title: Transient stimulation expands superior antitumor T cells for adoptive therapy.
abstract: Adoptive cell therapy is a potentially curative therapeutic approach for patients with cancer. In this treatment modality, antitumor T cells are exponentially expanded in vitro prior to infusion. Importantly, the results of recent clinical trials suggest that the quality of expanded T cells critically affects their therapeutic efficacy. Although anti-CD3 mAb-based stimulation is widely used to expand T cells in vitro, a protocol to generate T cell grafts for optimal adoptive therapy has yet to be established. In this study, we investigated the differences between T cell stimulation mediated by anti-CD3/CD28 mAb-coated beads and cell-based artificial antigen-presenting cells (aAPCs) expressing CD3/CD28 counter-receptors. We found that transient stimulation with cell-based aAPCs, but not prolonged stimulation with beads, resulted in the superior expansion of CD8+T cells. Transiently stimulated CD8+T cells maintained a stem cell-like memory phenotype and were capable of secreting multiple cytokines significantly more efficiently than chronically stimulated T cells. Importantly, the chimeric antigen receptor-engineered antitumor CD8+T cells expanded via transient stimulation demonstrated superior persistence and antitumor responses in adoptive immunotherapy mouse models. These results suggest that restrained stimulation is critical for generating T cell grafts for optimal adoptive immunotherapy for cancer.
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kagoya
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Munehide
authors.initials: M
authors.lastname: Nakatsugawa
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Ochi
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Immunology.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Cen
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Immunology.
authors.forename: Tingxi
authors.initials: T
authors.lastname: Guo
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Immunology.
authors.forename: Mark
authors.initials: M
authors.lastname: Anczurowski
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Saso
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Immunology.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marcus O
authors.initials: MO
authors.lastname: Butler
authors.affiliation: Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Immunology.
authors.forename: Naoto
authors.initials: N
authors.lastname: Hirano
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D006086:Graft vs Host Disease; D006801:Humans; D007114:Immunization / Q000379:methods*; D007156:Immunologic Memory / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D020014:K562 Cells; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines