嵌合抗原受体
细胞生物学
CD19
生物
T细胞
细胞
单细胞分析
癌症研究
化学
免疫学
抗原
免疫系统
遗传学
作者
Ali Rezvan,Gabrielle Romain,Mohsen Fathi,Darren Heeke,Melisa Martínez-Paniagua,Xingyue An,Irfan N Bandey,Arash Saeedi,Fatemeh Sadeghi,Kristen Fousek,Nahum Puebla-Osorio,Laurence J.N. Cooper,Chantale Bernatchez,Harjeet Singh,Nabil Ahmed,Mike Mattie,Adrian Bot,Sattva S. Neelapu,Navin Varadarajan
标识
DOI:10.1101/2022.06.22.497245
摘要
Adoptive immunotherapy with T cells expressing chimeric antigen receptors (CARs) for B-cell malignancies serves as a model for identifying subsets with superior clinical activity. We profiled the infusion products (IP) of 16 patients with large B-cell lymphoma (LBCL) using an integrated suite of single-cell assays to reveal the therapeutic potential of CD19-specific CAR+ T cells. Timelapse imaging microscopy in nanowell grids (TIMING) profiling revealed that T cells from responders showed migration (persistent motion for at least one body length), and migration was associated with serial killing capacity. In addition, confocal microscopy revealed that migration is linearly correlated with both mitochondrial volume and lysosomal volume; and scRNA-seq demonstrated that T cells from responders were enriched in pathways related to T-cell killing, migration and actin cytoskeleton, and TCR clustering. A marker-free sorting strategy enriched T cells with migratory capacity and validated serial killing, bioenergetics, and in vivo efficacy. In aggregate, we demonstrate that migration is a cell-intrinsic biomarker independent of CAR design or biomanufacturing, desired in the bioactivity of CAR+ T cells associated with clinical antitumor efficacy.
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