et al, 2016) Cytokine release syndrome and neurotoxicity (Kochenderfer et al, 2012;Brudno and Kochenderfer, 2016), longer time needed to generate autologous CAR T-cells (Neelapu et al, 2017), allogeneic T-cells may cause GvHD, and may be rapidly eliminated by the host immune system (Depil et al, 2020) Dendritic Cells (DCs) Leads to activation of specific T-cells and secretion of cytokines and chemokines. It can be used both in immunotherapy and vaccination (Lauruschkat et al, 2018) Cost inefficient, difficult to scale, and labor intensive (Lauruschkat et al, 2018) G-CSF Restores neutrophil counts (Wright et al, 2017) Lineage-specific (Costa, 1998), may stimulate leukemia (Rowe, 2000) GM-CSF Stimulates proliferation and differentiation of hematopoietic progenitor cells. Enhances antimicrobial function of mature neutrophils and monocytes against fungal targets (Safdar et al, 2013).…”

“…Recognize motifs on fungal species and induce inflammatory responses. It is useful for TLR-defective individuals (Netea et al, 2006) Difficult for manufacturing on a commercial scale, complex and unpredictable mode of action (Zeromski et al, 2019) TNF-α Stimulates PMNs (Lauruschkat et al, 2018) Hepatotoxicity, nephrotoxicity, and neurotoxicity after systemic administration (Lauruschkat et al, 2018) remains a logically attractive solution. Granulocytes engulf fungus, release antimicrobial peptides, and form extracellular traps (West et al, 2017).…”

“…Dectin-1, a naturally occurring receptor of the innate immune system that is not expressed on T-cells, has been targeted for CAR therapy. ß-glucan, the ligand for Dectin-1, is a polysaccharide found on the surface of many fungi (Lauruschkat et al, 2018 ). Kumaresan et al constructed a CAR T-cell adapting the fungal receptor Dectin-1 for Aspergillus to activate T-cells via chimeric CD28 and CD3-ζ.…”

Innate Inspiration: Antifungal Peptides and Other Immunotherapeutics From the Host Immune Response

“…Adjunct immunotherapy strategies include the adoptive transfer of activated immune cells with antifungal activity, the administration of immune-activating cytokines in combination with antifungal therapy or the use of antibody therapy. Other approaches being studied include transfusion of leukocytes preloaded with antifungals, modulated T cells (e.g., stimulated ex vivo and re-infused) and investigation of potential vaccine strategies (321,(327)(328)(329)(330)(331)(332). Some of these approaches will be described in subsequent sections.…”