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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
manufacturing large numbers of high quality cells remains challenging. Currently
approved T cell expansion technologies involve \anti-cd{3} and \anti-cd{28}
\glspl{mab}, usually mounted on magnetic beads. This method fails to
recapitulate many key signals found \invivo{} and is also heavily licensed by a
few companies, limiting its long-term usefulness to manufactures and clinicians.
Furthermore, we understand that highly potent 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.
approved T cell expansion technologies involve \acd{3} and \acd{28} \glspl{mab},
usually mounted on magnetic beads. This method fails to recapitulate many key
signals found \invivo{} 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 \acrlongpl{tcm} and \acrlongpl{tscm}. 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 thesis was to develop a microcarrier-based \gls{dms} T cell
expansion system as well as determine biologically-meaningful \glspl{cqa} and
\glspl{cpp} that could be used to optimize for highly-potent T cells. In Aim 1,
we develop and characterized the \gls{dms} system, including quality control
steps. We also demonstrate the feasiblity of expanding highly-potent memory and
CD4+ T cells, and showing compatibility with existing \gls{car} transduction
methods. In aim 2, we use \gls{doe} methodology to optimize the \gls{dms}
platform, and develop a computational pipeline to identify and model the effect
of measurable \glspl{cqa} and \glspl{cpp} on the final product. In aim 3, we
demonstrate the effectiveness of the \gls{dms} platform \invivo{}. This
thesis lays the groundwork for a novel T cell expansion method which can be used
in a clinical setting, and also provides a path toward optimizing for product
quality in an industrial setting.
The goal of this dissertation was to develop a microcarrier-based \gls{dms} T
cell expansion system and determine biologically-meaningful \glspl{cqa} and
\glspl{cpp} that could be used to optimize for highly-potent T cells. In
\cref{aim1}, we develop and characterized the \gls{dms} system, including
quality control steps. We also demonstrate the feasiblity of expanding
high-quality T cells. In \cref{aim2a,aim2b}, we use \gls{doe} methodology to
optimize the \gls{dms} platform, and develop a computational pipeline to
identify and model the effect of measurable \glspl{cqa}, and \glspl{cpp} on the
final product. In \cref{aim3}, we demonstrate the effectiveness of the \gls{dms}
platform \invivo{}. This thesis lays the groundwork for a novel T cell expansion
method which can be utilized at scale for a clinical trial and beyond.
\clearpage