https://doi.org/10.53453/ms.2024.9.5
Chimeric antigen receptor T–cell therapy for solid tumors:
indications, progress, challenges and possible strategies
Silvija Makrickaitė
1
, Dovilė Rimkūnaitė
1
, Gabrielė Nešta
2
1
Lithuanian University of Health Sciences, Academy of Medicine, Faculty of Medicine, Kaunas, Lithuania
2
Lithuanian University of Health Sciences Kaunas Clinics, Department of Oncology and Hematology, Kaunas,
Lithuania
Abstract
Background. Adoptive cell therapy using chimeric antigen receptor (CAR) technology is one of the most
advanced engineering platforms for cancer immunotherapy. CAR–T cells have shown remarkable efficacy in the
treatment of hematological malignancies. However, many challenges limit the therapeutic efficacy of CAR–T
cells in solid tumors. Here, we review these challenges and discuss strategies to improve the effector function of
CAR–T cells for the adoptive immunotherapy for solid tumors.
Aim. To select and analyze the material provided by experts about CAR–T cell therapy for solid tumors.
Materials and methods. The literature search was performed in the PubMed database using keywords “CAR–T
cell”, “solid tumors”, “cancer immunotherapy”, “tumor microenvironment”. The literature review includes 53
articles in English, published between 2014 and 2024.
Results. Better antitumor effect of CAR–T cell therapy can be achieved by finding more specific and abundant
surface antigens, promoting the expression of cytokines, choosing different injection methods, constructing
tertiary lymphatic structures, and improving immune memory. Moreover, other immune cells, such as NK cells
and macrophages, are becoming potential alternatives for CAR–T cells.
Conclusions. To improve the efficacy of CAR–T cell therapy, feasible solutions were proposed from the aspects
of design, infiltration and working of CAR–T cells. Further in–depth investigations should be conducted to
overcome the present restrictions of CAR–T cell therapy for it to be as effective in the treatment of solid tumors
as it is in the treatment of hematological ones.
Keywords: CAR–T cell, solid tumors, cancer immunotherapy, tumor microenvironment.
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Medical Sciences 2024 Vol. 12 (4), p. 38-46, https://doi.org/10.53453/ms.2024.9.5
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1. Introduction
Cell immunotherapy using chimeric antigen
receptor (CAR) technology is one of the most
advanced methods of cancer immunotherapy
engineering. CAR–T cells have demonstrated
excellent efficacy in treating malignant hematolo-
gical tumors, but there are many challenges limiting
their effectiveness in treating solid tumors, including
immunosuppressive tumor microenvironment
(TME), insufficient tumor infiltration, and the
absence of tumor–specific antigens [1]. Here we will
review these challenges and discuss future prospects
and potential strategies that could improve the
effector function of CAR–T cells in the treatment of
solid tumors.
2. Materials and methods
The literature review was conducted by searching
for scientific publications in the PubMed database,
using the following keywords in English: CAR–T
cell, solid tumors, cancer immunotherapy, tumor
microenvironment. The review includes articles
written in English, published during the period
2014–2024.
3. Results
3.1 CAR–T cell therapy – what is it?
CAR–T cell therapy is an innovative cancer
treatment approach in which genetically modified T
cells are used to combat cancer cells. CARs are
synthetic receptors that redirect lymphocytes,
typically T cells, to recognize and eliminate cells
expressing a specific target antigen [2, 3]. The
binding of CARs to target antigens is independent of
tissue compatibility complex receptors, thus
activating T cells and inducing a potent anti-tumor
response [4, 5].
3.2
Genetic modification of CAR–T cells
T cells are extracted from a patient's blood,
genetically modified in a lab to target specific cancer
antigens, and then reintroduced into the patient's
body. This modification process spans several
weeks. CAR–T cell therapy is designed to attack
only specific types of cancer, meaning a therapy
effective against one cancer type won't work against
another [2]. The therapy involves three key stages:
collecting T cells via apheresis, genetically
engineering T cells to recognize cancer cells, and
reinfusing the modified cells back into the patient to
fight the cancer [6, 7].
