期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 14, 期 664, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abh1209
关键词
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资金
- Bundesministerium fur Bildung und Forschung (BMBF)
- Wilhelm Sander Stiftung [2020.017.1]
- Deutsche Forschungsgemeinschaft [Transregio 221]
- Forderprogramm fur Forschung und Lehre of the LMU Medical School-Fellowship
- European Union [847507-HDM-FUN]
- Center for Personalized Molecular Immunotherapy within the EFRE-program of the European Union (Europaischer Fond fur Regionale Entwicklung)
- Innovative Medicines Initiative 2 Joint Undertaking (T2EVOLVE) [116026]
- European Union's Horizon 2020 Research and Innovation program
- EFPIA
This study demonstrates the potential of gene-engineered T cells to treat invasive fungal infections caused by Aspergillus fumigatus. The CAR T cells targeting A. fumigatus demonstrated antifungal activity both in vitro and in vivo. CD8(+) Af-CAR T cells released perforin and granzyme B to damage A. fumigatus hyphae, while CD8(+) and CD4(+) Af-CAR T cells activated macrophages to enhance the antifungal effect. In a mouse model of invasive pulmonary aspergillosis, adoptive transfer of CD8(+) Af-CAR T cells improved overall survival. These findings support the clinical development of Af-CAR T cell therapy for the treatment of IPA.
Aspergillus fumigatus is a ubiquitous mold that can cause severe infections in immunocompromised patients, typically manifesting as invasive pulmonary aspergillosis (IPA). Adaptive and innate immune cells that respond to A. fumigatus are present in the endogenous repertoire of patients with IPA but are infrequent and cannot be consistently isolated and expanded for adoptive immunotherapy. Therefore, we gene-engineered A. fumigatus-specific chimeric antigen receptor (Af-CAR) T cells and demonstrate their ability to confer antifungal reactivity in preclinical models in vitro and in vivo. We generated a CAR targeting domain AB90-E8 that recognizes a conserved protein antigen in the cell wall of A. fumigatus hyphae. T cells expressing the Af-CAR recognized A. fumigatus strains and clinical isolates and exerted a direct antifungal effect against A. fumigatus hyphae. In particular, CD8(+) Af-CAR T cells released perforin and granzyme B and damaged A. fumigatus hyphae. CD8(+) and CD4(+) Af-CAR T cells produced cytokines that activated macrophages to potentiate the antifungal effect. In an in vivo model of IPA in immunodeficient mice, CD8(+) Af-CAR T cells localized to the site of infection, engaged innate immune cells, and reduced fungal burden in the lung. Adoptive transfer of CD8(+) Af-CAR T cells conferred greater antifungal efficacy compared to CD4(+) Af-CAR T cells and an improvement in overall survival. Together, our study illustrates the potential of gene-engineered T cells to treat aggressive infectious diseases that are difficult to control with conventional antimicrobial therapy and support the clinical development of Af-CAR T cell therapy to treat IPA.
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