Introduction
Immunotherapy boosts the immune system's ability to fight cancer cells by modulating
the capacity of immune cells (1) (2) (3). In the last decade, there have been giant strides
in the use of immunotherapy to treat cancer, as evidenced by the approval of both
monoclonal antibodies to target different immune system components and adaptive T-
cell-based therapies (4).
Surgery, radiation therapy, and chemotherapy are typically recognized as the traditional
forms of cancer treatment. However, with its recent clinical successes, immunotherapy
has been dubbed the fourth pillar of cancer treatment (5). Because innate and adaptive
immunity consists of a wide variety of cells with various properties able to fight cancer,
the essential question was how immunotherapy could be harnessed to develop an
effective treatment against cancer (6).
Numerous cancer immunotherapy strategies are currently under investigation, which
encompasses immune checkpoint inhibitors, cancer vaccines, immunomodulators,
cytokines, monoclonal antibodies, and oncolytic viruses (OVs) (7). Although many of
these approaches have received clinical approval, they each possess inherent limitations
that hinder their full therapeutic potential. Consequently, this emphasizes the necessity
for pioneering treatments, such as chimeric antigen receptor (CAR)-T cell therapy, to
address these constraints.
Immune checkpoint inhibitors have emerged as potent allies in cancer treatment,
showing remarkable success in several malignancies. However, they have significant
limitations, including the development of resistance, immune-related adverse events,
and a low response rate in many tumor types. For instance, even in melanoma, where
immune checkpoint inhibitors have had the most success, only a subset of patients show
a durable response.
Cancer vaccines have shown promise in the preclinical setting but have struggled to
reproduce those results in the clinic. Often, the immune response they generate is
insufficient to overcome the immunosuppressive tumor microenvironment, and they
have so far been successful only in a limited number of cancers such as prostate cancer.
Immunomodulators, while potent in augmenting immune response, can induce
systemic side effects due to their non-specific nature. Additionally, resistance to these
agents can develop over time, and they often have a relatively narrow therapeutic
window. Monoclonal antibodies have also demonstrated remarkable efficacy in certain
cancers. Nevertheless, issues such as off-target toxicity, immunogenicity, resistance,
and a lack of response in a significant subset of patients persist.
These issues are indicative of the complex nature of cancer and the intricate interplay
between the tumor and the immune system, highlighting the need for innovative,
targeted therapies such as CAR-T cells. Although CAR-T cell therapy has its
limitations, such as cytokine release syndrome and the potential for on-target off-tumor
effects, it represents an exciting and promising approach in the field of cancer
immunotherapy.
The application of cellular immunotherapy precisely that which employs chimeric
antigen receptor T (CAR-T) cells, has yielded substantial advancements in the
management of malignant tumors, with a particular focus on blood cancers. It is worth
noting that targeted CD19-CAR-T cell therapy has demonstrated efficacy in the
treatment of aggressive and treatment-resistant acute leukemia (8).
CAR-T cell therapy is a groundbreaking immunotherapy where a patient’s own T cells
are genetically modified to express chimeric antigen receptors (CARs), enabling
targeted elimination of cancer cells. This modality has shown significant clinical
success in treating hematologic malignancies, particularly CD19-positive B-cell acute
lymphoblastic leukemia, large B-cell lymphoma, follicular lymphoma, and multiple
myeloma, with coverage under Japan’s national health insurance (9)
The manufacturing of CAR-T cells involves leukapheresis, genetic modification in
GMP-compliant facilities, ex vivo expansion, and rigorous quality control before
reinfusion into the patient. Prior to infusion, bridging therapies and lymphodepleting
chemotherapy enhance engraftment and efficacy (9).
Despite high response rates in blood cancers, CAR-T therapy faces considerable
limitations in solid tumors due to factors such as antigen heterogeneity, limited tumor
infiltration, and T cell exhaustion driven by immune checkpoint pathways like PD-1
and LAG-3. Strategies under investigation to address these issues include improved
antigen selection, engineered resistance to the tumor microenvironment (TME), and
enhanced cellular trafficking (9).
Serious adverse events—such as cytokine release syndrome (CRS), immune effector
cell-associated neurotoxicity syndrome (ICANS), and hemophagocytic
lymphohistiocytosis-like syndrome—pose clinical risks requiring close monitoring
(10) (11) (12).
CAR-T cell therapy also presents on-target/off-tumor toxicity challenges in solid
tumors, due to antigen expression in normal tissues. Furthermore, dense extracellular
matrices and suppressive immune cells like regulatory T cells, M2 macrophages, and
myeloid-derived suppressor cells hinder CAR-T cell efficacy. These complexities
highlight the need for next-generation CAR-T technologies tailored specifically to
overcome solid tumor barriers (13) (14).
