Reinforcing the Immunocompromised Host Defense against Fungi: Progress beyond the Current State of the Art

Abstract

Despite the availability of a variety of antifungal drugs, opportunistic fungal infections still remain life-threatening for immunocompromised patients, such as those undergoing allogeneic hematopoietic cell transplantation or solid organ transplantation. Suboptimal efficacy, toxicity, development of resistant variants and recurrent episodes are limitations associated with current antifungal drug therapy. Adjunctive immunotherapies reinforcing the host defense against fungi and aiding in clearance of opportunistic pathogens are continuously gaining ground in this battle. Here, we review alternative approaches for the management of fungal infections going beyond the state of the art and placing an emphasis on fungus-specific T cell immunotherapy. Harnessing the power of T cells in the form of adoptive immunotherapy represents the strenuous protagonist of the current immunotherapeutic approaches towards combating invasive fungal infections. The progress that has been made over the last years in this field and remaining challenges as well, will be discussed.

Keywords: T cell immunotherapy; fungal infections; fungus-specific T cells.

Figure 1

Standard and alternative therapeutic approaches for the management of invasive fungal infections.

Figure 2

Strategies for mono-fungus-, multi-fungus- or multi-pathogen-specific T cell manufacturing. A: PBMCs collected from a healthy donor can be activated with fungal extracts or with overlapping peptide libraries of fungal and viral antigens and directly be selected ex vivo with monoclonal antibody capture of cytokine-producing cells or antibodies binding to activation antigens attached to magnetic beads. Selected cells can subsequently be expanded in culture. B: Alternatively, FSTs or multi-pathogen-specific T cells can be expanded ex vivo upon stimulation with fungal extracts or with overlapping peptide libraries of fungal and viral antigens. C: Finally, FSTs can be produced by genetically modifying T cells to express a chimeric antigen receptor (CAR) that redirects their specificity to a desired antigen, e.g., Dectin-1 (D-CAR T cells). FST: fungal-specific T cells; PBMCs: peripheral blood mononuclear cells; APCs: antigen-presenting cells; mAb: monoclonal antibody.