Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells

• Published in: Nature biotechnology Vol. 36; no. 2; pp. 160 - 169
• Main Authors: Cheung, Alexander S, Zhang, David K Y, Koshy, Sandeep T, Mooney, David J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2018; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/107; 13/21; 13/31; 13/44; 14/19; 14/28; 14/34; 14/63; 631/1647/664/1364; 631/250/2152/1566/20; 631/250/24; 631/250/251/1567; 631/61/54/2295; 64/60; Agriculture; Animals; Antigen-presenting cells; Antigen-Presenting Cells - immunology; Antigens; Beads; Bioinformatics; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; CD19 antigen; CD28 antigen; CD28 Antigens - antagonists & inhibitors; CD28 Antigens - immunology; CD3 antigen; CD3 Complex - antagonists & inhibitors; CD3 Complex - immunology; Cell culture; Controlled release; Cues; Cytotoxicity; Dendritic cells; Dendritic Cells - immunology; Health aspects; Humans; Immunotherapy, Adoptive; Interleukin 2; Interleukin-2 - immunology; Life Sciences; Lipid bilayers; Lipid Bilayers - immunology; Lipids; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Lymphoma; Mice; Monocytes; Paracrine signalling; Primary Cell Culture; Receptors, Antigen, T-Cell - immunology; Rods; Scaffolds; Silica; Silicon dioxide; Silicon Dioxide - chemistry; Stimulation; Subpopulations; Sustained release; T cell receptors; T cells; T-Lymphocytes - immunology; T-Lymphocytes, Cytotoxic - immunology; Tissue Scaffolds; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt.4047

T cells are readily expanded in culture using a system that presents membrane-bound and soluble cues in a natural context. Therapeutic ex vivo T-cell expansion is limited by low rates and T-cell products of limited functionality. Here we describe a system that mimics natural antigen-presenting cells (APCs) and consists of a fluid lipid bilayer supported by mesoporous silica micro-rods. The lipid bilayer presents membrane-bound cues for T-cell receptor stimulation and costimulation, while the micro-rods enable sustained release of soluble paracrine cues. Using anti-CD3, anti-CD28, and interleukin-2, we show that the APC-mimetic scaffolds (APC-ms) promote two- to tenfold greater polyclonal expansion of primary mouse and human T cells compared with commercial expansion beads (Dynabeads). The efficiency of expansion depends on the density of stimulatory cues and the amount of material in the starting culture. Following a single stimulation, APC-ms enables antigen-specific expansion of rare cytotoxic T-cell subpopulations at a greater magnitude than autologous monocyte-derived dendritic cells after 2 weeks. APC-ms support over fivefold greater expansion of restimulated CD19 CAR-T cells than Dynabeads, with similar efficacy in a xenograft lymphoma model.