We have recently published a
Technical Report summarizing CAR T Cells and their application to cancers. We provide a summary here. The immune system is a powerful tool that can be used in a
variety of ways. One problem is that it seems that every day we discover
another subtlety regarding how this functions. It is a tool, and a very
powerful tool, that can be used as a scalpel or a butchering ax. With the
advent of CARs, specifically designed killer T cells, CTLs or cytotoxic T
cells, one can attack cancer cells, however at times this tool can explode in
our hands. This paper is an attempt to examine the CAR T Cells as a tool which
can be engineered. The problem we face however is that in engineering the tool
we oftentimes do not have a full grasp of its effects.
Our intent herein is not to provide a detailed up to date
review of CARs but to provide a summary introduction to the potential they
provide. This area is still very much a work in progress and as such is subject
to ongoing change.
Steven Rosenberg has been studying how best to use the
immune system to fight cancer. His 1992 was a prescient piece that laid out the
future opportunities. From then until now, some 25 years, we know a great deal
about the immune system which was lacking then and furthermore we have a wealth
of tools to manipulate the cells involved.
From Kahilil et al we have an introduction to CARs which
provide continuity from the work on monoclonal antibodies, MABs:
In the past decade, advances in the use of monoclonal
antibodies (mAbs) and adoptive cellular therapy to treat cancer by modulating
the immune response have led to unprecedented responses in patients with
advanced-stage tumors that would otherwise have been fatal. To date, three
immune-checkpoint-blocking mAbs have been approved in the USA for the treatment
of patients with several types of cancer, and more patients will benefit from
immunomodulatory mAb therapy in the months and years ahead.
Concurrently, the adoptive transfer of genetically
modified lymphocytes to treat patients with hematological malignancies has
yielded dramatic results, and we anticipate that this approach will rapidly
become the standard of care for an increasing number of patients. In this
Review, we highlight the latest advances in immunotherapy and discuss the role
that it will have in the future of cancer treatment, including settings for
which testing combination strategies and 'armored' CAR T cells are recommended.
From Batlevi et al we have a discussion on the flow from
MABs to CARs with a nexus to checkpoint inhibitors, namely PD-1 inhibitors:
The success of the anti-CD20 monoclonal antibody
rituximab in the treatment of lymphoid malignancies provided proof-of-principle
for exploiting the immune system therapeutically. Since the FDA approval of
rituximab in 1997, several novel strategies that harness the ability of T cells
to target cancer cells have emerged.
Reflecting on the promising clinical efficacy of these
novel immunotherapy approaches, the FDA has recently granted 'breakthrough'
designation to three novel treatments with distinct mechanisms.
First, chimeric antigen receptor (CAR)-T-cell therapy is
promising for the treatment of adult and pediatric relapsed and/or refractory
acute lymphoblastic leukemia (ALL).
Second, blinatumomab, a bispecific T-cell engager (BiTE®)
antibody, is now approved for the treatment of adults with
Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL.
Finally, the monoclonal antibody nivolumab, which targets
the PD-1 immune-checkpoint receptor with high affinity, is used for the
treatment of Hodgkin lymphoma following treatment failure with
autologous-stem-cell transplantation and brentuximab vedotin.
Herein, we review the background and development of these
three distinct immunotherapy platforms, address the scientific advances in
understanding the mechanism of action of each therapy, and assess the current
clinical knowledge of their efficacy and safety. We also discuss future
strategies to improve these immunotherapies through enhanced engineering,
biomarker selection, and mechanism-based combination regimens.
One of the observations when dealing with cancer and the
immune system is that once when on tries a specific approach one often finds
new mechanisms which can either be used or must be thwarted.
From Jackson et al there is a discussion of the work of CARs
using CD-19 targets:
The engineered expression of chimeric antigen receptors
(CARs) on the surface of T cells enables the redirection of T-cell specificity.
Early clinical trials using CAR T cells for the treatment of patients with
cancer showed modest results, but the impressive outcomes of several trials of
CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies
have generated an increased enthusiasm for this approach. Important lessons
have been derived from clinical trials of CD19-specific CAR T cells, and
ongoing clinical trials are testing CAR designs directed at novel targets
involved in hematological and solid malignancies.
In this Review, we discuss these trials and present
strategies that can increase the antitumor efficacy and safety of CAR T-cell
therapy. Given the fast-moving nature of this field, we only discuss studies
with direct translational application currently or soon-to-be tested in the
clinical setting.