3.3 CAR structure
3.3.1 Extracellular antigen–binding domain
The CAR antigen–binding domain grants specificity
to target antigens, usually derived from the variable
regions of monoclonal antibodies to form a single–
chain variable fragment (scFv). This allows CARs to
target cancer antigens on cell surfaces, activating T
cells independently of the tissue compatibility
complex [2]. However, there are also CARs that can
recognize antigens associated with intracellular
tumors using T cell receptors that depend on the
tissue compatibility complex, mimicking CAR [7,
8]. The affinity and specificity of CARs depend on
the interaction and positioning of scFv's heavy and
light chains [9]. While a high affinity is crucial for
effective antigen binding and T cell activation,
excessively high affinity can lead to toxicity [10,
11]. Factors like epitope location and antigen density
also play roles in optimizing CAR function,
highlighting the need to consider these elements to
enhance CAR–T cell efficacy [7].
3.3.2
Intracellular region
In CAR–T cells, there is an intracellular structural
region that connects the binding units to the
transmembrane domain. This allows the antigen–
binding domain to reach the target epitope. The
length and composition of the hinge region can
affect CAR functionality, including flexibility, CAR
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expression, signaling, epitope recognition, and
activation strength [12, 13]. The spacer length is also
important for the formation of the immunological
synapse. The optimal spacer length depends on the
position of the target epitope and steric hindrances
in the target cell [7]. Short spacers are better for
binding distal membrane epitopes, while long
spacers provide flexibility to access proximal
membrane or complex glycosylated antigens [12].
The choice of hinge region often relies on amino
acid sequences from CD8, CD28, IgG1, or IgG4, but
spacers derived from IgG can interact with Fcγ
receptors and lead to CAR–T cell depletion [7]. To
avoid this effect, different spacer regions or
additional engineering can be used.
3.3.3 Transmembrane domain
The transmembrane domain is a crucial yet
understudied component of CAR structures, mainly
anchoring the CAR to the T cell membrane and
impacting CAR–T cell function, including
expression, stability, signaling, and synapse
formation [14]. Commonly sourced from proteins
like CD3ζ, CD4, CD8α, or CD28, the specific
effects of different transmembrane domains on CAR
functionality are not well understood due to frequent
modifications. For instance, the CD3ζ domain can
enhance T cell activation but might reduce CAR
stability compared to CD28. Furthermore, the
combination of transmembrane and hinge domains
influences cytokine production and activation–
induced cell death [15]. Studies indicate that optimal
CAR–T cell signaling and stability are achieved by
matching the intracellular with the appropriate
transmembrane domain, with CD8α or CD28
domains potentially enhancing performance [7].
3.3.4 Intracellular signaling domain
In CAR engineering, significant focus has been
placed on the stimulatory effects to develop CARs
with optimal intracellular domains [7]. First–
generation CARs from the late 1990s, which
included CD3ζ or FcRγ signaling domains, were
found inadequate alone for effective T cell response,
showing limited clinical effectiveness [7, 16].
Second–generation CARs incorporate an additional
co–stimulatory domain, such as FDA–approved
CD28 or 4–1BB, enhancing T cell differentiation
and metabolic functions. These have shown strong
therapeutic responses in hematological
malignancies and are being tested in solid tumors [4,
17, 18]. Alternative co–stimulatory domains like
ICOS, CD27, MYD88, CD40, and OX40 have
demonstrated preclinical efficacy. Third–generation
CARs, featuring two co–stimulatory domains along
with CD3ζ, vary in effectiveness across preclinical
models, with some showing superior outcomes
compared to second–generation CARs [19].
3.4 Indications and adverse effects of CAR–
T cell therapy
3.4.1 Indications
Currently, CAR–T cell therapy is approved and used
to treat B–cell lymphomas and B–cell leukemias,
including acute lymphoblastic leukemia and chronic
lymphocytic leukemia. CAR–T cell therapy has
shown excellent clinical efficacy in treating these
diseases, however, the occurrence of adverse
reactions limits further therapeutic effectiveness of
CAR–T cells in treating other hematological or solid
tumors [18].
