ADD introduction section

tex/thesis.bbl

@@ -0,0 +1,210 @@
+\begin{thebibliography}{10}
+\expandafter\ifx\csname url\endcsname\relax
+  \def\url#1{\texttt{#1}}\fi
+\expandafter\ifx\csname urlprefix\endcsname\relax\def\urlprefix{URL }\fi
+\providecommand{\bibinfo}[2]{#2}
+\providecommand{\eprint}[2][]{\url{#2}}
+
+\bibitem{Fesnak2016}
+\bibinfo{author}{Fesnak, A.~D.}, \bibinfo{author}{June, C.~H.} \&
+  \bibinfo{author}{Levine, B.~L.}
+\newblock \bibinfo{title}{Engineered t cells: the promise and challenges of
+  cancer immunotherapy}.
+\newblock \emph{\bibinfo{journal}{Nature Reviews Cancer}}
+  \textbf{\bibinfo{volume}{16}}, \bibinfo{pages}{566--581}
+  (\bibinfo{year}{2016}).
+
+\bibitem{Rosenberg2015}
+\bibinfo{author}{Rosenberg, S.~A.} \& \bibinfo{author}{Restifo, N.~P.}
+\newblock \bibinfo{title}{Adoptive cell transfer as personalized immunotherapy
+  for human cancer}.
+\newblock \emph{\bibinfo{journal}{Science}} \textbf{\bibinfo{volume}{348}},
+  \bibinfo{pages}{62--68} (\bibinfo{year}{2015}).
+
+\bibitem{Roddie2019}
+\bibinfo{author}{Roddie, C.}, \bibinfo{author}{O'Reilly, M.},
+  \bibinfo{author}{Pinto, J. D.~A.}, \bibinfo{author}{Vispute, K.} \&
+  \bibinfo{author}{Lowdell, M.}
+\newblock \bibinfo{title}{Manufacturing chimeric antigen receptor t cells:
+  issues and challenges}.
+\newblock \emph{\bibinfo{journal}{Cytotherapy}}  (\bibinfo{year}{2019}).
+
+\bibitem{Dwarshuis2017}
+\bibinfo{author}{Dwarshuis, N.~J.}, \bibinfo{author}{Parratt, K.},
+  \bibinfo{author}{Santiago-Miranda, A.} \& \bibinfo{author}{Roy, K.}
+\newblock \bibinfo{title}{Cells as advanced therapeutics: State-of-the-art,
+  challenges, and opportunities in large scale biomanufacturing of high-quality
+  cells for adoptive immunotherapies}.
+\newblock \emph{\bibinfo{journal}{Advanced Drug Delivery Reviews}}
+  \textbf{\bibinfo{volume}{114}}, \bibinfo{pages}{222--239}
+  (\bibinfo{year}{2017}).
+
+\bibitem{Wang2016}
+\bibinfo{author}{Wang, X.} \& \bibinfo{author}{Rivi{\`{e}}re, I.}
+\newblock \bibinfo{title}{Clinical manufacturing of {CAR} t cells: foundation
+  of a promising therapy}.
+\newblock \emph{\bibinfo{journal}{Molecular Therapy - Oncolytics}}
+  \textbf{\bibinfo{volume}{3}}, \bibinfo{pages}{16015} (\bibinfo{year}{2016}).
+
+\bibitem{Piscopo2017}
+\bibinfo{author}{Piscopo, N.~J.} \emph{et~al.}
+\newblock \bibinfo{title}{Bioengineering solutions for manufacturing challenges
+  in {CAR} t cells}.
+\newblock \emph{\bibinfo{journal}{Biotechnology Journal}}
+  \textbf{\bibinfo{volume}{13}}, \bibinfo{pages}{1700095}
+  (\bibinfo{year}{2017}).
+
+\bibitem{Bashour2015}
+\bibinfo{author}{Bashour, K.~T.} \emph{et~al.}
+\newblock \bibinfo{title}{Functional characterization of a t cell stimulation
+  reagent for the production of therapeutic chimeric antigen receptor t cells}.
+\newblock \emph{\bibinfo{journal}{Blood}} \textbf{\bibinfo{volume}{126}},
+  \bibinfo{pages}{1901--1901} (\bibinfo{year}{2015}).
+
+\bibitem{Gendron2003}
+\bibinfo{author}{Gendron, S.}, \bibinfo{author}{Couture, J.} \&
+  \bibinfo{author}{Aoudjit, F.}
+\newblock \bibinfo{title}{Integrin $\alpha$2$\beta$1inhibits fas-mediated
+  apoptosis in t lymphocytes by protein phosphatase 2a-dependent activation of
