diff --git a/tex/thesis.tex b/tex/thesis.tex index 04a90b1..0c41ace 100644 --- a/tex/thesis.tex +++ b/tex/thesis.tex @@ -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