ADD background on T cells at large

tex/thesis.tex

@@ -61,6 +61,8 @@
 
 \renewcommand{\glossarysection}[2][]{} % remove glossary title
 \makeglossaries
+\newacronym{til}{TIL}{tumor infiltrating lymphocyte}
+\newacronym{tcr}{TCR}{T cell receptor}
 \newacronym{act}{ACT}{adoptive cell therapies}
 \newacronym{qc}{QC}{quality control}
 \newacronym{tcm}{T\textsubscript{cm}}{central memory T cell}
@@ -76,6 +78,7 @@
 \newacronym{gmp}{GMP}{Good Manufacturing Practices}
 \newacronym{cho}{CHO}{Chinese hamster ovary}
 \newacronym{all}{ALL}{acute lymphoblastic leukemia}
+\newacronym{cll}{CLL}{chronic lymphoblastic leukemia}
 \newacronym{pdms}{PDMS}{polydimethylsiloxane}
 \newacronym{dc}{DC}{dendritic cell}
 \newacronym{il}{IL}{interleukin}
@@ -113,7 +116,6 @@
 \newacronym{bmi}{BMI}{body mass index}
 \newacronym{a2b1}{A2B1}{integrin $\upalpha$1$\upbeta$1}
 \newacronym{a2b2}{A2B2}{integrin $\upalpha$1$\upbeta$2}
-\newacronym{til}{TIL}{tumor infiltrating lymphocytes}
 \newacronym{nsg}{NSG}{NOD scid gamma}
 \newacronym{colb}{COL-B}{collagenase B}
 \newacronym{cold}{COL-D}{collagenase D}
@@ -631,15 +633,75 @@ However, the characteristic shared by all the cell types in this application is
 the fact that they are adherent. In this work, we explore the use of
 microcarrier for T cells, which are naturally non-adherent.
 
+\subsection{overview of T cells in immunotherapies}
+
+% all numbers reflect the citation index in my review paper
+
+One of the first successful T cell-based immunotherapies against cancer is
+\glspl{til} [78]. This method works by taking tumor specimens from a patient,
+allowing the tumor-reactive lymphocytes to expand \exvivo{}, and then
+administered back to the patient along with a high dose of \il{2} [44]. In
+particular, \gls{til} therapy has shown robust results in treating melanoma [1],
+although \gls{til} have been found in other solid tumors such as
+gastointestinal, cervical, lung, and ovarian [78-83], and their presence is
+generally associate with favorable outcomes [84]. \glspl{til} are heterogenous
+cell mixtures and generally are comprised of CD3 T cells and $\upgamma\updelta$
+T cells [85, 86]. To date, there are over 250 open clinical trials using
+\glspl{til}.
+
+Besides \gls{til}, the other broad class of T cell immunotherapies that has
+achieved great success in treating cancer in recent decades are gene-modified T
+cells. Rather than expand T cells that are present natively (as is the case with
+\gls{til} therapy), gene-modified T cell therapies entail extracting T cells
+from either the cancer patient (autologous) or a healthy donor (allogeneic) and
+reprogramming them genetically to target a tumor antigen. In theory this offers
+much more flexibility.
+
+T cells with transduced \glspl{tcr} were first designed to overcome the
+limitations of \gls{til} [78,79]. In this case, T cells are transduced \exvivo{}
+with a lentiviral vector to express a \gls{tcr} targeting a tumor antigen. T
+cells transduced with \glspl{tcr} against MART-1 have shown robust results in
+melanoma patients [9], and analogous therapies targeted toward MY-ESO-1 have
+shown robust results against synovial sarcoma [10]. To date, there are over 200
+clinical trials using T cells with transduced \glspl{tcr}.
+
+While transduced \glspl{tcr} offer some flexibility in retargeting T cells
+toward relevant tumor antigens, they are still limited in that they can only
+target antigens that are presented via \gls{mhc} complexes. \gls{car} T cells
+overcome this limitation by using a the heavy and light chains (scFv) from a
+\gls{mab} which can target any antigen recognizable by antibodies. \gls{car} T
+cells were first demonstrated in 1989, where the author swapped the
+antigen-recognition domains of a native \gls{tcr} with a that of a foreign
+\gls{tcr} [91]. Since then, this method has progressed to using an scFv with a
+CD3$\upzeta$ stimulatory domain along with the CD28, OX-40, or 4-1BB domains for
+costimulation. Since these can all be expressed with one protein sequence,
+\gls{car} T cells are relatively simple to produce and require only a single
+genetic transduction step (usually a lentiviral vector) to reprogram a batch T
+cells \exvivo{} toward the desired antigen. \gls{car} T cells have primarily
+found success in against CD19- and CD20-expressing tumors such as \gls{all} and
+\gls{cll} (eg B-cell malignancies).
+
+% BACKGROUND where else have they been approved?
+Out of all the T cell therapies discussed thus far, \gls{car} T cells have
+experienced the most commercial success and excitement. In 2017, Novartis and
+Kite Pharma acquired FDA approval for \textit{Kymriah} and \textit{Yescarta}
+respectively, both of which are \gls{car} T cell therapies against B-cell
+malignancies.
+% BACKGROUND beef this up, this is a big deal
+\gls{car} T cells are under further exploration for use in many other tumors,
+including multiple myeloma, mesothelioma, pancreatic cancer, glioblastoma,
+neuroblastoma, and prostate cancer, breast cancer, non-small-cell lung cancer,
+and others [78,79,94,95]. To date, there are almost 1000 clinical trials using
+\gls{car} T cells.
+
+% TODO there are other T cells like virus-specific T cells and gd T cells, not
+% that they matter...
+
 \subsection*{current T cell manufacturing technologies}
 
-\Gls{car} T cell therapy has received great interest from both academia and
+Despite these success of T cell therapies (especially \gls{car} T cell
-industry due to its potential to treat cancer and other
+therapies) they are constrained by an expensive and difficult-to-scale
-diseases\cite{Fesnak2016, Rosenberg2015}. In 2017, Novartis and Kite Pharma
+manufacturing process\cite{Roddie2019, Dwarshuis2017}.
-acquired FDA approval for \textit{Kymriah} and \textit{Yescarta} respectively,
-two \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\cite{Roddie2019, Dwarshuis2017}.
 
 Of critical concern, state-of-the-art manufacturing techniques focus only on
 Signal 1 and Signal 2-based activation via \acd{3} and \acd{28} \glspl{mab},
@@ -683,6 +745,14 @@ cytokine release properties and ability to resist exhaustion\cite{Wang2018,
   Yang2017}, and no method exists to preferentially expand the CD4 population
 compared to state-of-the-art systems.
 
+\subsection{methods to scale T cells}
+
+\subsection{overview of T cell quality}
+
+% memory
+% CD4
+% viability
+
 \subsection*{integrins and T cell signaling}
 
 Because the microcarriers used in this work are derived from collagen, one key