318 lines
7.3 KiB
TeX
318 lines
7.3 KiB
TeX
% \documentclass[twocolumn]{article}
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\documentclass{report}
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\usepackage[top=1in,left=1.5in,right=1in,bottom=1in]{geometry}
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\usepackage{siunitx}
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\usepackage{multicol}
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\setlength{\columnsep}{1cm}
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\usepackage[acronym]{glossaries}
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\usepackage[T1]{fontenc}
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\usepackage{enumitem}
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\usepackage{titlesec}
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\usepackage{titlecaps}
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\usepackage{upgreek}
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\usepackage{graphicx}
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\usepackage{subcaption}
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\usepackage{nth}
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\usepackage[capitalize]{cleveref}
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\usepackage[version=4]{mhchem}
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\usepackage{pgfgantt}
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\usepackage{setspace}
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\doublespacing{}
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\titleformat{\chapter}[block]{\filcenter\bfseries\large}
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{\MakeUppercase{\chaptertitlename} \thechapter: }{0pt}{\uppercase}
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% \titleformat{\chapter}[block]{\filcenter\bfseries\large}{}{0pt}{\uppercase}
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\titleformat{\section}[block]{\bfseries\large}{}{0pt}{\titlecap}
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\titleformat{\subsection}[block]{\itshape\large}{}{0pt}{\titlecap}
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\titleformat{\subsubsection}[runin]{\bfseries\itshape\/}{}{0pt}{\titlecap}
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\setlist[description]{font=$\bullet$~\textbf\normalfont}
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\sisetup{per-mode=symbol,list-units=single}
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\DeclareSIUnit\activityunit{U}
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\DeclareSIUnit\carrier{carriers}
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\DeclareSIUnit\cell{cells}
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\DeclareSIUnit\ab{mAbs}
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\DeclareSIUnit\molar{M}
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\DeclareSIUnit\gforce{\times{} g}
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% add acronyms here
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\renewcommand{\glossarysection}[2][]{} % remove glossary title
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\makeglossaries
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\newacronym{act}{ACT}{adoptive cell therapies}
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\newacronym{car}{CAR}{chimeric antigen receptor}
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\newacronym[longplural={monoclonal antibodies}]{mab}{mAb}{monoclonal antibody}
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\newacronym{ecm}{ECM}{extracellular matrix}
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\newacronym{cqa}{CQA}{critical quality attribute}
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\newacronym{cpp}{CPP}{critical process parameter}
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\newacronym{dms}{DMS}{degradable microscaffold}
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\newacronym{doe}{DOE}{design of experiments}
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\newcommand{\mytitle}{
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\Large{
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\textbf{
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Optimizing T Cell Manufacturing and Quality Using Functionalized
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Degradable Microscaffolds
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}
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}
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}
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\newcommand{\mycommitteemember}[3]{
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\begin{flushleft}
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\noindent
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#1 \\
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#2 \\
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\textit{#3}
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\end{flushleft}
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}
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\newenvironment{mytitlepage}{
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\begin{singlespace}
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\begin{center}
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}
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{
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\end{center}
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\end{singlespace}
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}
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\begin{document}
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\begin{titlepage}
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\begin{mytitlepage}
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\mytitle{}
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\vfill
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\Large{
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A Dissertation \\
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Presented to \\
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The Academic Faculty \\
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\vspace{1.5em}
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by
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\vspace{1.5em}
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Nathan John Dwarshuis, B.S. \\
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\vfill
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In Partial Fulfillment \\
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of the Requirements for the Degree \\
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Doctor of Philosophy in Biomedical Engineering in the \\
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Wallace H. Coulter Department of Biomedical Engineering
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\vfill
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Georgia Institute of Technology and Emory University \\
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August 2021
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\vfill
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COPYRIGHT \copyright{} BY NATHAN J. DWARSHUIS
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}
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\end{mytitlepage}
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\end{titlepage}
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\onecolumn \pagenumbering{roman}
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\clearpage
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\begin{mytitlepage}
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\mytitle{}
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\end{mytitlepage}
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\vfill
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\large{
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\noindent
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Committee Members
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\begin{multicols}{2}
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\begin{singlespace}
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\mycommitteemember{Dr.\ Krishnendu\ Roy\ (Advisor)}
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{Department of Biomedical Engineering}
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{Georgia Institute of Technology and Emory University}
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\vspace{1.5em}
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\mycommitteemember{Dr.\ Madhav\ Dhodapkar}
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{Department of Hematology and Medical Oncology}
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{Emory University}
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\vspace{1.5em}
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\mycommitteemember{Dr.\ Melissa\ Kemp}
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{Department of Biomedical Engineering}
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{Georgia Institute of Technology and Emory University}
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\columnbreak{}
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\null{}
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\vfill
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\mycommitteemember{Dr.\ Wilbur\ Lam}
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{Department of Biomedical Engineering}
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{Georgia Institute of Technology and Emory University}
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\vspace{1.5em}
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\mycommitteemember{Dr.\ Sakis\ Mantalaris}
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{Department of Biomedical Engineering}
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{Georgia Institute of Technology and Emory University}
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\end{singlespace}
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\end{multicols}
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\vspace{1.5em}
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\hfill Date Approved:
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}
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\clearpage
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\chapter*{acknowledgements}
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\addcontentsline{toc}{chapter}{acknowledgements}
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Thank you to Lex Fridman and Devin Townsend for being awesome and inspirational.
