CAR T-Cell

REVIEW
published: 22 June 2022

doi: 10.3389/fbioe.2022.797440
Chimeric Antigen Receptor T-Cells: An

Overview of Concepts, Applications,
Limitations, and Proposed Solutions
Alaa Alnefaie 1, Sarah Albogami 2*†, Yousif Asiri 3, Tanveer Ahmad 4, Saqer S. Alotaibi 2,
Mohammad M. Al-Sanea 5 and Hisham Althobaiti 6
1
Department of Medical Services, King Faisal Medical Complex, Taif, Saudi Arabia, 2Department of Biotechnology, College of
Science, Taif University, Taif, Saudi Arabia, 3Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi
Arabia, 4Multidisciplinary Centre for Advanced Research and Studies, Jamia Millia Islamia, New Delhi, India, 5Department of
Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia, 6Chief of Medical Department, King
Faisal Medical Complex (KFMC), Taif, Saudi Arabia
Adaptive immunity, orchestrated by B-cells and T-cells, plays a crucial role in protecting the
body from pathogenic invaders and can be used as tools to enhance the body’s defense
mechanisms against cancer by genetically engineering these immune cells. Several
Edited by:
Umberto Galderisi, strategies have been identified for cancer treatment and evaluated for their efficacy
University of Campania Luigi Vanvitelli, against other diseases such as autoimmune and infectious diseases. One of the most
Italy
advanced technologies is chimeric antigen receptor (CAR) T-cell therapy, a pioneering
Reviewed by:
Navin Chintala,
therapy in the oncology field. Successful clinical trials have resulted in the approval of six
Memorial Sloan Kettering Cancer CAR-T cell products by the Food and Drug Administration for the treatment of
Center, United States
hematological malignancies. However, there have been various obstacles that limit the
Yiran Zheng,
Soochow University, China use of CAR T-cell therapy as the first line of defense mechanism against cancer. Various
*Correspondence: innovative CAR-T cell therapeutic designs have been evaluated in preclinical and clinical
Sarah Albogami trial settings and have demonstrated much potential for development. Such trials testing
[email protected]
†
the suitability of CARs against solid tumors and HIV are showing promising results. In
ORCID ID:
Sarah Albogami,
addition, new solutions have been proposed to overcome the limitations of this therapy.
orcid.org/0000-0003-0774-5550 This review provides an overview of the current knowledge regarding this novel
technology, including CAR T-cell structure, different applications, limitations, and
Specialty section:
This article was submitted to
proposed solutions.
Preclinical Cell and Gene Therapy,
Keywords: chimeric antigen receptor T-cell, adaptive immunity, autoimmune disorder, cancer immunotherapy, solid
a section of the journal
tumor, tumor infiltration
Frontiers in Bioengineering and
Biotechnology
Received: 18 October 2021 1 INTRODUCTION
Accepted: 18 May 2022
Published: 22 June 2022 The global cancer burden, cancer incidence, and mortality estimations have increased rapidly.
Citation: According to the International Agency for Research on Cancer, 19.3 million diagnosed cases and 10.0
Alnefaie A, Albogami S, Asiri Y, million deaths worldwide in 2020 have been attributed to cancer (Sung et al., 2021). The relationship
Ahmad T, Alotaibi SS, Al-Sanea MM between cancer and the immune system was shown by Rudolf Virchow more than 150 years ago
and Althobaiti H (2022) Chimeric
(Adams et al., 2015). Interest in immune system activation as a therapeutic approach for treating
Antigen Receptor T-Cells: An Overview
of Concepts, Applications, Limitations,
cancer began in the late 19th century when William Coley injected heat-inactivated bacteria into the
and Proposed Solutions. tumor mass, resulting in its size reduction. Although the failure to achieve desirable clinical outcomes
Front. Bioeng. Biotechnol. 10:797440. with early immunotherapies such as interferon-gamma (IFN-γ) and interleukin (IL)-2 treatments,
doi: 10.3389/fbioe.2022.797440 novel immunotherapies launched in the 21st century have achieved robust clinical results,
Frontiers in Bioengineering and Biotechnology | www.frontiersin.org 1 June 2022 | Volume 10 | Article 797440
Alnefaie et al. CAR-T Cell Therapy for Cancer
establishing cancer immunotherapy as one of the foremost activation and differentiation and eventually causing T-cell
anchors of anticancer therapies (Lesterhuis et al., 2011; Jiang exhaustion (Wherry, 2011; Schietinger and Greenberg, 2014).