CAR T cells are chimeric antigen receptors on T cells.
Chimeric because one designs them specifically for the target cells and
essentially crated a multiheaded receptor that matches the antigen presented by
the tumor cell.
We provide a simple example below for a third-generation
CAR:
The function of this designed T cell it to allow a normal
CTL, killer T cell, attach to a cancer cell with a recognizable antigen, and
then to do what CTLs do well, allow the attacked cell to go into apoptosis, and
just disappear, its constituents being used elsewhere.
We demonstrate this process graphically above. We now review
some of the key functions of T cells. The two types of T cells of interest are
T helper and T killer or cytotoxic T cells, CTL. The CTL is the prime target of
interest for it is the cell which can attach to a tumor cell and effect
apoptosis of the tumor cell by its normal operations. The T helper supports the
CTL by expressing IL-2 which allows for proliferation of that specific CTL
type.
The CTL has surface receptors as shown below. Two are
extending well beyond the cell wall and the remaining four are below the cell
wall and provide for intra cellular activation. The complex acts in unison
attaching to targeted cells. Now the essence of CARs is to modify this receptor
so as to effect targeting of tumor cells and their exposed antigens.
This CTL binding process is shown below. Simply the process
is as follows:
1. An antigen presenting cell, APC, in this case a tumor
cell, presents an antigen using the MHC I molecule. Also, the tumor cell may
have another surface protein that results in the presentation of a tumor
specific surface molecule like CD-19 in the case of hematological malignancies.
The process starts with the ability to identify this molecule.
2. Then the CTL has a matching or cognate receptor which
aligns with the MHC I and Ag combination and it attaches itself, and via CD-8
strongly binds to the cell, also using CD-3.
3. Upon binding the CTL can release cytokines or equivalents
that result in the apoptosis of the cell.
We show the apoptosis below. Here the bound CTL recognizes
the cancer cell and then releases apoptosis inciting proteins.
Thus, for any cancer cell we should be able to use this
process, if we first know the Ag that is presented and second if we can create
a receptor on a T killer cell, CTL, that recognizes that ligand and in turn can
activate the apoptotic process.
In the simplest terms this is how we might proceed.
1. Extract a tumor cell.
2. Ascertain the surface molecules and determine which one
is unique to that type of cell and NOT common in other cells. You don't want
the CTLs attacking everything.
3. Create a binding receptor for that ligand.
4. Extract the patient's CTL and insert by some reverse
transcription manner, or CRISPR type approach the genes for that designed
receptor.
5. Grow these modified cells in vitro using IL-2 or the
like.
6. Insert these back in the patient.
This is the "back of the envelope" approach to CAR
therapy. Of course, there are many obstacles and the approach uses tools which
may have to be gathered from afar. But as those who have developed CARs have
shown it is doable.
Now what we have described above is not that simple. There
are what are called a variety of "Checkpoint Inhibitors" that are an
integral part of the control mechanisms of the immune system so that it does
not go wild and destroy itself.
Let us begin with a brief review of PD-1 pathways. We have
previously discussed the CTLA-4 blockage and the current approaches used to
inactivate that element of T cell suppression. We summarize that again in the
figure below.
Now CTLA-4 is not the only inhibitor of T cell action. PD-1
also can be activated and thus suppress T cell activity. This means that is we
can find a way to inactivate or inhibit PD-1 then we have another way to seek
possible activation of the T cells. In fact, perhaps we can do both and secure
a super active T cell base. That is in essence the Wolchok approach. We depict
this in the figure below.
The paper by Okazaki and Honjo in 2007 also details many of
the critical elements regarding the PD-1 and its ligands. It details many of
the recognized disease states as well. As they state:
Since the discovery of PD-1 in 1992, the biological
function of PD-1 remained mystery for many years. Generation of Pdcd1mice and
the discovery of its ligands turned around the situation and the function of
PD-1 was unveiled thick and fast in these 5 years. Consequently, it became
clear that PD-1 plays critical roles in the regulation of autoimmunity, tumor
immunity, infectious immunity, transplantation immunity, allergy and immune
privilege. The development of autoimmune diseases by Pdcd1 mice especially
enchanted clinicians and promoted clinical research as well.
Currently, many groups are trying to generate not only
PD-1 antagonists for the treatment of cancer and infectious diseases but also
PD-1 agonists for the treatment of autoimmune diseases, allergy and transplant
rejection. Among these, humanized antibody against human PD-1 was approved by
Food and Drug Administration of the United States as an investigational new
drug in August 1, 2006. Clinical trials will test its clinical efficacy on
cancer and infectious diseases.
