phd_thesis/tex/thesis.tex

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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}
\DeclareSIUnit\gforce{\times{} g}

% add acronyms here
\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}

\newcommand{\mytitle}{
  \Large{
    \textbf{
      Optimizing T Cell Manufacturing and Quality Using Functionalized
      Degradable Microscaffolds
    }
  }
}

\newcommand{\mycommitteemember}[3]{
  \begin{flushleft}
    \noindent
    #1 \\
    #2 \\
    \textit{#3}
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\begin{document}

\begin{titlepage}
  \begin{mytitlepage}
    \mytitle{}

    \vfill

    \Large{
      A Dissertation \\
      Presented to \\
      The Academic Faculty \\

      \vspace{1.5em}

      by

      \vspace{1.5em}

      Nathan John Dwarshuis, B.S. \\

      \vfill

      In Partial Fulfillment \\
      of the Requirements for the Degree \\
      Doctor of Philosophy in Biomedical Engineering in the \\
      Wallace H. Coulter Department of Biomedical Engineering

      \vfill

      Georgia Institute of Technology and Emory University \\
      August 2021

      \vfill

      COPYRIGHT \copyright{} BY NATHAN J. DWARSHUIS
    }
  \end{mytitlepage}
\end{titlepage}

\onecolumn \pagenumbering{roman}
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\vfill

\large{
  \noindent
  Committee Members

  \begin{multicols}{2}
    \begin{singlespace}

      \mycommitteemember{Dr.\ Krishnendu\ Roy\ (Advisor)}
      {Department of Biomedical Engineering}
      {Georgia Institute of Technology and Emory University}

      \vspace{1.5em}

      \mycommitteemember{Dr.\ Madhav\ Dhodapkar}
      {Department of Hematology and Medical Oncology}
      {Emory University}

      \vspace{1.5em}

      \mycommitteemember{Dr.\ Melissa\ Kemp}
      {Department of Biomedical Engineering}
      {Georgia Institute of Technology and Emory University}

      \columnbreak{}
      \null{}
      \vfill

      \mycommitteemember{Dr.\ Wilbur\ Lam}
      {Department of Biomedical Engineering}
      {Georgia Institute of Technology and Emory University}

      \vspace{1.5em}

      \mycommitteemember{Dr.\ Sakis\ Mantalaris}
      {Department of Biomedical Engineering}
      {Georgia Institute of Technology and Emory University}

    \end{singlespace}
  \end{multicols}

  \vspace{1.5em}

  \hfill Date Approved:
}

\clearpage

\chapter*{acknowledgements}
\addcontentsline{toc}{chapter}{acknowledgements} 

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

\clearpage

\chapter*{summary}
\addcontentsline{toc}{chapter}{summary} 

\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

\tableofcontents

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\listoffigures

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\listoftables

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\chapter*{acronyms}
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\printglossary[type=\acronymtype]

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\pagenumbering{arabic}

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\chapter{introduction}

\section*{overview}

Insert overview here

\section*{hypothesis}

Insert hypothesis here

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

\section*{outline}

\subsection*{Aim 1}

Aim 1

\subsection*{Aim 2}

Aim 2

\subsection*{Aim 3}

Aim 3

\chapter{background and significance}
\subsection*{background}
\subsection*{current T cell manufacturing technologies}

bla bla

\section*{strategies to optimize cell manufacturing}

bla bla

\subsection*{strategies to characterize cell manufacturing}

bla bla

\section{Innovation}

\chapter{aim 1}

\section{introduction}
\section{methods}
\section{results}
\section{discussion}

\chapter{Aim 2}

\section{introduction}
\section{methods}
\section{results}
\section{discussion}

\chapter{Aim 3}

\section{introduction}
\section{methods}
\section{results}
\section{discussion}

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

\onecolumn
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% TODO some people put appendices here....not sure if I need to

\chapter{References}
\renewcommand{\section}[2]{} % noop the original bib section header

\bibliography{../proposal}

\bibliographystyle{naturemag}

\end{document}