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Novel T cells with improved in vivo anti-tumor activity generated by rna electroporation

Protein & Cell 2017年第7期8卷 514-526页

作者： Xiaojun Liu Shuguang Jiang Chongyun Fang Hua Li Xuhua Zhang Fuqin Zhang Carl H. June Yangbing Zhao Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology School of Basic Medical Sciences Shandong University Jinan 250012 China Center for Cellular Immunotherapies University of Pennsylvania Cancer Center Philadelphia PA 19104 USA Department of Pathology and Laboratory Medicine Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104-5156 USA

The generation of T cells with maximal anti-tumor activities will significantly impact the field of T-cell- based adoptive immunotherapy. In this report, we found that OKT3/IL-2-stimulated T cells were phenotypically more heterogeneous, with enhanced anti-tumor activity in vitro and when locally administered in a solid tumor mouse model. To further improve the OKT3/IL-2-based T cell manufacturing procedure, we developed a novel T cell stimulation and expansion method in which peripheral blood mononuclear cells were electroporated with mrna encoding a chimeric membrane protein consisting of a single-chain variable fragment against CD3 and the intracellular domains of CD28 and 4-1BB （OKT3-28BB）. The expanded T cells were phenotypically and functionally similar to T cells expanded by OKT3/IL-2. Moreover, co-electroporation of CD86 and 4-1BBL could further change the phenotype and enhance the in vivo anti-tumor activity. Although T cells expanded by the co- electroporation of OKT3-28BB with CD86 and 4-1BBL showed an increased central memory phenotype, the T cells still maintained tumor lytic activities as potent as those of OKT3/IL-2 or OKT3-28BB-stimulated T cells. In different tumor mouse models, T cells expanded by OKT3-28BB rna electroporation showed anti-tumor activities superior to those of OKT3/IL-2 T cells. Hence, T cells with both a less differentiated phenotype and potent tumor killing ability can be generated by rna electroporation, and this T cell manufacturing procedure can be further optimized by simply co-delivering other splices of rna, thus providing a simple and cost-effec- tive method for generating high-quality T cells for adop- tive immunotherapy.

关键词： T lymphocytes CAR manufacture genetransfer rna electroporation

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