T. et al., 2016; Castro et al., 2018). T effector cell exhaustion is highlighted by the loss of effector
The effective eradication of cancer cells via the immune system functions such as proliferation, cytotoxicity, metabolic and
involves several steps known as the cancer-immunity cycle, transcriptional molecule alterations, and immune checkpoint
defined as a series of steps involving increased antitumor upregulation (Guo et al., 2018; Li H. et al., 2019). Different
T-cell responses that are initiated upon recognition of the factors have been identified that play several roles in T-cell
tumor-associated antigens (TAAs) captured from dying tumor exhaustion; the intrinsic factors relate to transcription,
cells by antigen-presenting cells (APCs) such as dendritic cells epigenetic, and metabolic factors, whereas the extrinsic factors
(DCs). Upon capturing TAA’s, DCs get activated, express CCR7, include extracellular and cytokine interactions that create the
mature, and 1) migrate to draining lymph nodes, 2) present the TME and the immunosuppressive network (Maimela et al., 2019;
captured antigens to naïve CD4+ and CD8+ T-cells via the major Zhang et al., 2020). Therefore, the use of engineered T-cells
histocompatibility complex (MHC) class I and II molecules, 3) targeting specific cell-surface antigens is considered a great
express T-cell costimulatory molecules, for example, CD40, approach to ensure specificity and overcome the shortcomings
CD80, and CD86, 4) secrete critical cytokines to regulate of other available immunotherapies.
T-cell responses, 5) activate naïve CD8+ T-cells converting In this review, we present a comprehensive prospect of the
them into cytotoxic T-cells, which immigrate from lymphoid developmental and experimental progress in the field of chimeric
organs into the bloodstream and reach tissues and ultimately antigen receptor (CAR) T-cell therapy while relating to some
infiltrate the tumor. Activated cytotoxic T cells recognize the aspects of adaptive immunity as the rationale behind the
specific TAA (presented to them by DC’s) found on MHC class I evolution of this cutting-edge technology. The significance of
(MHC-I) molecules of tumor cells and kill the tumor cells via this review is the broad inclusiveness of current therapeutic
secreting perforins and granzymes that result in the release of applications of CAR T-cells in hematological malignancies,
additional TAAs, which trigger the initiation of another cycle of solid tumors, and human immunodeficiency virus (HIV)
cancer immunity (Chen and Mellman, 2013). infection while focusing on some recently published results of
Cancer eradication through cytotoxic immune responses is pre-clinical and clinical trials, pointing out some drawbacks, and
evident; however, cancers can grow progressively, suggesting suggesting some modifications.