+  the {MAPK}/{ERK} pathway}.
+\newblock \emph{\bibinfo{journal}{Journal of Biological Chemistry}}
+  \textbf{\bibinfo{volume}{278}}, \bibinfo{pages}{48633--48643}
+  (\bibinfo{year}{2003}).
+
+\bibitem{Ohtani2008}
+\bibinfo{author}{Ohtani, O.} \& \bibinfo{author}{Ohtani, Y.}
+\newblock \bibinfo{title}{Structure and function of rat lymph nodes}.
+\newblock \emph{\bibinfo{journal}{Archives of Histology and Cytology}}
+  \textbf{\bibinfo{volume}{71}}, \bibinfo{pages}{69--76}
+  (\bibinfo{year}{2008}).
+
+\bibitem{Boisvert2007}
+\bibinfo{author}{Boisvert, M.}, \bibinfo{author}{Gendron, S.},
+  \bibinfo{author}{Chetoui, N.} \& \bibinfo{author}{Aoudjit, F.}
+\newblock \bibinfo{title}{Alpha2beta1 integrin signaling augments t cell
+  receptor-dependent production of interferon-gamma in human t cells}.
+\newblock \emph{\bibinfo{journal}{Molecular Immunology}}
+  \textbf{\bibinfo{volume}{44}}, \bibinfo{pages}{3732--3740}
+  (\bibinfo{year}{2007}).
+
+\bibitem{Ben-Horin2004}
+\bibinfo{author}{Ben-Horin, S.} \& \bibinfo{author}{Bank, I.}
+\newblock \bibinfo{title}{The role of very late antigen-1 in immune-mediated
+  inflammation}.
+\newblock \emph{\bibinfo{journal}{Clinical Immunology}}
+  \textbf{\bibinfo{volume}{113}}, \bibinfo{pages}{119--129}
+  (\bibinfo{year}{2004}).
+
+\bibitem{Forget2014}
+\bibinfo{author}{Forget, M.-A.} \emph{et~al.}
+\newblock \bibinfo{title}{Activation and propagation of tumor-infiltrating
+  lymphocytes on clinical-grade designer artificial antigen-presenting cells
+  for adoptive immunotherapy of melanoma}.
+\newblock \emph{\bibinfo{journal}{Journal of Immunotherapy}}
+  \textbf{\bibinfo{volume}{37}}, \bibinfo{pages}{448--460}
+  (\bibinfo{year}{2014}).
+
+\bibitem{Cheung2018}
+\bibinfo{author}{Cheung, A.~S.}, \bibinfo{author}{Zhang, D. K.~Y.},
+  \bibinfo{author}{Koshy, S.~T.} \& \bibinfo{author}{Mooney, D.~J.}
+\newblock \bibinfo{title}{Scaffolds that mimic antigen-presenting cells enable
+  ex vivo expansion of primary {T} cells}.
+\newblock \emph{\bibinfo{journal}{Nature Biotechnology}}
+  \textbf{\bibinfo{volume}{36}}, \bibinfo{pages}{160--169}
+  (\bibinfo{year}{2018}).
+
+\bibitem{Rio2018}
+\bibinfo{author}{del R{\'{\i}}o, E.~P.}, \bibinfo{author}{Miguel, M.~M.},
+  \bibinfo{author}{Veciana, J.}, \bibinfo{author}{Ratera, I.} \&
+  \bibinfo{author}{Guasch, J.}
+\newblock \bibinfo{title}{Artificial 3d culture systems for t cell expansion}.
+\newblock \emph{\bibinfo{journal}{{ACS} Omega}} \textbf{\bibinfo{volume}{3}},
+  \bibinfo{pages}{5273--5280} (\bibinfo{year}{2018}).
+
+\bibitem{Delalat2017}
+\bibinfo{author}{Delalat, B.} \emph{et~al.}
+\newblock \bibinfo{title}{{3D printed lattices as an activation and expansion
+  platform for T cell therapy}}.
+\newblock \emph{\bibinfo{journal}{Biomaterials}}
+  \textbf{\bibinfo{volume}{140}}, \bibinfo{pages}{58--68}
+  (\bibinfo{year}{2017}).
+
+\bibitem{meyer15_immun}
+\bibinfo{author}{Meyer, R.~A.} \emph{et~al.}
+\newblock \bibinfo{title}{Immunoengineering: Biodegradable nanoellipsoidal
+  artificial antigen presenting cells for antigen specific t-cell activation
+  (small 13/2015)}.
+\newblock \emph{\bibinfo{journal}{Small}} \textbf{\bibinfo{volume}{11}},