Now we can examine the features of PD-1. As Freeman states:
T cell activation requires a TCR mediated signal, but the
strength, course, and duration are directed by costimulatory molecules and
cytokines from the antigen-presenting cell (APC). An unexpected finding was
that some molecular pairs attenuate the strength of the TCR signal, a process
termed co-inhibition.
The threshold for the initiation of an immune response is
set very high, with a requirement for both antigen recognition and costimulatory
signals from innate immune recognition of ‘‘danger’’ signals. Paradoxically, T
cell activation also induces expression of co-inhibitory receptors such as
programmed death-1 (PD-1).
Cytokines produced after T cell activation such as INF-
and IL-4 up-regulate PD-1 ligands, establishing a feedback loop that attenuates
immune responses and limits the extent of immune-mediated tissue damage unless
overridden by strong costimulatory signals. PD-1 is a CD28 family member
expressed on activated T cells, B cells, and myeloid cells. In proximity to the
TCR signaling complex, PD-1 delivers a co-inhibitory signal upon binding to
either of its two ligands, PD-L1 or PD-L2.
Engagement of ligand results in tyrosine phosphorylation
of the PD-1 cytoplasmic domain and recruitment of phosphatases, particularly
SHP2
Additional insight can also be provided by examining the
regulatory T cells as well. As Francisco et al state:
Regulatory T cells (Tregs) and the PD-1: PD-ligand (PD-L)
pathway is both critical to terminating immune responses. Elimination of either
can result in the breakdown of tolerance and the development of autoimmunity.
The PD-1: PD-L pathway can thwart self-reactive T cells and protect against
autoimmunity in many ways. In this review, we highlight how PD-1 and its
ligands defend against potentially pathogenic self-reactive effector T cells by
simultaneously harnessing two mechanisms of peripheral tolerance: (i) the
promotion of Treg development and function and (ii) the direct inhibition of potentially
pathogenic self-reactive T cells that have escaped into the periphery.
Treg cells induced by the PD-1 pathway may also assist in
maintaining immune homeostasis, keeping the threshold for T-cell activation
high enough to safeguard against autoimmunity. PD-L1 expression on
non-hematopoietic cells as well as hematopoietic cells endows PD-L1 with the
capacity to promote Treg development and enhance Treg function in lymphoid
organs and tissues that are targets of autoimmune attack. At sites where
transforming growth factor-β is present (e.g. sites of immune privilege or
inflammation), PD-L1 may promote the de novo generation of Tregs.
CAR cells are essentially engineered T cells, specifically
cytotoxic T lymphocytes, CTL, engineered to target specific cells such as those
in various hematopoietic cell lines. such as leukemias and lymphomas. There is
no fundamental reason that they cannot be used for solid tumors but there are
certain operational barriers which must be overcome.
As Kershaw et al note:
There are two main types of antigen receptors used in
genetic redirection.
The first utilizes the native alpha and beta chains of a
TCR specific for tumor antigen.
The second is termed a chimeric antigen receptor (CAR),
which is composed of an extracellular domain derived from tumor-specific
antibody, linked to an intracellular signaling domain. Genes encoding these
receptors are inserted into patient's T cells using viral vectors to generate
tumor reactive T cells….
The specificity of CARs is derived from tumor-specific
antibodies, which are relatively simple to generate through immunization of
mice. Recombinant techniques can be used to humanize antibodies, or mice
expressing human immunoglobulin genes can be used to generate fully human
antibodies. Single-chain variable fragments of antibodies are used in the extracellular
domain of CARs, which are joined through hinge and transmembrane regions to
intracellular signaling domains.
As Miller and Sadelain note:
The advent of gene transfer technologies, in particular
those enabling the transduction of human T lymphocytes using gibbon ape
leukemia virus envelope-pseudotyped g-retroviral vectors, created new
opportunities for immune intervention based on T cell engineering. Patients’ T
cells, easily accessible in peripheral blood, can be genetically instructed to
target tumors by transduction of receptors for antigen, utilizing either the
physiological TCR or synthetic receptors now known as CARs.
Both approaches have shown clinical successes,
particularly in melanoma, targeting NYESO1, and in acute lymphoblastic leukemia,
CARs are artificial, composite receptors for antigen that integrate principles
of B cell and T cell antigen recognition. They are particularly attractive in
that they elude human leucocyte antigen (HLA) restriction and are thus
applicable to all patients irrespective of their HLA haplotypes, unlike TCRs.
