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