+  \bibinfo{pages}{1612--1612} (\bibinfo{year}{2015}).
+
+\bibitem{Lambert2017}
+\bibinfo{author}{Lambert, L.~H.} \emph{et~al.}
+\newblock \bibinfo{title}{{Improving T Cell Expansion with a Soft Touch.}}
+\newblock \emph{\bibinfo{journal}{Nano letters}} \textbf{\bibinfo{volume}{17}},
+  \bibinfo{pages}{821--826} (\bibinfo{year}{2017}).
+
+\bibitem{Xu2014}
+\bibinfo{author}{Xu, Y.} \emph{et~al.}
+\newblock \bibinfo{title}{Closely related t-memory stem cells correlate with in
+  vivo expansion of car.cd19-t cells and are preserved by il-7 and il-15.}
+\newblock \emph{\bibinfo{journal}{Blood}} \textbf{\bibinfo{volume}{123}},
+  \bibinfo{pages}{3750--3759} (\bibinfo{year}{2014}).
+
+\bibitem{Fraietta2018}
+\bibinfo{author}{Fraietta, J.~A.} \emph{et~al.}
+\newblock \bibinfo{title}{Determinants of response and resistance to {CD}19
+  chimeric antigen receptor ({CAR}) t cell therapy of chronic lymphocytic
+  leukemia}.
+\newblock \emph{\bibinfo{journal}{Nature Medicine}}
+  \textbf{\bibinfo{volume}{24}}, \bibinfo{pages}{563--571}
+  (\bibinfo{year}{2018}).
+
+\bibitem{Gattinoni2011}
+\bibinfo{author}{Gattinoni, L.} \emph{et~al.}
+\newblock \bibinfo{title}{A human memory t cell subset with stem
+  cell{\textendash}like properties}.
+\newblock \emph{\bibinfo{journal}{Nature Medicine}}
+  \textbf{\bibinfo{volume}{17}}, \bibinfo{pages}{1290--1297}
+  (\bibinfo{year}{2011}).
+
+\bibitem{Gattinoni2012}
+\bibinfo{author}{Gattinoni, L.}, \bibinfo{author}{Klebanoff, C.~A.} \&
+  \bibinfo{author}{Restifo, N.~P.}
+\newblock \bibinfo{title}{{Paths to stemness: building the ultimate antitumour
+  T cell.}}
+\newblock \emph{\bibinfo{journal}{Nature reviews. Cancer}}
+  \textbf{\bibinfo{volume}{12}}, \bibinfo{pages}{671--84}
+  (\bibinfo{year}{2012}).
+
+\bibitem{Wang2018}
+\bibinfo{author}{Wang, D.} \emph{et~al.}
+\newblock \bibinfo{title}{Glioblastoma-targeted {CD}4+ {CAR} t cells mediate
+  superior antitumor activity}.
+\newblock \emph{\bibinfo{journal}{{JCI} Insight}} \textbf{\bibinfo{volume}{3}}
+  (\bibinfo{year}{2018}).
+
+\bibitem{Yang2017}
+\bibinfo{author}{Yang, Y.} \emph{et~al.}
+\newblock \bibinfo{title}{{TCR} engagement negatively affects {CD}8 but not
+  {CD}4 {CAR} t cell expansion and leukemic clearance}.
+\newblock \emph{\bibinfo{journal}{Science Translational Medicine}}
+  \textbf{\bibinfo{volume}{9}}, \bibinfo{pages}{eaag1209}
+  (\bibinfo{year}{2017}).
+
+\bibitem{Heathman2015}
+\bibinfo{author}{Heathman, T. R.~J.} \emph{et~al.}
+\newblock \bibinfo{title}{Expansion, harvest and cryopreservation of human
+  mesenchymal stem cells in a serum-free microcarrier process}.
+\newblock \emph{\bibinfo{journal}{Biotechnology and Bioengineering}}
+  \textbf{\bibinfo{volume}{112}}, \bibinfo{pages}{1696--1707}
+  (\bibinfo{year}{2015}).
+
+\bibitem{Sart2011}
+\bibinfo{author}{Sart, S.}, \bibinfo{author}{Errachid, A.},
+  \bibinfo{author}{Schneider, Y.-J.} \& \bibinfo{author}{Agathos, S.~N.}
+\newblock \bibinfo{title}{Controlled expansion and differentiation of
+  mesenchymal stem cells in a microcarrier based stirred bioreactor}.
+\newblock \emph{\bibinfo{journal}{{BMC} Proceedings}}
+  \textbf{\bibinfo{volume}{5}} (\bibinfo{year}{2011}).
+
+\end{thebibliography}