CARs may also overcome HLA downregulation by tumors, which deprives T cells of
a ligand for their endogenous TCR.
The critical function of CARs is, however, not to merely
target the T cells to a tumor antigen, but to enhance T cell function. Thus,
effective CARs further integrate principles of T cell costimulation and provide
a broad spectrum of functional enhancements acquired by directly soliciting
selected costimulatory pathways
Juillerat et al note:
Adoptive immunotherapy using engineered T-cells has
emerged as a powerful approach to treat cancer. The potential of this approach
relies on the ability to redirect the specificity of T cells through genetic
engineering and transfer of chimeric antigen receptors (CARs) or engineered
TCRs1. Numerous clinical studies have demonstrated the potential of adoptive
transfer of CAR T cells for cancer therapy but also raised the risks associated
with the cytokine-release syndrome (CRS) and the “on-target off-tumor” effect.
To date, few strategies have been developed to
pharmacologically control CAR engineered T-cells and may rely on suicide
mechanisms. Such suicide strategies leading to a complete eradication of the
engineered T-cells will result in the premature end of the treatment.
Consequently, implementing non-lethal control of engineered CAR T-cells
represents an important advancement to improve the CAR T-cell technology and
its safety.
Small molecule
based approaches that rely on dimerizing partner proteins have already been
used to study, inter alia, the mechanism of T-cell receptor triggering15. Very
recently, Lim and colleagues have adapted this approach to control engineered
T-cells through the use of a multichain receptor.
Here, we describe a strategy to create a switchable
engineered CAR T-cells. Our approach is based on engineering a system that is
directly integrated in the hinge domain that separate the scFv from the cell
membrane. In addition, we chose to implement this strategy in a novel CAR
architecture that relies on the FceRI receptor scaffold.
The particularity of this design resides in the
possibility to split or combine different key functions of a CAR such as
activation and costimulation within different chains of a receptor complex,
mimicking the complexity of the TCR native architecture. In this report, we
showed that the hinge engineering approaches allowed to turn a T-cell endowed
with an engineered CAR from an off-state to an on-state.
By controlling the scFv presentation at the cell surface
upon addition of the small molecule, our system allowed to further induce the
cytolytic properties of the engineered T-cell. Overall, this non-lethal system
offers the advantage of a “transient CAR T-cell” for safety while letting open
the possibility of multiple specific cytotoxicity cycles using a small molecule
drug.
Principles of T Cell Engineering and CAR Design
(A) Integration of B cell and T cell antigen recognition
principles in the design of CARs. The heavy and light chain chains, which are
components of the B cell receptor and Igs, are fused to the T-cell-activating z
chain of the TCR-associated CD3 complex to generate non-MHC restricted,
activating receptors capable of redirecting T cell antigen recognition and
cytotoxicity.
(B and C) Integration of T cell activation and
costimulation principles in dual signaling CARs designed to enhance T cell
function and persistence in addition to retargeting T cell specificity. In
(B), the physiological abTCR associated with the CD3
signaling complex is flanked by the CD28 costimulatory receptor.
(C) shows a prototypic second-generation CAR, which
comprises three canonical components: an scFv for antigen recognition, the
cytoplasmic domain of the CD3z chain for T cell activation, and a costimulatory
domain to enhance T cell function and persistence. Unlike the abTCR/CD3
complex, which comprises g, d, ε, and z signaling chains and is modulated by a
multitude of costimulatory receptors, CARs possess in a single molecule the
ability to trigger and modulate antigen-specific T cell functions.
There are currently three generations of CAR T cell design.
We examine each here. As Cartellieri et al note:
In an attempt to extend the recognition specificity of T
lymphocytes beyond their classical MHC-peptide complexes, a gene-therapeutic
strategy has been developed that allows redirecting T cells to defined tumor
cell surface antigens. This strategy uses both the cellular and humoral arm of
the immune response by assembling an antigen-binding moiety, most commonly a
single chain variable fragment (scFv) derived from a monoclonal antibody,
together with an activating immune receptor.
