Generation of Antitumor T Cells For Adoptive Cell Therapy With Artificial Antigen Presenting Cells

作者：Bishwas Shrestha, Yongliang Zhang, Bin Yu, Gongbo Li, Justin C. Boucher, Nolan J. Beatty, Ho-chien Tsai, Xuefeng Wang, Asmita Mishra, Kendra Sweet, Jeffrey E. Lancet, Linda Kelley, Marco L. Davila · 发表于：Journal of Immunotherapy · 年份：2019 · DOI：10.1097/cji.0000000000000306 · 被引用次数：29 · 研究领域：CAR-T cell therapy research、Virus-based gene therapy research、Viral Infectious Diseases and Gene Expression in Insects

Adoptive cell therapy with ex vivo expanded tumor infiltrating lymphocytes or gene engineering T cells expressing chimeric antigen receptors (CAR) is a promising treatment for cancer patients. This production utilizes T-cell activation and transduction with activation beads and RetroNectin, respectively. However, the high cost of production is an obstacle for the broad clinical application of novel immunotherapeutic cell products. To facilitate production we refined our approach by using artificial antigen presenting cells (aAPCs) with receptors that ligate CD3, CD28, and the CD137 ligand (CD137L or 41BBL), as well as express the heparin binding domain (HBD), which binds virus for gene-transfer. We have used these aAPC for ex vivo gene engineering and expansion of tumor infiltrating lymphocytes and CAR T cells. We found that aAPCs can support efficacious T-cell expansion and transduction. Moreover, aAPCs expanded T cells exhibit higher production of IFN-γ and lower traits of T-cell exhaustion compared with bead expanded T cells. Our results suggest that aAPC provide a more physiological stimulus for T-cell activation than beads that persistently ligate T cells. The use of a renewable cell line to replace 2 critical reagents (beads and retronectin) for CAR T-cell production can significantly reduce the cost of production and make these therapies more accessible to patients.