tex/thesis.tex

@@ -48,6 +48,12 @@
 \newacronym{cpp}{CPP}{critical process parameter}
 \newacronym{dms}{DMS}{degradable microscaffold}
 \newacronym{doe}{DOE}{design of experiments}
+\newacronym{gmp}{GMP}{Good Manufacturing Practices}
+\newacronym{cho}{CHO}{Chinese hamster ovary}
+\newacronym{all}{ALL}{acute lymphoblastic leukemia}
+\newacronym{pdms}{PDMS}{polydimethylsiloxane}
+\newacronym{dc}{DC}{dendritic cell}
+\newacronym{il2}{IL2}{interleukin 2}
 
 \newcommand{\mytitle}{
   \Large{
@@ -234,6 +240,87 @@ quality in an industrial setting.
 
 \chapter{introduction}
 
+T cell-based immunotherapies have received great interest from clinicians and
+industry due to their potential to treat, and often cure, cancer and other
+diseases\cite{Fesnak2016,Rosenberg2015}. In 2017, Novartis and Kite Pharma
+received FDA approval for \textit{Kymriah} and \textit{Yescarta} respectively,
+two genetically-modified \gls{car} T cell therapies against B cell malignancies.
+Despite these successes, \gls{car} T cell therapies are constrained by an
+expensive and difficult-to-scale manufacturing process with little control on
+cell quality and phenotype3,4. State-of-the-art T cell manufacturing techniques
+focus on anti-CD3 and anti-CD28 activation and expansion, typically presented on
+superparamagnetic, iron-based microbeads (Invitrogen Dynabead, Miltenyi MACS
+beads), on nanobeads (Miltenyi TransACT), or in soluble tetramers
+(Expamer)\cite{Roddie2019,Dwarshuis2017,Wang2016, Piscopo2017, Bashour2015}.
+These strategies overlook many of the signaling components present in the
+secondary lymphoid organs where T cells expand in vivo. Typically, T cells are
+activated under close cell-cell contact, which allows for efficient
+autocrine/paracrine signaling via growth-stimulating cytokines such as
+\gls{il2}. Additionally, the lymphoid tissues are comprised of \gls{ecm}
+components such as collagen, which provide signals to upregulate proliferation,
+cytokine production, and pro-survival pathways\cite{Gendron2003, Ohtani2008,
+  Boisvert2007, Ben-Horin2004}. We hypothesized that culture conditions that
+better mimic these in vivo expansion conditions of T cells, can significantly
+improve the quality and quantity of manufactured T cells and provide better
+control on the resulting T cell phenotype.
+
+% TODO mention the Cloudz stuff that's in my presentation
+
+A variety of solutions have been proposed to make the T cell expansion process
+more physiological. One strategy is to use modified feeder cell cultures to
+provide activation signals similar to those of \glspl{dc}\cite{Forget2014}.
+While this has the theoretical capacity to mimic many components of the lymph
+node, it is hard to reproduce on a large scale due to the complexity and
+inherent variability of using cell lines in a fully \gls{gmp}-compliant manner.
+Others have proposed biomaterials-based solutions to circumvent this problem,
+including lipid-coated microrods\cite{Cheung2018}, 3D-scaffolds via either
+Matrigel\cite{Rio2018} or 3d-printed lattices\cite{Delalat2017}, ellipsoid
+beads\cite{meyer15_immun}, and \gls{mab}-conjugated \gls{pdms}
+beads\cite{Lambert2017} that respectively recapitulate the cellular membrane,
+large interfacial contact area, 3D-structure, or soft surfaces T cells normally
