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AntigenâSpecific Stimulation and Expansion of CARâT Cells Using Membrane Vesicles as Target Cell Surrogates
Development of CARâT therapy led to immediate success in the treatment of B cell leukemia. Manufacturing of therapyâcompetent functional CARâT cells needs robust protocols for ex vivo/in vitro expansion of modified Tâcells. This step is challenging, especially if nonâviral lowâefficiency delivery protocols are used to generate CARâT cells. Modern protocols for CARâT cell expansion are imperfect since nonâspecific stimulation results in rapid outgrowth of CARânegative T cells, and removal of feeder cells from mixed cultures necessitates additional purification steps. To develop a specific and improved protocol for CARâT cell expansion, cellâderived membrane vesicles are taken advantage of, and the simple structural demands of the CARâantigen interaction. This novel approach is to make antigenic microcytospheres from common cell lines stably expressing surfaceâbound CAR antigens, and then use them for stimulation and expansion of CARâT cells. The data presented in this article clearly demonstrate that this protocol produced antigenâspecific vesicles with the capacity to induce stronger stimulation, proliferation, and functional activity of CARâT cells than is possible with existing protocols. It is predicted that this new methodology will significantly advance the ability to obtain improved populations of functional CARâT cells for therapy.
Antigenic vesicles (AVs) bind specifically to the surface of their cognate CARâT cells. The binding of AVs to CARâT cells results in the activation and proliferation of CARâT cells. AVs induce CARâT cellsâ functional maturation and increase CARâT cellsâ cytotoxic activity. Incubation with AVs results in antigenâspecific expansion of functional CARâT cells