Multifunctional T-cell Analyses to Study Response and Progression in Adoptive Cell Transfer Immunotherapy

作者：Chao Ma, Ann Cheung, Thinle Chodon, Richard C. Koya, Zhongqi Wu, Charles Ng, Earl Avramis, Alistair J. Cochran, Owen N. Witte, David Baltimore, Bartosz Chmielowski, James S. Economou, Begonya Comin-Anduix, Antoni Ribas, James R. Heath · 发表于：Cancer Discovery · 年份：2013 · DOI：10.1158/2159-8290.cd-12-0383 · 被引用次数：148 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、Immune Cell Function and Interaction

UNLABELLED: Adoptive cell transfer (ACT) of genetically engineered T cells expressing cancer-specific T-cell receptors (TCR) is a promising cancer treatment. Here, we investigate the in vivo functional activity and dynamics of the transferred cells by analyzing samples from 3 representative patients with melanoma enrolled in a clinical trial of ACT with TCR transgenic T cells targeted against the melanosomal antigen MART-1. The analyses included evaluating 19 secreted proteins from individual cells from phenotypically defined T-cell subpopulations, as well as the enumeration of T cells with TCR antigen specificity for 36 melanoma antigens. These analyses revealed the coordinated functional dynamics of the adoptively transferred, as well as endogenous, T cells, and the importance of highly functional T cells in dominating the antitumor immune response. This study highlights the need to develop approaches to maintaining antitumor T-cell functionality with the aim of increasing the long-term efficacy of TCR-engineered ACT immunotherapy. SIGNIFICANCE: A longitudinal functional study of adoptively transferred TCR–engineered lymphocytes yielded revealing snapshots for understanding the changes of antitumor responses over time in ACT immunotherapy of patients with advanced melanoma.