3.4.2 Adverse effects
CAR–T cell therapy can have serious side effects
that vary depending on the patient and their health
condition. Adverse reactions include cytokine
release syndrome (CRS), immune cell–related
neurotoxicity, off–target effects, anaphylaxis,
infections from infusion, tumor lysis syndrome, B–
cell aplasia, hemophagocytic lymphohistiocytosis,
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macrophage activation syndrome, and coagulation
disorders [6]. Early identification and effective
treatment of these reactions are crucial as they can
be life–threatening. Ongoing research aims to
develop CAR–T cells with greater anti–tumor
activity and less toxicity to the human body [20, 21].
3.5 Challenges and potential strategies of
CAR–T cell therapy
3.5.1 Lack of antigen specificity and
heterogeneity
Unlike hematological cancers, solid tumors are
characterized by heterogeneity. One consequence of
tumor heterogeneity is the expression of
heterogeneous antigens, leading to the growth of
tumor cell subpopulations when a single target
antigen is attacked. While CAR–T cells targeting a
single antigen initially induce a high response rate,
in some patients treated with these cells, the
malignant tumor cells partially or completely lose
the expression of the target antigen, a phenomenon
known as "antigen escape" [22]. Overcoming
antigen specificity and heterogeneity loss in solid
tumors can be achieved by modifying CAR–T cells
to target two or more antigens, for example, using
dual CAR constructs with different individual
antigen recognition domains or tandem CAR–T
cells with two individual antigen recognition
domains in one CAR [23]. Multiple tandem CARs
have been tested in preclinical models, including
HER2 and IL13Ra2 for glioblastoma and HER2 and
MUC1 for breast cancer, achieving better anti–
tumor responses compared to single targeted therapy
[24, 25]. Efforts are also being made to develop
CAR–T cells expressing a bispecific T–cell engager
(BiTE), which would activate bystander T cells to
recognize tumor cells – this includes the expression
of transgenic cytokines (such as IL–18, IL–36g) or
CD40L [26]. Future optimization of target antigen
selection could lead to not only improved anti–
tumor responses but also reduced incidence of
antigen escape.
3.5.2 Physical barriers
CAR–T cell therapy for solid tumors faces
challenges due to physical barriers that hinder cell
penetration, such as the dense extracellular matrix
and uneven tumor vasculature, which cause tissue
hypoxia and limit T cell movement [27]. This
hypoxia increases CTLA–4 and PD–L1 expression
and reduces necessary adhesion molecules,
complicating T cell infiltration into the tumor
microenvironment [28]. To improve infiltration and
minimize systemic toxicity, therapies are
administered directly to the tumor area. Various
delivery methods, like intravenous and intratumoral
injections, are explored to optimize efficacy [29].
Intravenous delivery can lead to cytokine release
syndrome, a potentially fatal condition, while
intratumoral injections reduce systemic side effects
and prevent the loss of CAR–T cells due to
migration [29]. Some tumors can be injected via the
third space, e.g., CNS tumors via cerebrospinal fluid
or lung tumors via the pleural cavity [31, 32].
Additionally, engineering CAR–T cells to express
heparanase might help them break through the
extracellular matrix, facilitating deeper tumor
penetration [33].
3.5.3
Immunosuppressive tumor microen-
vironment
The solid tumor microenvironment is a significant
barrier to CAR–T cell therapy due to the
immunosuppressive conditions that hinder T cell
proliferation and survival. Key suppressive factors
include cytokines, immune checkpoints like PD–1
and CTLA–4, and a challenging metabolic
environment [34]. Additionally, the tumor stroma
contains myeloid–derived suppressor cells
(MDSCs), tumor–associated macrophages (TAMs),
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and regulatory T cells (Tregs) that promote tumor
growth and metastasis [35]. To overcome these
issues, strategies include enhancing the tumor's
metabolic environment with essential amino acids
and neutralizing suppressive factors by promoting
IL–15 expression in T cells [37]. Moreover, simply
infiltrating the tumor with CAR–T cells is
insufficient; these cells must also produce cytokines
to attract more immune cells (Figure 1).
Figure 1: CAR–T cell interaction with a cancer cell.
CD3ζ, Cluster of differentiation 3 zeta, Costim,
Costimulatory domain, scFv, Single–chain variable
fragment, TAA, Tumor associated antigen.
Enhancements in cytokine production such as IL–7,
CCL19, CCL21, IL–12, CXCL11, and CCR2b have
shown promise [38–41]. Improving CAR–T cell
survival also involves targeting immunosuppressive
cells like M2 macrophages, MDSCs, and Tregs.
