1. 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.
- Author
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Wang X, Borquez-Ojeda O, Stefanski J, Du F, Qu J, Chaudhari J, Thummar K, Zhu M, Shen LB, Hall M, Gautam P, Wang Y, Sénéchal B, Sikder D, Adusumilli PS, Brentjens RJ, Curran K, Geyer MB, Mailankhody S, O'Cearbhaill R, Park JH, Sauter C, Slovin S, Smith EL, and Rivière I
- Abstract
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.)- Published
- 2021
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