Once this artificial immune receptor is expressed at the
surface of a modified T lymphocyte, upon binding of the scFv to its antigen an
activating signal is transmitted into the lymphocyte, which in turn triggers
its effector functions against the target cell (Figure 2). In the first
attempts to reconfigure T cells with antibody specificity the variable parts of
the TCR α and β chains were replaced with scFv fragments derived from
monoclonal antibodies. These hybrid T-cell receptors were functionally
expressed and recognized the corresponding antigens in a non-MHC-restricted
manner. As a consequence of the finding, that CD3ζ chain signaling on its own
is sufficient for T-cell activation, the first “true” chimeric single-chain
receptors were created by fusing a scFv directly to the CD3ζ chain. At that
time this concept was called the “T body approach”. Nowadays these types of
artificial lymphocyte signaling receptors are commonly referred to as chimeric
immune receptors (CIRs) or chimeric antigen receptors (CARs).
The use of CARs to redirect T cells specifically against
TAA-expressing tumor cells has a number of theoretical advantages over
classical T-cell-based immunotherapies. In contrast to the long-lasting
procedure of in vitro selection, characterization, and expansion of T-cell
clones with native specificity for MHC tumor peptide complexes, genetic modification
of polyclonal T-cell populations allows to generate TAA-specific T cells in one
to two weeks. Engraftment with CARs enables T cells to MHC-independent antigen
recognition; thus, major immune escape mechanisms of tumors such as
downregulation of MHC molecules are efficiently bypassed.
Furthermore, proliferation and survival of modified T
cells can be improved by the implementation of a multitude of signaling domains
from different immune receptors in a single CAR
Following Cartellieri et al we note regarding all three
generations that:
Evolution of CAR signaling capacities.
First generation CARs transmitted activating signals only
via ITAM-bearing signaling chains like CD3ζ or FcεRIγ, licensing the engrafted
T cells to eliminate tumor cells.
Second generation CARs contain an additional
costimulatory domain (CM I), predominantly the CD28 domain. Signaling through
these costimulatory domain leads to enhanced proliferation, cytokine secretion,
and renders engrafted T cells resistant to immunosuppression and induction of
AICD.
(Third Generation) Recent developments fused the
intracellular part of a second costimulatory molecule (CM II) in addition to
CD28 and ITAM-bearing signaling chains, thus generating tripartite signaling
CARs. T cells engrafted with third generation CARs seem to have superior
qualities regarding effector functions and in vivo persistence.
The first generation shown below is the simplest.
The second generation is as per below with the added
element.
The third generation has added flexibility as shown below
and described above.
Now the insertion of the genes to create the previously
described receptors uses a reverse transcription process. It is akin to what we
see in HIV reverse transcription and specifically uses lentiviruses as the
delivery mechanism.
As Naldini notes regarding lentiviruses:
Major hurdles for hematopoietic-stem-cell (HSC) gene
therapy include achieving efficient ex vivo gene transfer into long-term
repopulating HSCs, preventing activation of oncogenes by the nearby integration
of a vector and controlling transgene expression to avoid ectopic or
constitutive expression that leads to toxicity.
As compared to early generation gammaretroviral vectors
(γ-RVs), HIV-derived lentiviral vectors result in more efficient gene transfer
and stable, robust transgene expression in HSCs and their multilineage progeny.
Extensive preclinical work indicated important features in vector biology and
design that affect genotoxicity and highlighted strategies to alleviate it. The
self-inactivating long terminal repeats (LTRs) and integration-site preferences
of lentiviral vectors were shown to substantially alleviate insertional
genotoxicity.
When tested in γ-RVs, the self-inactivating LTR design
was shown to improve the safety of this platform as well. Retrospective analysis
of several earlier trials suggests that disease background, transgene function,
ex vivo culture and the efficiency of host repopulation can all influence the
likelihood that insertional genotoxicity will manifest in a trial.
These data helped to shape the ideas that not all
integrating vectors have the same effects and that genome-wide integration of
improved vector designs, although still a mutagenic event, can be tolerated in
the absence of aggravating circumstances. Self-inactivating lentiviral vectors
are also being used to engineer T cells with chimeric antigen receptors (CARs)
or T-cell antigen receptors for use in adoptive immunotherapy for the treatment
of cancer. The advantages of this new platform in comparison to
earlier-generation γ-RVs, which perform satisfactorily in this cell target, are
yet to be fully established. Lentiviral vectors are thought to give rise to
more robust and stable transgene expression in T cells in vivo, and could
facilitate more efficient and versatile ex vivo gene transfer while supporting
coordinated expression of multiple transgenes.
These advantages will become more relevant as the
gene-therapy field implements refined strategies, such as improved T-cell
manipulation to preserve T memory stem cells, or more demanding
cell-engineering tasks, such as the co-expression of multiple CARs (to improve
specificity) or a conditional safety switch/suicide gene (to improve safety).