Combining CAR–T cell therapy with immune
checkpoint inhibitors ensures both a robust T cell
infiltrate and prolonged T cell function [42].
Pretreatments like oxaliplatin and
cyclophosphamide can boost CAR–T cell
accumulation in tumors and improve response to
therapy [43, 44]. Special attention has been given to
tertiary lymphoid structures (TLS), which enhance
antigen–specific immune responses and help CAR–
T cells survive in the tumor microenvironment [43,
44]. TLS also promote continuous immune cell
influx to sustain immunity. Techniques such as
vascular network normalization in melanoma
treatments and the use of biomaterials like collagen
matrices and hydrogels further support TLS
formation and immune cell penetration [45].
3.6 CAR–based immunotherapy
3.6.1 CAR–NK cell therapy
CAR–NK cell therapy involves genetically
modifying natural killer (NK) cells so they express
CARs targeted at specific cancer cell antigens. NK
cells are part of the innate immune system and
regulate the death of cancer cells by recognizing
target ligands. Unlike CAR–T cells, which attack
tumor cells using specific antibodies against scFv,
NK cells can be activated through their activating
and inhibitory receptors [47]. Additionally, NK cells
can induce the death of target cells via the death
receptor pathway: death ligands expressed on the
surface of NK cells (e.g., FasL, TRAIL) bind to
death receptors on target cancer cells and promote
their apoptosis [48]. CAR–NK cells can be
generated from various sources, including
peripheral and cord blood, induced pluripotent stem
cells, and cell lines. A major advantage of CAR–NK
therapy over CAR–T cell therapy is its safety and
lower risk of side effects such as cytokine release
syndrome (CRS), neurotoxicity, and graft–versus–
host disease [49]. Despite the advantages of CAR–
NK cells, they face significant challenges in
combating solid tumors due to the
immunosuppressive tumor microenvironment
(TME) and tumor heterogeneity, which, like CAR–
T cells, limit their penetration into the tumor and
survival within it. CAR–NK therapy is still in early
development but has the potential to be safe and
effective for cancer patients – further research is
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needed to determine its long–term safety and
efficacy [50].
3.6.2 CAR–M therapy
CAR–M therapy is a promising treatment method
that involves modifying macrophages to express
CARs for the recognition and destruction of cancer
cells. It also modulates the function of CAR–M cells
in the tumor environment to enhance the anti–cancer
response [51]. This therapy is promising for treating
solid tumors due to the macrophages' ability to
penetrate the tumor microenvironment: Tumor–
associated macrophages (TAMs) are the dominant
immune cells in the TME, attracted by chemokines
and growth factors released by cancer cells [52].
TAMs consist of M1 macrophages, which exhibit
anti–tumor activity, and M2 macrophages, which
promote tumor growth. The cytotoxicity of CAR–M
is activated by antigen–expressing tumor cells:
CAR–M in the M0 state transitions to the M1
phenotype, which has specific phagocytic activity
against solid tumor cells and can modulate the
immunosuppressive tumor microenvironment by
releasing cytokines and chemokines. CAR–M also
has the potential to enhance the adaptive immune
system by presenting antigens to T cells and
activating their cytotoxicity. Several ongoing
preclinical studies are investigating the efficacy of
CAR–M therapy in treating various types of solid
tumors. Current clinical trials are evaluating its
safety and effectiveness in treating various types of
cancer [53].
4. Discussion
Although CAR–T cell therapy has shown clinical
success in treating malignant hematological tumors,
there remain many challenges and obstacles in
treating solid tumors. To improve the efficacy of
CAR–T cell therapy, several solutions have been
proposed concerning CAR–T cell engineering,
infiltration, and function. By optimizing the
selection of target antigens, enhancing cytokine
expression, choosing different injection methods,
developing tertiary lymphoid structures, and
improving immune memory, a better anti–tumor
response can be expected. Additionally, other
immune cells such as NK cells and macrophages,
due to their properties, have become potential
alternatives to CAR–T cells. Thus, a better
understanding of the challenges posed by solid
tumors and ongoing clinical trials encourage the
development of CAR–T cells that could show
similar efficacy as in the treatment of malignant
hematological tumors.
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