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Nathan Dwarshuis 2021-08-04 12:18:54 -04:00
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@ -421,29 +421,27 @@ Thank you to Lex Fridman and Devin Townsend for being awesome and inspirational.
\Gls{act} using \gls{car} T cells have shown promise in treating cancer, but \Gls{act} using \gls{car} T cells have shown promise in treating cancer, but
manufacturing large numbers of high quality cells remains challenging. Currently manufacturing large numbers of high quality cells remains challenging. Currently
approved T cell expansion technologies involve \anti-cd{3} and \anti-cd{28} approved T cell expansion technologies involve \acd{3} and \acd{28} \glspl{mab},
\glspl{mab}, usually mounted on magnetic beads. This method fails to usually mounted on magnetic beads. This method fails to recapitulate many key
recapitulate many key signals found \invivo{} and is also heavily licensed by a signals found \invivo{} and is also heavily licensed by a few companies,
few companies, limiting its long-term usefulness to manufactures and clinicians. limiting its long-term usefulness to manufactures and clinicians. Furthermore,
Furthermore, we understand that highly potent T cells are generally highly potent anti-tumor T cells are generally less-differentiated subtypes such
less-differentiated subtypes such as central memory and stem memory T cells. as \acrlongpl{tcm} and \acrlongpl{tscm}. Despite this understanding, little has
Despite this understanding, little has been done to optimize T cell expansion been done to optimize T cell expansion for generating these subtypes, including
for generating these subtypes, including measurement and feedback control measurement and feedback control strategies that are necessary for any modern
strategies that are necessary for any modern manufacturing process. manufacturing process.
The goal of this thesis was to develop a microcarrier-based \gls{dms} T cell The goal of this dissertation was to develop a microcarrier-based \gls{dms} T
expansion system as well as determine biologically-meaningful \glspl{cqa} and cell expansion system and determine biologically-meaningful \glspl{cqa} and
\glspl{cpp} that could be used to optimize for highly-potent T cells. In Aim 1, \glspl{cpp} that could be used to optimize for highly-potent T cells. In
we develop and characterized the \gls{dms} system, including quality control \cref{aim1}, we develop and characterized the \gls{dms} system, including
steps. We also demonstrate the feasiblity of expanding highly-potent memory and quality control steps. We also demonstrate the feasiblity of expanding
CD4+ T cells, and showing compatibility with existing \gls{car} transduction high-quality T cells. In \cref{aim2a,aim2b}, we use \gls{doe} methodology to
methods. In aim 2, we use \gls{doe} methodology to optimize the \gls{dms} optimize the \gls{dms} platform, and develop a computational pipeline to
platform, and develop a computational pipeline to identify and model the effect identify and model the effect of measurable \glspl{cqa}, and \glspl{cpp} on the
of measurable \glspl{cqa} and \glspl{cpp} on the final product. In aim 3, we final product. In \cref{aim3}, we demonstrate the effectiveness of the \gls{dms}
demonstrate the effectiveness of the \gls{dms} platform \invivo{}. This platform \invivo{}. This thesis lays the groundwork for a novel T cell expansion
thesis lays the groundwork for a novel T cell expansion method which can be used method which can be utilized at scale for a clinical trial and beyond.
in a clinical setting, and also provides a path toward optimizing for product
quality in an industrial setting.
\clearpage \clearpage