ADD introductions to all aims
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@ -2024,6 +2024,22 @@ likely serve as a drop-in substitution to provide these benefits.
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\chapter{aim 2a}\label{aim2a}
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\chapter{aim 2a}\label{aim2a}
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\section{introduction}
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\section{introduction}
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The purpose of this sub-aim was to develop computational methods to identify novel
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\glspl{cqa} and \glspl{cpp} that could be used for release criteria, process
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control, and process optimization for the \gls{dms} platform. We hypothesized
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that T cells grown using the \gls{dms} system would produce detectable
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biological signatures in the media supernatent which corresponded to clinically
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relevent responses such as the fold expansion of the T cells or the resulting
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phenotype. We tested this hypothesis by activating T cells under a variety of
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conditions using a \gls{doe}, sampling the media at intermediate timepoints, and
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creating models to predict the outcome of the cultures. We should stress that
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the specific \glspl{cpp} and \glspl{cqa} determined by this aim are not
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necessarily universal, as this was not performed with equipment that would
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normally be used at scale. However, the process outlined here is one that can
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easily be adaptable to any system, and the specific findings themselves offer
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interesting insights that warrant further study.
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\section{methods}
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\section{methods}
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\subsection{study design}
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\subsection{study design}
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@ -2776,6 +2792,15 @@ sensors and controls for formate, lactate, along with ethanol and glucose.
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\chapter{aim 2b}\label{aim2b}
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\chapter{aim 2b}\label{aim2b}
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\section{introduction}
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\section{introduction}
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The purpose of this sub-aim was to further explore the \gls{dms} platform,
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specifically for mechanisms and pathways that could be the basis for additional
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\glspl{cpp} that could be optimized to yield higher quantity and quality of T
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cells. Our strategy in general was to perturb the \gls{dms} system from the
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normal operating conditions at which it was used up until this point either
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through temporal modulation of activation signal or by blocking pathways of
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interest using \glspl{mab}.
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\section{methods}
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\section{methods}
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\subsection{DMSs temporal modulation}
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\subsection{DMSs temporal modulation}
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@ -3246,6 +3271,21 @@ advantage via \gls{il15} signaling.
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\chapter{aim 3}\label{aim3}
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\chapter{aim 3}\label{aim3}
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\section{introduction}
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\section{introduction}
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% DO NOT COMMENT OUT THIS LINE: the real purpose of this aim was to appease
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% Nature Biotech because they think that animal models are necessary for good
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% science. This entire aim exists because of their foolishness.
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The purpose of this aim was to verify that \gls{car} T cells produced using the
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\gls{dms} system will show potent anti-tumor properties in a complex \invivo{}
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system compared to state-of-the-art bead technology. We hypothesized that due to
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the increased \ptmem{} and \pth{} phenotypes as shown in \cref{aim1}, that
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\gls{dms}-expanded T cells would show longer survival and lower tumor burden
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than those expanded with beads. We explored the effect of dosing at different
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levels and the effect of harvesting T cells at early timepoints in the culture,
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which has been shown to produce lower-differentiated T cells with higher
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potency\cite{Ghassemi2018}.
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\section{methods}
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\section{methods}
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\subsection{CD19-CAR T cell generation}
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\subsection{CD19-CAR T cell generation}
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