Clinical Manufacture of FT819: Use of a Clonal Multiplexed-Engineered Master Induced Pluripotent Stem Cell Line to Mass Produce Off-the-Shelf CAR T-Cell Therapy

作者：Xu Yuan, Raedun Clarke, Yi-Shin Lai, Chia‐Wei Chang, Bi-Huei Yang, Gloria Hsia, Ramzey Abujarour, Tom Lee, Sjoukje van der Stegen, Helena Shaked, Abubakar Jalloh, Stéphanie Moreno, Jason ORourke, Eric Sung, Alma Gutierrez, Betsy Rezner, Meghan Eberhart, Rebecca Magdaleno, Xiuyan Wang, Brigitte Sénéchal, Devanjan Sikder, Dell Farnan, Mark Plavsic, Jerome Bressi, Isabelle Rivière, Bahram Valamehr · 发表于：Blood · 年份：2021 · DOI：10.1182/blood-2021-152985 · 被引用次数：12 · 研究领域：CAR-T cell therapy research

Abstract FT819 is a first-of-kind, allogeneic, off-the-shelf CAR T-cell therapy derived from a clonal master induced pluripotent stem cell (iPSC) line precisely engineered to insert a novel 1XX anti-CD19 chimeric antigen receptor (CAR) under the regulation of the T-cell receptor alpha constant (TRAC) locus for optimized control of anti-tumor activity and to completely delete T-cell receptor (TCR) expression to eliminate the potential of graft-versus-host disease (GvHD). Unlike conventional allogeneic CAR T-cell therapies which require repeatedly sourcing of T cells from various donors as the starting material, the use of a clonal master engineered iPSC line serves as a renewable starting cell source and ensures routine mass production of a uniformly engineered, homogenous CAR T-cell product for broad patient access. T cell-derived iPSCs were generated using a proprietary non-integrating cellular reprogramming system and genetically modified to integrate a novel anti-CD19 1XX CAR into both alleles of the TRAC gene. After single cell subcloning, each engineered iPSC clone was screened for multiple critical quality attributes including pluripotency, identity, genomic stability, cassette integration, on/off-target integration, T-cell differentiation propensity, and CAR T-cell function. Accordingly, the ideal single cell-derived engineered iPSC clone was selected as the clonal master iPSC line for FT819 and was converted into a master cell bank (MCB). The iPSC MCB serves as a rene...