Adoptive transfer of NK cells engineered with a CD5-based chimeric antigen receptor (SRCD5CAR) to treat invasive fungal infections.

Abstract

The treatment of invasive fungal infections (IFI) poses a major health challenge due to their severity, the scarcity and toxicity of current antifungal drugs, and the emergence of drug-resistant strains, thus forcing the search for novel strategies. Approaches involving adoptive transfer of immune cells harboring chimeric antigen receptors (CARs) are gaining momentum in several clinical settings. Based on the fungal β-glucan-binding properties of the lymphocyte scavenger receptor CD5, we assayed NK and T cells engineered with a CD5-based second generation CAR (SRCD5CAR) for the treatment of IFI. In vitro results revealed that SRCD5CAR expression specifically potentiates NK cell activation (i.e., CD69 expression and cytokine/chemokine production) and killing (i.e., CD107a expression and perforin/granzyme production) against different pathogenic fungal species (i.e., Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus and Fusarium solani). Further in vivo infusion of SRCD5CAR-NK cells into fungal-infected NSG mice increased survival rates and decreased fungal burden in target organs. Similar in vitro and in vivo anti-fungal observations were also obtained for SRCD5CAR-T cells. Overall, the superior and specific performance exhibited by SRCD5CAR-transduced NK cells open new avenues for the development of novel off-the-shelf adoptive transfer of allogeneic cells against IFI, be those alone or adjunctive to antifungal drugs.