We now review the process below. We have initially presented
a logical approach, then we explained how it could be accomplished and now we
return and demonstrate how this could be accomplished. We explain in detail in
the Appendix a multiplicity of such protocols in use today.
Now the mechanism above may lose some elements of control
and switch mechanisms to turn it on or off have been considered.
From Wu et al a specific mechanism is presented with its
advantages and possible concerns. They state:
Cell-based therapies have emerged as a promising
treatment modality for diseases such as cancer and autoimmunity. T cells
engineered with synthetic receptors known as chimeric antigen receptors (CARs)
have proven effective in eliminating chemotherapy resistant forms of B cell
cancers. Such CAR T cells recognize antigens on the surface of tumor cells and
eliminate them. However, CAR T cells also have adverse effects, including life threatening
inflammatory side effects associated with their potent immune activity.
Risks for severe toxicity present a key challenge to the
effective administration of such cell-based therapies on a routine basis.
The ON-switch CAR exemplifies a simple and effective
strategy to integrate cell-autonomous decision-making (e.g., detection of
disease signals) with exogenous, reversible user control. The rearrangement and
splitting of key modular components provides a simple strategy for achieving
integrated multi-input regulation. This work also highlights the importance of
developing optimized bio-inert, orthogonal control agents such as small
molecules and light, together with their cellular cognate response components,
in order to advance precision-controlled cellular therapeutics.
We graphically demonstrate this mechanism below.
The authors continue:
Titratable control of engineered therapeutic T cells
through an ON-switch chimeric antigen receptor. A conventional CAR design
activates T cells upon target cell engagement but can yield severe toxicity due
to excessive immune response.
The ON-switch CAR design, which has a split architecture,
requires a priming small molecule, in addition to the cognate antigen, to
trigger therapeutic functions. The magnitude of responses such as target cell
killing can be titrated by varying the dosage of small molecule to mitigate
toxicity. scFv, single-chain variable fragment; ITAM, immune receptor tyrosine-based
activation motif.
CAR T cell therapy has had successes and failures. It seems
to be appropriate for hematological cancers and some related ones where
immunodeficiency is an element. However, it often has some several unintended
consequences. The immune system is a very powerful system in the body. Setting
CTLs loose to do what they do best can be at times very overpowering. In addition,
the use of these systems without a means to throttle them back can present a
danger to a wide selection of patients. We examine some of these issues as
follows.
As Brudno1 and Kochenderfer have noted:
CAR T cells could damage tissues that express the antigen
recognized by the CAR. This mechanism of toxicity can be minimized but not eliminated
by an exhaustive search for expression of a targeted antigen on normal tissues
during preclinical development of a CAR.
Examples of this mechanism of toxicity have been reported
in the literature. In one study, 3 patients with metastatic renal cell
carcinoma who received infusions of autologous T cells transduced with aCAR targeting
carboxyanhydrase- IX experienced grade increases in alanine aminotransferase,
aspartate aminotransferase, or total bilirubin.
Liver biopsies of affected patients revealed a
cholangitis with a T-cell infiltration surrounding the bile ducts, and bile
duct epithelial cells were unexpectedly found to express carboxy-anhydrase-IX.
A patient with metastatic colorectal cancer who received
an infusion of autologous CAR T cells directed against the antigenERBB2
(Her-2/neu) experienced acute respiratory distress and pulmonary edema
requiring mechanical ventilation. The patient subsequently died.
As Pegram et al note:
CD19-targeted chimeric antigen receptor (CAR) T cells are
currently being tested in the clinic with very promising outcomes. However,
limitations to CAR T cell therapy exist. These include lack of efficacy against
some tumors, specific targeting of tumor cells without affecting normal tissue
and retaining activity within the suppressive tumor microenvironment. Whilst
promising clinical trials are in progress, preclinical development is focused
on optimizing CAR design, to generate “armored CAR T cells” which are protected
from the inhibitory tumor microenvironment. Studies investigating the
expression of cytokine transgenes, combination therapy with small molecule
inhibitors or monoclonal antibodies are aimed at improving the anti-tumor
efficacy of CAR T cell therapy. Other strategies aimed at improving CAR T cell
therapy include utilizing dual CARs and chemokine receptors to more
specifically target tumor cells. This review will describe the current clinical
data and some novel “armored CAR T cell” approaches for improving anti-tumor
efficacy therapy.
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