their ability to mask and not be recognized by the immune
system as seen in carcinogen-induced mouse models. This
mechanism prompted Schreiber and others to hypothesize the 2 ADOPTIVE IMMUNE THERAPY
immunoediting concept to explain the progressive growth of
otherwise immunogenic cancers (Shankaran et al., 2001; Dunn Cancer immune therapy, which exploits the body’s immune
et al., 2004; Schreiber et al., 2011; Matsushita et al., 2012). The system to combat cancer cells, can be classified into three
immunoediting process of human cancers can be related to categories: adoptive cell therapies (ACTs), tumor vaccines, and
neoepitope presentation. Non-silent point mutations that lead immune checkpoint inhibitors (ICIs). These therapies have
to antigenic neoepitopes (T-cell recognition) are lost more proven beneficial in patients with advanced tumors, and some
frequently in cancers than in silent point mutations, thus have reached complete remission (Li D. et al., 2019). ACT is
preventing T-cells from recognizing and identifying cancer mainly based on the concept that the immune system can control
cells (Rooney et al., 2015). This concept suggests that the a patient’s cancer in the long-term and has been demonstrated by
ability of cancers to progress and grow could be impaired by three independent approaches. The first approach involved
loss of immunogenicity; however, this perception alone tumor-infiltrating lymphocytes (TILs), which can be isolated
contradicts another evidence that T-cells are adequately from tumor lesions (e.g., melanoma) and expanded in vitro,
activated to enhance their cancer recognition by the followed by patient re-infusion, resulting in tumor regression
administration of immune-activating cytokines or immune and remission in a considerable number of patients. However, the
checkpoints releases such as programmed cell death-1 (PD-1) downsides of the TILs approach included access limitations to the
or cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) that removable metastases or tumors, time-consuming preparation of
leads to robust tumor responses in patients and mice (Chambers T cells, and tumor-reactive T-cell clones were rarely found, which
et al., 2001; Pardoll, 2012). T cells are central infiltrates of the hindered the success of this strategy. The second approach
heterogeneous tumor microenvironment (TME), and their involved T-cell receptor (TCR) engineering, where TCRs
population consists of naïve, effector, memory, and regulatory identified from TILs were virally transduced into peripheral
T cells (Hashimoto et al., 2018). The antigen stimulation of T cell blood T-cells, making them capable of inducing tumor
receptors (TCRs) initiates an intrinsic program that guides the regressions upon re-infusion into the patient. Unfortunately,
differentiation of T cells into cytotoxic effectors capable of this method was explicitly restricted because of its dependency
eradicating the antigen; however, these cells start dying on identifying MHC peptides expressed by tumors via their MHC
gradually except for a small number of surviving memory complexes (Dudley et al., 2002; Zacharakis et al., 2018;
T cells that provide long-term protection against the antigen Benmebarek et al., 2019). The third ACT approach is CAR-
(Chang et al., 2014). Chronic exposure of T cells to the same engineered T cells and is marked as the beginning of a new era in
antigen leads to remarkable alterations, thus affecting their cancer therapy by providing a transformative approach to tumor
exclusion and gained attention over the other two as it offered a composed of an antigen-specific immunoglobin separated by a
series of innovative modifications (Kershaw et al., 2006; Lamers flexible linker and attached to the transmembrane domain by a
et al., 2011; Mikkilineni and Kochenderfer, 2017). CARs are spacer (hinge) responsible for the transmission of receptor-
synthetic receptors that have the specificity of a monoclonal binding signals (Zhang et al., 2017). 2) transmembrane
antibody and a signaling domain capable of inducing a domain is essential for receptor stability and surface
cascade of events in the CAR-engineered immune cells (e.g., expression; it is a hydrophobic alpha helix that extends in the
T-lymphocytes) upon target engagement. Engineering immune cell membrane (Ramos and Dotti, 2011; Zhang et al., 2017). 3)
cells to express CARs is achieved by transferring protein-coding intracellular domain (endo-domain), which upon stimulation,
sequences using viral vectors (e.g., Lentiviral or Retroviral). CAR clusters and undergoes conformational changes, thus enabling
T-cells display immunological characteristics similar to activated the recruitment and phosphorylation of downstream signaling
T cells such as generating an immune response against target cells proteins (Cantrell, 2002; Su and Vale, 2018). The intracellular
and expanding within the patient ensuring long-term protection domain classifies CARs into five generations: first has a single
