diff --git a/tex/thesis.tex b/tex/thesis.tex index 58c3aa0..f77d3f7 100644 --- a/tex/thesis.tex +++ b/tex/thesis.tex @@ -13,6 +13,9 @@ \usepackage[capitalize]{cleveref} \usepackage[version=4]{mhchem} \usepackage{pgfgantt} +\usepackage{setspace} + +\doublespacing \titleformat{\section}[block]{\bfseries\large}{}{0pt}{\uppercase} \titleformat{\subsection}[block]{\bfseries\large}{}{0pt}{\titlecap} @@ -33,10 +36,18 @@ \renewcommand{\glossarysection}[2][]{} % remove glossary title \makeglossaries \newacronym{act}{ACT}{adoptive cell therapies} +\newacronym{car}{CAR}{chimeric antigen receptor} +\newacronym[longplural={monoclonal antibodies}]{mab}{mAb}{monoclonal antibody} +\newacronym{ecm}{ECM}{extracellular matrix} +\newacronym{cqa}{CQA}{critical quality attribute} +\newacronym{cpp}{CPP}{critical process parameter} +\newacronym{dms}{DMS}{degradable microscaffold} +\newacronym{doe}{DOE}{design of experiments} \begin{document} \begin{titlepage} + \begin{singlespace} \begin{center} \huge\textbf{Optimizing T Cell Manufacturing and Quality Using @@ -98,6 +109,7 @@ Dr. Sakis Mantalaris \\ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University } +\end{singlespace} \end{titlepage} \onecolumn \pagenumbering{roman} @@ -116,7 +128,32 @@ Thank you to Lex Fridman and Devin Townsend for being awesome and inspirational. \section*{abstract} -Insert abstract here. +\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-CD3 and CD28 \glspl{mab}, +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, +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. + +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 \textit{in vivo}. 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. + \clearpage