Columbia University engineers say they have developed a novel technique for improving T-cell manufacture by focusing on the bioprocessing materials. The team’s approach (“Enhanced Activation and Expansion of T Cells Using Mechanically Soft Elastomer Fibers”), published in Advanced Biosystems, uses a polymer mesh to activate the T cells. This method, which makes the fibers out of a mechanically soft material, boosted T-cell growth.
“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,” write the investigators.
“This platform also rescues expansion of T cells isolated from CLL [chronic lymphocytic leukemia] 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.”
“Our report shows that this soft mesh material increases the number of functional cells that can be produced in a single step,” explains Lance Kam, Ph.D. “In fact, our system provided nearly an order of magnitude more cells in a single process. What's especially exciting is that we've been able to expand cells isolated from patients undergoing treatment for leukemia. These cells are often very difficult to activate and expand, and this has been a barrier to using cellular immunotherapy for the people who need it.”
According to the researchers, other cell types can sense the mechanical stiffness of a material. For example, the rigidity of a material used to culture stem cells can direct differentiation, with a softer material promoting production of neuron, while a stiffer substrate encourages bone cell differentiation. This effect can be as strong as the chemicals normally used to direct differentiation. However, a similar effect was unexpected in T cells for activation.
“This makes sense for cells normally involved in force-related activities, like muscle cells or fibroblasts that are involved in wound closure and healing. Our group was one of the first to explore this possibility for T cells, which are not associated with such functions,” notes Dr. Kam.
These experiments, involving his Microscale Biocomplexity Laboratory group, discovered that T cells can sense the mechanical rigidity of the materials commonly used in the laboratory. To turn this into a clinically useful system, his group partnered with the Biomaterials and Interface Tissue Engineering Laboratory of Helen Lu, Ph.D., to create a microfiber-based platform.
Beyond simplifying the process of cell expansion and improving T-cells expansion, Drs. Kam and Lu envision that the mesh platform will have applications beyond immunotherapy. They are refining their platform and exploring how T cells from cancer patients respond to their materials.
Scientists from Harvard recently reported that they have developed a 3D biomaterial scaffold that leads to much faster ex vivo expansion of functional T cells than current methods.