Depletion of high-content CD14 + cells from apheresis products is critical for successful transduction and expansion of CAR T cells during large-scale cGMP manufacturing.

Autor:	Wang X; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Borquez-Ojeda O; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Stefanski J; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Du F; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Qu J; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Chaudhari J; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Thummar K; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Zhu M; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Shen LB; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Hall M; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Gautam P; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Wang Y; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sénéchal B; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sikder D; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Adusumilli PS; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Brentjens RJ; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Curran K; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Geyer MB; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Mailankhody S; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., O'Cearbhaill R; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Park JH; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sauter C; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Slovin S; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Smith EL; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Rivière I; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2021 Jul 16; Vol. 22, pp. 377-387. Date of Electronic Publication: 2021 Jul 16 (Print Publication: 2021).
DOI:	10.1016/j.omtm.2021.06.014
Abstrakt:	With the US Food and Drug Administration (FDA) approval of four CD19- and one BCMA-targeted chimeric antigen receptor (CAR) therapy for B cell malignancies, CAR T cell therapy has finally reached the status of a medicinal product. The successful manufacturing of autologous CAR T cell products is a key requirement for this promising treatment modality. By analyzing the composition of 214 apheresis products from 210 subjects across eight disease indications, we found that high CD14 + cell content poses a challenge for manufacturing CAR T cells, especially in patients with non-Hodgkin's lymphoma and multiple myeloma caused by the non-specific phagocytosis of the magnetic beads used to activate CD3 + T cells. We demonstrated that monocyte depletion via rapid plastic surface adhesion significantly reduces the CD14 + monocyte content in the apheresis products and simultaneously boosts the CD3 + content. We established a 40% CD14 + threshold for the stratification of apheresis products across nine clinical trials and demonstrated the effectiveness of this procedure by comparing manufacturing runs in two phase 1 clinical trials. Our study suggests that CD14 + content should be monitored in apheresis products, and that the manufacturing of CAR T cells should incorporate a step that lessens the CD14 + cell content in apheresis products containing more than 40% to maximize the production success. Competing Interests: P.S.A. has received research funding from ATARA Biotherapeutics; has served on the Scientific Advisory Board or as consultant to ATARA Biotherapeutics, Bayer, Carisma Therapeutics, Imugene, and Takeda Therapeutics; and has patents, royalties, and intellectual property on mesothelin-targeted CARs and other T cell therapies, method for detection of cancer cells using virus, and pending patent applications on T cell therapies. E.L.S. has patents, royalties, and intellectual property on BCMA-targeted CARs and serves as consultant for BMS. I.R. has intellectual property rights from Juno Therapeutics. (© 2021.)
Databáze:	MEDLINE
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