GM-CSF disruption in CART cells modulates T cell activation and enhances CART cell anti-tumor activity.

Autor: Cox MJ; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Division of Hematology, Mayo Clinic, Rochester, MN, USA.; Bioinformatics and Computational Biology, University of Minnesota Graduate School, Minneapolis, MN, USA., Manriquez Roman C; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Division of Hematology, Mayo Clinic, Rochester, MN, USA.; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA., Tapper EE; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Siegler EL; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Chappell D; Humanigen, Inc, Burlingame, CA, USA., Durrant C; Humanigen, Inc, Burlingame, CA, USA., Ahmed O; Humanigen, Inc, Burlingame, CA, USA., Sinha S; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Mwangi R; Bioinformatics and Computational Biology, University of Minnesota Graduate School, Minneapolis, MN, USA.; Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA., Scott NS; Bioinformatics and Computational Biology, University of Minnesota Graduate School, Minneapolis, MN, USA.; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA., Hefazi M; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Schick KJ; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Division of Hematology, Mayo Clinic, Rochester, MN, USA.; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA.; Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA., Horvei P; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Department of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, USA., Ruff MW; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Department of Neurology, Mayo Clinic, Rochester, MN, USA., Can I; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Division of Hematology, Mayo Clinic, Rochester, MN, USA.; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA.; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA., Adada M; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Division of Hematology, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Bezerra E; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Division of Hematology, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Kankeu Fonkoua LA; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Division of Hematology, Mayo Clinic, Rochester, MN, USA.; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Parikh SA; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Kay NE; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Sakemura R; T Cell Engineering, Mayo Clinic, Rochester, MN, USA.; Division of Hematology, Mayo Clinic, Rochester, MN, USA., Kenderian SS; T Cell Engineering, Mayo Clinic, Rochester, MN, USA. kenderian.saad@mayo.edu.; Division of Hematology, Mayo Clinic, Rochester, MN, USA. kenderian.saad@mayo.edu.; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA. kenderian.saad@mayo.edu.; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA. kenderian.saad@mayo.edu.; Department of Immunology, Mayo Clinic, Rochester, MN, USA. kenderian.saad@mayo.edu.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2022 Jun; Vol. 36 (6), pp. 1635-1645. Date of Electronic Publication: 2022 Apr 19.
DOI: 10.1038/s41375-022-01572-7
Abstrakt: Inhibitory myeloid cells and their cytokines play critical roles in limiting chimeric antigen receptor T (CART) cell therapy by contributing to the development of toxicities and resistance following infusion. We have previously shown that neutralization of granulocyte-macrophage colony-stimulating factor (GM-CSF) prevents these toxicities and enhances CART cell functions by inhibiting myeloid cell activation. In this report, we study the direct impact of GM-CSF disruption during the production of CD19-directed CART cells on their effector functions, independent of GM-CSF modulation of myeloid cells. In this study, we show that antigen-specific activation of GM-CSF KO CART19 cells consistently displayed reduced early activation, enhanced proliferation, and improved anti-tumor activity in a xenograft model for relapsed B cell malignancies. Activated CART19 cells significantly upregulate GM-CSF receptors. However, the interaction between GM-CSF and its upregulated receptors on CART cells was not the predominant mechanism of this activation phenotype. GM-CSF KO CART19 cell had reduced BH3 interacting-domain death agonist (Bid), suggesting an interaction between GM-CSF and intrinsic apoptosis pathways. In conclusion, our study demonstrates that CRISPR/Cas9-mediated GM-CSF knockout in CART cells directly ameliorates CART cell early activation and enhances anti-tumor activity in preclinical models.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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