+experience in vivo. While these have been shown to provide superior expansion
+compared to traditional microbeads, none of these methods has been able to show
+preferential expansion of functional naïve/memory and CD4 T cell populations.
+Generally, T cells with a lower differentiation state such as naïve and memory
+cells have been shown to provide superior anti-tumor potency, presumably due to
+their higher potential to replicate, migrate, and engraft, leading to a
+long-term, durable response\cite{Xu2014, Fraietta2018, Gattinoni2011,
+  Gattinoni2012}. Likewise, CD4 T cells are similarly important to anti-tumor
+potency due to their cytokine release properties and ability to resist
+exhaustion\cite{Wang2018, Yang2017}. Therefore, methods to increase naïve/memory
+and CD4 T cells in the final product are needed, a critical consideration being
+ease of translation to industry and ability to interface with scalable systems
+such as bioreactors.
+
+% TODO probably need to address some of the modeling stuff here as well
+
+This thesis describes a novel degradable microscaffold-based method derived from
+porous microcarriers functionalized with anti-CD3 and anti-CD28 \glspl{mab} for
+use in T cell expansion cultures. Microcarriers have historically been used
+throughout the bioprocess industry for adherent cultures such as stem cells and
+\gls{cho} cells, but not with suspension cells such as T
+cells\cite{Heathman2015, Sart2011}. The microcarriers chosen to make the DMSs in
+this study have a microporous structure that allows T cells to grow inside and
+along the surface, providing ample cell-cell contact for enhanced autocrine and
+paracrine signaling. Furthermore, the carriers are composed of gelatin, which is
+a collagen derivative and therefore has adhesion domains that are also present
+within the lymph nodes. Finally, the 3D surface of the carriers provides a
+larger contact area for T cells to interact with the \glspl{mab} relative to
+beads; this may better emulate the large contact surface area that occurs
+between T cells and \glspl{dc}. These microcarriers are readily available in
+over 30 countries and are used in an FDA fast-track-approved combination retinal
+pigment epithelial cell product (Spheramine, Titan Pharmaceuticals) {\#}[Purcell
+documentation]. This regulatory history will aid in clinical translation. We
+show that compared to traditional microbeads, \gls{dms}-expanded T cells not
+only provide superior expansion, but consistently provide a higher frequency of
+naïve/memory and CD4 T cells (CCR7+CD62L+) across multiple donors. We also
+demonstrate functional cytotoxicity using a CD19 \gls{car} and a superior
+performance, even at a lower \gls{car} T cell dose, of \gls{dms}-expanded
+\gls{car}-T cells in vivo in a mouse xenograft model of human B cell \gls{all}.
+Our results indicate that \glspl{dms} provide a robust and scalable platform for
+manufacturing therapeutic T cells with higher naïve/memory phenotype and more
+balanced CD4+ T cell content.
+
 \section*{overview}
 
 Insert overview here
@@ -310,7 +397,7 @@ bla bla
 \chapter{References}
 \renewcommand{\section}[2]{} % noop the original bib section header
 
-\bibliography{../proposal}
+\bibliography{references}
 
 \bibliographystyle{naturemag}