A novel lentiviral vector-based approach to generate CAR T cells targeting Aspergillus fumigatus

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Abstract Invasive aspergillosis (IA) is a common and deadly mold infection in immunocompromised patients. As morbidity and mortality of IA are primarily driven by poor immune defense, adjunct immunotherapies, such as chimeric antigen receptor (CAR) T cells, are direly needed. Here, we propose a novel approach to generate Aspergillus fumigatus (AF)-CAR T cells using the scFv domain of AF-269-5 mAb and a lentiviral vector system. These cells successfully targeted mature hyphal filaments of representative clinical and reference AF isolates and elicited potent release of cytotoxic effectors and type 1 T-cell cytokines. Furthermore, AF-CAR T cells generated from peripheral blood mononuclear cells of four healthy human donors and expanded with cytokine stimulation (IL-2, IL-7+IL-15) regimens significantly suppressed mycelial growth of AF-293 after 18 h of co-culture. Moreover, cyclophosphamide-immunosuppressed NSG mice with invasive pulmonary aspergillosis that received two doses of 5 million AF-CAR T cells on days 0 and 2 after AF infection showed significantly reduced morbidity on day 4 post-infection (p<0.001) and significantly improved 7-day survival (p=0.049) compared to mice receiving non-targeting control T cells. In conclusion, we developed a novel lentiviral strategy to obtain AF-CAR T cells with high targeting efficacy, yielding significant anti-AF activity in vitro and short-term protection in vivo.

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