Unlike other therapies, CAR-T cells are engineered to specifically recognize and target
cancer cells, offering a high degree of specificity (15). This is achieved by genetically
modifying a patient's T cells to express a CAR, which is designed to recognize a specific
antigen present on the surface of tumor cells (16). This unique attribute makes CAR-T
cell therapy stand out from other therapies, such as immune checkpoint inhibitors and
cancer vaccines, which typically rely on modulating the patient's immune system to
fight cancer and often struggle with issues of specificity and efficacy.
Furthermore, CAR-T cell therapies have demonstrated unprecedented response rates,
particularly in certain hematological malignancies. For example, they have shown
impressive results in treating B-cell malignancies such as refractory acute
lymphoblastic leukemia (ALL), where other treatment modalities have failed (17).
Moreover, the 'living drug' nature of CAR-T cells, which allows for their expansion and
persistence in the patient, offers a sustained antitumor response, a feature not shared by
many other therapies, such as monoclonal antibodies. Despite these advantages, it is
essential to acknowledge that CAR-T cell therapy is not without its challenges,
including the risk of cytokine release syndrome, neurotoxicity, and the potential for 'on-
target, off-tumor' effects. However, advancements are continually being made in CAR
design and T-cell engineering to improve safety and efficacy.
The source of T cells for CAR T-cell production can be either the patient (autologous)
or a donor (allogenic). Blood is collected by venipuncture or apheresis from the patient
and donor. The T cells undergo purification and are subjected to genetic engineering
(14). CARs are artificially generated receptors that have been built to specifically target
antigens expressed on the cell surface (15). T cells are typically engineered to express
CARs by transducing patient T cells with a virus that encodes aDNA construct. The
resulting CAR T cells are then expanded ex vivo and infused back into the patient.
Genetic engineering is performed using viral or non-viral methods to eliminate the
expression of proteins such as HLA class I and II, in allogeneic T cells (16). This helps
mitigate rejection by the hosts’ immune system.
The CAR is comprised of four primary structural elements: a cytoplasmic signaling
domain, a hinge, a transmembrane domain, and an extracellular antigen-recognition
domain (18). Each domain has specific functions, and modifying the structures of the
domains allows for different functionalities of the CAR.
Extracellular antigen-recognition domain, this domain is responsible for recognizing
and binding to target antigens. Typically, the antigen-binding region consists of
variable light (VL) and variable heavy (VH) chains from monoclonal antibodies. The
chains are interconnected through flexible linkers in the middle, forming single-chain
variable fragments (scFv) (19) (20). Although initially designed to specifically target
and attach to tumor-specific antigens located outside of cells, subsequent research has
demonstrated that the scFv also possesses the capability to identify tumor-specific
antigens found inside cells (21) (22), The structure, location, and interaction mode of
the VH and VL chains influence both CAR specificity and affinity (23), with scFv
affinity significantly affecting the anti-tumor properties.
A high affinity for antigen binding is beneficial for the efficient identification of tumor-
associated antigens (TAAs), which in turn triggers signal transduction and T-cell
activation. Excessive affinity, however, can result in cytotoxicity or toxicity in T cells
harboring CAR due to their interaction (24) (25) (26). Interestingly, scFvs that target
the same protein with similar affinity may have varying effects on the anti-tumor
capabilities of CAR-T cells (27). Therefore, optimizing the pairing between CAR and
its target is crucial for identifying the ideal scFv for CAR engineering.
Additionally, certain scFvs can trigger ligand-independent tonic signaling and induce
the differentiation and even death of effector T cells. This may impair CAR-T-cell
proliferation, ultimately leading to disease recurrence (28). Therefore, when developing
CARs, it is of utmost importance to select scFvs that prevent the initiation of ligand-
independent tonic signaling and to thoroughly evaluate aspects such as the density of
the target antigen and the position of the epitope (29).
Hinge and transmembrane domains, these domains have crucial functions in enabling
access to specific antigens and controlling the activation of CAR-T cells. The hinge
region serves as a linkage between the extracellular region, where the antigen attaches,
and the cytoplasmic domain, which is responsible for transmitting signals. This linkage
provides the necessary flexibility and length to overcome obstacles caused by steric
hindrance. Significantly, the characteristics of the hinge can impact various aspects of
CAR function, including flexibility, epitope recognition, activation output strength, and
CAR expression (30) (31).
