ADD hypotheis
This commit is contained in:
parent
8bc312a045
commit
8f6319c223
|
@ -55,6 +55,9 @@
|
|||
\newacronym{dc}{DC}{dendritic cell}
|
||||
\newacronym{il2}{IL2}{interleukin 2}
|
||||
|
||||
%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%
|
||||
% my commands
|
||||
|
||||
\newcommand{\mytitle}{
|
||||
\Large{
|
||||
\textbf{
|
||||
|
@ -73,6 +76,15 @@
|
|||
\end{flushleft}
|
||||
}
|
||||
|
||||
\newcommand{\invivo}{\textit{in vivo}}
|
||||
|
||||
\newcommand{\invitro}{\textit{in vitro}}
|
||||
|
||||
\newcommand{\exvivo}{\textit{ex vivo}}
|
||||
|
||||
%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%
|
||||
% my environments
|
||||
|
||||
\newenvironment{mytitlepage}{
|
||||
\begin{singlespace}
|
||||
\begin{center}
|
||||
|
@ -82,6 +94,9 @@
|
|||
\end{singlespace}
|
||||
}
|
||||
|
||||
%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%%
|
||||
% document
|
||||
|
||||
\begin{document}
|
||||
|
||||
\begin{titlepage}
|
||||
|
@ -191,7 +206,7 @@ Thank you to Lex Fridman and Devin Townsend for being awesome and inspirational.
|
|||
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,
|
||||
signals found \invivo{} 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
|
||||
|
@ -208,7 +223,7 @@ 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
|
||||
demonstrate the effectiveness of the \gls{dms} platform \invivo{}. 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.
|
||||
|
@ -240,6 +255,8 @@ quality in an industrial setting.
|
|||
|
||||
\chapter{introduction}
|
||||
|
||||
\section*{overview}
|
||||
|
||||
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
|
||||
|
@ -253,14 +270,14 @@ 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
|
||||
secondary lymphoid organs where T cells expand \invivo{}. 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
|
||||
better mimic these \invivo{} 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.
|
||||
|
||||
|
@ -278,7 +295,7 @@ 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
|
||||
experience \invivo{}. 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
|
||||
|
@ -316,18 +333,19 @@ 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}.
|
||||
\gls{car}-T cells \invivo{} 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
|
||||
|
||||
\section*{hypothesis}
|
||||
|
||||
Insert hypothesis here
|
||||
The hypothesis of this dissertation was that using \glspl{dms} created from
|
||||
off-the-shelf microcarriers and coated with activating \glspl{mab} would lead to
|
||||
higher quantity and quality T cells as compared to state-of-the-art bead-based
|
||||
expansion. The objective of this dissertation was to develop this platform, test
|
||||
its effectiveness both \invivo{} and \invivo{}, and develop computational
|
||||
pipelines that could be used in a manufacturing environment.
|
||||
|
||||
\section*{specific aims}
|
||||
\subsection*{aim 1}
|
||||
|
|
Loading…
Reference in New Issue