From 054f6104ebf0511b780aa769aed866066beddd00 Mon Sep 17 00:00:00 2001 From: ndwarshuis Date: Sun, 1 Aug 2021 21:52:19 -0400 Subject: [PATCH] ADD background on T cells at large --- tex/thesis.tex | 86 +++++++++++++++++++++++++++++++++++++++++++++----- 1 file changed, 78 insertions(+), 8 deletions(-) diff --git a/tex/thesis.tex b/tex/thesis.tex index c30bb19..8d6db56 100644 --- a/tex/thesis.tex +++ b/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 -industry due to its potential to treat cancer and other -diseases\cite{Fesnak2016, Rosenberg2015}. In 2017, Novartis and Kite Pharma -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}. +Despite these success of T cell therapies (especially \gls{car} T cell +therapies) they 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