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\sisetup{per-mode=symbol,list-units=single}
\DeclareSIUnit\activityunit{U}
\DeclareSIUnit\carrier{carriers}
\DeclareSIUnit\cell{cells}
\DeclareSIUnit\ab{mAbs}
\DeclareSIUnit\molar{M}
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\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}

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

    \vfill

    \LARGE Nathan John Dwarshuis, B.S. \\

    \vspace{1.5em}

    \Large PhD Thesis \\
    Doctor of Philosophy in Biomedical Engineering \\
    Georgia Institute of Technology and Emory University

    \vspace{1.5em}

    \large\today

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  \large{

  \noindent
  Committee Members

  \vspace{1.5em}
  
  \noindent
  Dr. Krishnendu Roy (Advisor) \\
  Wallace H. Coulter Department of Biomedical Engineering, Georgia
  Institute of Technology and Emory University

  \vspace{1.5em}

  \noindent
  Dr. Madhav Dhodapkar \\
  Department of Hematology and Medical Oncology, Emory University

  \vspace{1.5em}

  \noindent
  Dr. Melissa Kemp \\
  Wallace H. Coulter Department of Biomedical Engineering, Georgia
  Institute of Technology and Emory University

  \vspace{1.5em}

  \noindent
  Dr. Wilbur Lam \\
  Wallace H. Coulter Department of Biomedical Engineering, Georgia
  Institute of Technology and Emory University

  \vspace{1.5em}

  \noindent
  Dr. Sakis Mantalaris \\
  Wallace H. Coulter Department of Biomedical Engineering, Georgia
  Institute of Technology and Emory University }
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\section*{acknowledgements}

Thank you to Lex Fridman and Devin Townsend for being awesome and inspirational.

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\section*{abstract}

\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.


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\tableofcontents

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\listoffigures

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\listoftables

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\twocolumn
\section*{acronyms}

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\pagenumbering{arabic}

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\section{introduction}

\subsection*{overview}

Insert overview here

\subsection*{hypothesis}

Insert hypothesis here

\subsection*{specific aims}
\subsubsection*{aim 1}
\subsubsection*{aim 2}
\subsubsection*{aim 3}

\subsection*{outline}

\subsubsection*{Aim 1}

Aim 1

\subsubsection*{Aim 2}

Aim 2

\subsubsection*{Aim 3}

Aim 3

\section{background and significance}
\subsubsection*{background}
\subsubsection*{current T cell manufacturing technologies}

bla bla

\subsection*{strategies to optimize cell manufacturing}

bla bla

\subsubsection*{strategies to characterize cell manufacturing}

bla bla

\subsection{Innovation}

\section{aim 1}

\subsection{introduction}
\subsection{methods}
\subsection{results}
\subsection{discussion}

\section{Aim 2}

\subsection{introduction}
\subsection{methods}
\subsection{results}
\subsection{discussion}

\section{Aim 3}

\subsection{introduction}
\subsection{methods}
\subsection{results}
\subsection{discussion}

\section{conclusions and future work}
\subsection{conclusions}
\subsection{future work}

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\section{References}
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