Adaptive immunity provides our bodies with a powerful and robust means to neutralize a wide range of ever-changing challenges, such as viruses and bacteria in the environment. This system has been re-engineered to treatment of human diseases, as seen in the field of immunotherapy. In particular, training T cells, key agents of the immune system, to target cancer is on the cusp of being developed into practical therapies. Current research focuses largely on designing and even personalizing the ways in which cells recognize their targets. This project focuses on growth and production of T cells, which is essential to future therapies and complementary to that of improving targeting. This project focuses on the systems used to grow cells, developing and optimizing a new biomaterial platform. Recent studies show that in addition to molecular factors presented on materials, cell growth is dependent on the mechanical rigidity of these materials. Moreover, additional results suggest that the precise conditions used to optimally grow cells, including molecular factors and rigidity, may change as a function of individual and disease progression. This project seeks to develop a systematic way to identifying parameters that promote optimal expansion of cells based on properties of an individual's cells. Successful completion of this project has the potential to improve the reliability and efficacy of cellular immunotherapy, which will reduce the burden of cancer on society. While the direct impact of this work will be on T cell expansion, the methods and concepts to be developed will be widely applicable to other cell expansion systems and to other aspects of biomaterial design. Given the remarkable opportunities for custom manufacturing that are becoming available, the concept that a biomaterial can be optimized for an individual's therapy is compelling. In addition, this project will provide training in the process of converting academic discoveries into practical solutions, developing a workforce capable of commercializing new ways of improving human health. Additional education and outreach opportunities will accelerate interdisciplinary studies between immunology and biomedical engineering, greatly enhancing both underlying fields.
The expansion of a starting population of T cells into a therapeutically relevant product is a vital step in emerging forms of adoptive cellular immunotherapy. This project focuses on development and optimization of a new platform for cell expansion, consisting of electrospun fibers of elastomer coated with antibodies to CD3 and CD28, receptors on the T cell surface that when engaged provide function activation of cells, initiating expansion. Previous studies from the PI's group showed that reducing the mechanical rigidity of activating substrates corresponds with improved T cell expansion, even rescuing cells from patients undergoing care for CLL which typically show signs of unresponsiveness and exhaustion. Furthermore, preliminary results suggest that the specific set of conditions that best expand a population of T cells depends on the individual and disease progression. The concept inspiring this project is that having a systematic means for identifying optimal conditions for expansion, based on readily obtainable biomarkers or clinical history of a patient, will improve the reliability of cell production for cellular immunotherapy, making these treatments effective for an increasing number of patients. The first stage will be carried out with cells from healthy donors, investigating the effect of fiber coating, culture conditions, and, in particular, mechanical rigidity of the fibers that make up our system on cell expansion. Two commercially available platforms will be included in these experiments for comparison. Markers associated with clinical efficacy, including cell proliferative potential and the phenotypic makeup of the resultant population, will be analyzed as a function of the design parameters. In the second stage, this knowledge will be used to understand expansion of cells from patients undergoing care for Chronic Lymphocytic Leukemia (CLL), including data of clinical history and both protein and genomic markers that are currently collected as part of treatment. If successful, the data generated by this study will provide a way to personalize and optimize T cell expansion for immunotherapy by bringing together two underlying fields of research: 1) the emerging field of immune mechanobiology, specifically that T cells can respond to the rigidity of their environment and 2) the personalization of biomaterials to an individual's cell response. This strategic union of fields represents a new approach to making T cell manufacturing more reliable and available to a wider range of patients.