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\clearpage
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\chapter*{summary}
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\addcontentsline{toc}{chapter}{summary}
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\Gls{act} using \gls{car} T cells have shown promise in treating cancer, but
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manufacturing large numbers of high quality cells remains challenging. Currently
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approved T cell expansion technologies involve anti-CD3 and CD28 \glspl{mab},
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usually mounted on magnetic beads. This method fails to recapitulate many key
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signals found \textit{in vivo} and is also heavily licensed by a few companies,
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limiting its long-term usefulness to manufactures and clinicians. Furthermore,
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we understand that highly potent T cells are generally less-differentiated
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subtypes such as central memory and stem memory T cells. Despite this
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understanding, little has been done to optimize T cell expansion for generating
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these subtypes, including measurement and feedback control strategies that are
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necessary for any modern manufacturing process.
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The goal of this thesis was to develop a microcarrier-based \gls{dms} T cell
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expansion system as well as determine biologically-meaningful \glspl{cqa} and
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\glspl{cpp} that could be used to optimize for highly-potent T cells. In Aim 1,
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we develop and characterized the \gls{dms} system, including quality control
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steps. We also demonstrate the feasiblity of expanding highly-potent memory and
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CD4+ T cells, and showing compatibility with existing \gls{car} transduction
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methods. In aim 2, we use \gls{doe} methodology to optimize the \gls{dms}
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platform, and develop a computational pipeline to identify and model the effect
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of measurable \glspl{cqa} and \glspl{cpp} on the final product. In aim 3, we
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demonstrate the effectiveness of the \gls{dms} platform \textit{in vivo}. This
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thesis lays the groundwork for a novel T cell expansion method which can be used
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in a clinical setting, and also provides a path toward optimizing for product
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quality in an industrial setting.
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\clearpage
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\tableofcontents
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\clearpage
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\listoffigures
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\clearpage
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\listoftables
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\clearpage
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% \twocolumn
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\chapter*{acronyms}
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\addcontentsline{toc}{chapter}{acronyms}
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\printglossary[type=\acronymtype]
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\clearpage
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\pagenumbering{arabic}
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\clearpage
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\chapter{introduction}
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\section*{overview}
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Insert overview here
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\section*{hypothesis}
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Insert hypothesis here
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\section*{specific aims}
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\subsection*{aim 1}
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\subsection*{aim 2}
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\subsection*{aim 3}
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\section*{outline}
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\subsection*{Aim 1}
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Aim 1
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\subsection*{Aim 2}
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Aim 2
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\subsection*{Aim 3}
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Aim 3
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\chapter{background and significance}
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\subsection*{background}
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\subsection*{current T cell manufacturing technologies}
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bla bla
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\section*{strategies to optimize cell manufacturing}
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bla bla
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\subsection*{strategies to characterize cell manufacturing}
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bla bla
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\section{Innovation}
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\chapter{aim 1}
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\section{introduction}
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\section{methods}
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\section{results}
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\section{discussion}
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\chapter{Aim 2}
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\section{introduction}
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\section{methods}
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\section{results}
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\section{discussion}
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\chapter{Aim 3}
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\section{introduction}
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\section{methods}
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\section{results}
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\section{discussion}
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\chapter{conclusions and future work}
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\section{conclusions}
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\section{future work}
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\onecolumn
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\clearpage
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% TODO some people put appendices here....not sure if I need to
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\chapter{References}
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\renewcommand{\section}[2]{} % noop the original bib section header
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\bibliography{../proposal}
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\bibliographystyle{naturemag}
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\end{document}
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