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  \LARGE{\textbf{Optimizing T Cell Manufacturing and Quality Using
      Functionalized Degradable Microscaffolds}}

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  Nathan J. Dwarshuis

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  165 pages
  
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  Directed by Krishnendu Roy
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Adoptive cell therapy using chimeric antigen receptor (CAR) T cells have shown
promise in treating cancer, but manufacturing large numbers of high quality
cells remains challenging. Currently approved T cell expansion technologies
involve anti-CD3 and anti-CD28 antibodies, usually mounted on magnetic beads.
This method fails to recapitulate many key signals found \textit{in vivo} and is
also heavily licensed by a few companies, limiting its long-term usefulness to
manufactures and clinicians. Furthermore, highly potent, anti-tumor T cells are
generally less-differentiated subtypes such as central memory and stem memory T
cells. Despite this understanding, little has been done to optimize T cell
expansion for generating these subtypes, including measurement and feedback
control strategies that are necessary for any modern manufacturing process.

The goal of this dissertation was to develop a microcarrier-based degradable
microscaffold (DMS) T cell expansion system and determine
biologically-meaningful critical quality attitudes and critical process
parameters that could be used to optimize for highly-potent T cells. We
developed and characterized the DMS system, including quality control steps. We
also demonstrated the feasibility of expanding high-quality T cells. We used
Design of Experiments methodology to optimize the DMS platform, and we developed
a computational pipeline to identify and model the effects of measurable
critical quality attributes and critical process parameters on the final
product. Finally, we demonstrated the effectiveness of the DMS platform
\textit{in vivo}. This thesis lays the groundwork for a novel T cell expansion
method which can be utilized at scale for clinical trials and beyond.

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