Current approaches to expand T cells ex vivo for therapeutic applications are limited by low expansion rates and T-cell products of limited functionality. To address these issues, we have recently described a system that mimics natural antigen-presenting cells (APCs). These APC-mimetic scaffolds (APC-ms) consist of a fluid lipid bilayer supported by mesoporous silica micro-rods (MSRs). The lipid bilayer presents membrane-bound cues for T-cell receptor stimulation and costimulation at predefined densities, while the micro-rods enable sustained release of soluble paracrine cues. Using anti-CD3, anti-CD28 and controlled release of interleukin-2, we have shown that the APC-ms promotes ten-fold greater polyclonal expansion of primary mouse and human T cells than commercial beads (Dynabeads), and can be used to tune the phenotypic attributes of expanded T-cell products. APC-ms also support over 5-fold greater expansion of CD19 CAR-T cells than Dynabeads, with increased efficacy in a clinically-relevant xenograft lymphoma model. While APC-ms is a promising T cell expansion system, there are several development activities that would aid its clinical and commercial translation. The current MSR synthesis process has not been standardized for this application, and lacks established SOPs to yield material products with consistent properties. Currently, surface cues are presented on APC-ms using biotin-streptavidin, but the use of click chemistry in place of streptavidin could provide a number of advantages. While APC-ms is designed to completely degrade during the process of T cell culture period, obviating the need for its removal before cell delivery, we have not yet thoroughly explored the impact of any potential residual materials on the infused T cell products. These needs lead to the following specific objectives for this project (1) Establish SOPs for APC-ms synthesis. This will include identifying MSR critical quality attributes (CQAs) for functional APC-ms and understanding how critical process parameters (CPPs) in MSR synthesis affect those CQAs (2) Develop a process to directly and selectively conjugate surface cues onto lipid bilayers, via click chemistry, to simplify and modularity of APC-ms assembly and function. (3) Characterize residual APC-ms materials during T cell processing, and perform a thorough in vivo safety assessment. The successful achievement of these aims will immediately address key issues related to using APC-ms as an ex vivo T-cell expansion platform.

Public Health Relevance

T cell products can be life-saving, but current approaches to produce these therapies have significant limitations. Studies that are critical to develop a new system to produce therapeutic T cells in a more rapid manner, with more control over the function of the end product will be performed in this project. These studies will lay the groundwork for commercial and clinical application of this new technology.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1)
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Osorio, Manuel
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Harvard University
United States
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