Cytokine release by CAR-T cells is also affected by the unique characteristics of the
hinge and transmembrane domains. In vivo studies have suggested that T cells with
CD28 domains exhibit inferior anti-tumor effects relative to those with CD8 domains
(32). Furthermore, these domains may have distinct functions, with the hinge regulating
the CAR signal threshold. In contrast, the transmembrane domain controls the intensity
of the signal by regulating the CAR expression level (33).
CAR-T cells having domains derived from CD8αhave been found to enhance CAR
expression and induce tonic signaling, resulting in high-level secretion of IL-2,
ultimately leading to increased cell activation (34). Furthermore, T cells produced with
CD19-CAR and including CD28 and CD8 transmembrane domains have different
activities. The former interacts with natural binding partners to control the activity of
CAR-T cells (35).
Cytoplasmic domain, the intracellular domain of CAR usually contains at least one co-
stimulatory domain together with an activation domain. Optimizing the co-stimulatory
functions is a vital factor to consider in CAR engineering in order to produce an ideal
domain structure.
Early attempts in CAR-T cell development used complexes between immunoglobulin
scFvs and CD3, which were first described in 1989 (18). However, the tyrosine-based
activation motifs did not activate T lymphocytes effectively, resulting in limited
cytokine secretion and reduced in vivo survival time (36). Clinical studies also showed
low efficacy, confirming these findings (37).
Subsequent generations of CARs included co-stimulatory molecules, such as CD137
(4-1BB), CD134, and CD28, in the chimeric receptor. This inclusion enabled T cells to
achieve sustained proliferation both in vitro and in vivo, along with robust cytokine
secretion, leading to high response rates in clinical or preclinical studies (38) (39).
Among these co-stimulatory domains, CD28 and 4-1BB have received significant
research attention and obtained FDA approval for their incorporation into CAR-T cell
products (40). Novel co-stimulatory domains, such as CD27 and OX40 (CD134), have
been found to be effective, although they have not yet been examined in clinical settings
(41) (42).
Recent advancements in fourth-generation CAR-T cell therapies have enabled the
targeted production of specific cytokines, such as IL-12, which can attract and activate
other immune cells (43). Utilizing proliferative cytokines such as IL-2 and IL-15 has
demonstrated the ability to enhance the effectiveness of CAR-T cells, resulting in robust
anti-tumor activity (44). IL-15 plays a crucial role in maintaining the balance and
survival of T cells. Research has shown that CD19 CAR-T cells, which have IL-15
expression driven by the antigen, exhibited enhanced survival, growth, and
effectiveness against B cell malignancies in animal models. In addition, the potential of
IL-7 and IL-21 to augment the effectiveness and durability of CAR-T cells has also
been examined (45). Studies have demonstrated that IL-7 facilitates the balanced
growth of T cells, whilst overexpression of IL-21 has been found to sustain the long-
term presence of T cells in vivo. Research has shown that the continuous production of
IL-7 in CD19-CAR-T cells improves the effectiveness of fighting against tumors. On
the other hand, the expression of IL-21 in CAR-T cells has demonstrated significant
growth and long-lasting presence in xenograft models, leading to enhanced tumor
regulation and increased survival (46). These data strongly support the requirement to
assess further the effectiveness of CAR-T cells that simultaneously express IL-15 and
IL-21 in cancer patients.
Moreover, the failure of CAR-T cells to recognize antigen-negative tumor cells can
contribute to tumor recurrence after treatment. Nevertheless, fourth-generation cells
can resolve this issue by releasing targeted cytokines, resulting in improved T-cell
activity. In addition, they attract and activate innate immune cells, leading to the
efficient elimination of antigen-negative tumor cells in specific areas (47).
While CAR T-cell therapy has revolutionized cancer treatment globally, its
implementation remains challenging, especially in resource-limited settings like Libya.
Ulrich et al. (2022) (48) emphasize that the cost of a single treatment can exceed €1.5
million per patient, a financial burden that Libya’s healthcare system is unequipped to
support, given the absence of structured reimbursement mechanisms. In addition to
economic strain, Libya faces infrastructural deficits—including a lack of accredited
treatment centers and specialized personnel trained in high-complexity cellular
therapies. The logistical requirements of centralized manufacturing and cold-chain
transport introduce further obstacles, which are exacerbated by fragmented supply
networks. Moreover, Libyan patients must often seek care abroad, where access is
constrained by financial hardship, geopolitical instability, and limited referral systems.
Compounding these challenges are the absence of a national cancer registry and formal
regulatory frameworks, hindering both patient identification and treatment oversight.
These limitations underscore the urgent need for international collaboration, capacity
building, and cost-effective innovations to make CAR T-cell therapy a feasible option
in settings like Libya.
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