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Expansion of an initial population of T cells is essential for cellular immunotherapy. In Chronic Lymphocytic Leukemia (CLL), expansion is often complicated by lack of T cell proliferation, as these cells frequently show signs of exhaustion. This report seeks to identify specific biomarkers or measures of cell function that capture the proliferative potential of a starting population of cells. Mixed CD4+/CD8+ T cells from healthy donors and individuals previously treated for CLL were characterized on the basis of proliferative potential and in vitro cellular functions. Single-factor analysis found little correlation between the number of populations doublings reached during expansion and either Rai stage (a clinical measure of CLL spread) or PD-1 expression. However, inclusion of in vitro IL-2 secretion and the propensity of cells to align onto micropatterned features of activating proteins as factors identified three distinct groups of donors. Notably, these group assignments provided an elegant separation of donors with regards to proliferative potential. Furthermore, these groups exhibited different motility characteristics, suggesting a mechanism that underlies changes in proliferative potential. This study describes a new set of functional readouts that augment surface marker panels to better predict expansion outcomes and clinical prognosis. 

This report examines how sensing of substrate topography can be used to modulate T cell activation, a key coordinating step in the adaptive immune response. Inspired by the native T cell–antigen presenting cell interface, micrometer scale pits with varying depth are fabricated into planar substrates. Primary CD4⁺T cells extend actin‐rich protrusions into the micropits. T cell activation, reflected in secretion of cytokines interleukin‐2 and interferon gamma, is sensitive to the micropit depth. Surprisingly, arrays of micropits with 4 μm depth enhance activation compared to flat substrates but deeper micropits are less effective at increasing cell response, revealing a biphasic dependence in activation as a function of feature dimensions. Inhibition of cell contractility abrogates the enhanced activation associated with the micropits. In conclusion, this report demonstrates that the 3D, microscale topography can be used to enhance T cell activation, an ability that most directly can be used to improve production of these cells for immunotherapy.

 

Emerging cellular therapies require effective platforms for producing clinically relevant numbers of high‐quality cells. This report introduces a materials‐based approach to improving expansion of T cells, a compelling agent for treatment of cancer and a range of other diseases. The system consists of electrospun fibers, which present activating antibodies to CD3 and CD28. These fibers are effective in activating T cells, initiating expansion, and simplify processing of the cellular product, compared to current bead‐base platforms. In addition, reducing the mechanical rigidity of these fibers enhances expansion of mixed populations of human CD4⁺and CD8⁺T cells, providing eightfold greater production of cells in each round of cell growth. This platform also rescues expansion of T cells isolated from CLL patients, which often show limited responsiveness and other features resembling exhaustion. By simplifying the process of cell expansion and improving T cell expansion, the system introduced here provides a powerful tool for the development of cellular immunotherapy.