(Porter et al., 2011; Grupp et al., 2013; Heiblig et al., 2015). activation domain, a cytoplasmic domain mostly CD3 zeta
(CD3ζ), and some studies used the gamma chain (γ) of the Fc
receptors, the second generation has CD3ζ plus one
3 EVOLUTION OF CAR-T CELLS costimulatory domain, obtained from costimulatory molecules
such as 4-1BB or CD28 connected to an activator domain (CD3ζ/
Conventional T cells can distinguish between foreign peptide- γ chain of Fc receptor) to enhance both cell proliferative and
MHCs (pMHCs) and the body’s pMHCs via their TCRs, which cytotoxic competences of CAR T cells (Finney et al., 1998;
can trigger a small number of agonist pMHCs compared with Hombach et al., 2001; Acuto and Michel, 2003). The third
thousands self-pMHCs (Sykulev et al., 1996; Irvine et al., 2002; generation is similar to the second generation but has multiple
Huang et al., 2013). Genetic insertion of CARs, in immune cells, costimulatory domains with CD3ζ, such as 4-1BB and CD28,
particularly T-cells, redirects them to target a preferred antigen CD134, and CD137 (Sadelain et al., 2013; Zhang et al., 2017;
(Jackson et al., 2016). CARs are bioengineered receptors which Guedan et al., 2019). The fourth generation CARs, known as
specifically target a desired antigen; almost 30 years ago, the first T cells redirected for universal cytokine-mediated killing
CARs were generated and undergone multiple modifications (TRUCKs), were engineered to release transgenic cytokine-like
since they contributed to their development and evolution interleukin 12 (IL-12) upon CAR signaling in the tumor tissue to
(Kobold et al., 2015; Lim and June, 2017). The flexibility of overcome TME immunosuppression and endorse robust
CARs arises from their ability to recognize antigens in the therapeutic outcomes (Chmielewski et al., 2014; Chmielewski
absence of MHC presentation, which is the opposite of innate and Abken, 2015, 2020). IL-12 is responsible for the induction of
TCRs (Lim and June, 2017). Additionally, CARs have advanced IFN-γ, perforin, and granzymes in T-cells, and inhibits Treg
properties compared with conventional T-cells, as they combine proliferation (Kubin et al., 1994; Cao et al., 2009). Other
the antigen-binding ability of monoclonal antibodies with T-cell cytokines studied in the fourth generation are IL-15 and IL-18
self-renewal and lytic capacity (Ramos and Dotti, 2011; Curran (Hurton et al., 2016). IL-15 belongs to the γ-chain family and
et al., 2012; Maher, 2012). Also, TCRs can recognize short peptide holds important properties for T cell expansion and survival
sequences, whereas CAR T-cells can recognize several tumor (Klebanoff et al., 2004). Additionally, IL-18 CAR T-cells
antigens in different forms, such as proteins, glycolipids, and treatment of large pancreatic and lung tumors exhibited
carbohydrates (Abbott et al., 2020). CAR T-cell recognition and changes in the immune cell landscape related to the tumor; a
destruction of tumor cells occur in an independent-manner of significant increase in the macrophages (CD206− M1) and NKs
MHCs; this promotes enhanced cell recognition undisturbed by (NKG2D+) was observed besides a decrease in Tregs such as M2
the tumor’s ability to avoid MHC-restricted recognition of macrophages suppressive CD103+ DCs, suggesting the ability of
T-cells, such as the tumor’s ability to encourage defective “IL-18 TRUCKs” to sensitize large tumor lesions for efficient
antigen processing by downregulating human leukocyte immune destruction (Chmielewski and Abken, 2017).The fifth
antigen (HLA) class I molecules (Dotti et al., 2014). It is generation of CARs is currently being explored; it is mainly
considered an advantage where MHC expression is suppressed designed based on the second generation. However, it contains a
or lost due to the immunosuppressive cancer microenvironment truncated cytoplasmic receptor (IL-12) and a β-chain domain
(Garrido et al., 2016). CARs have been proven effective in (IL-2Rβ truncated intracellular interleukin 2β chain receptor)
treating cancers, especially hematological tumors. The along with the transcription factor STAT3/5 binding motif
specificity of CARs in targeting cancers makes them an (Tokarew et al., 2019) (Figure 1).
appealing alternative to standard cancer treatments such as The structure and design of CARs contribute to their signaling
chemotherapy and radiation (Sadelain et al., 2013). CARs mechanisms, effector functions, efficacy, and toxicity. The ligand
consist of three major domains: 1) extracellular domain recognition and signaling of CARs are affected by both the single-
(ectodomain), which can be further divided into an antigen- chain variable fragment (scFv) and cytoplasmic domains;
recognition domain, a single peptide on the cell surface cleaved however, the transmembrane and spacer domains (non-
from the mature CAR cell (Goulart et al., 2017). The antigen- signaling) affect the function of CARs (Jayaraman et al., 2020).
recognition domain is a single-chain fragment variant (scFV) Generally, CAR T-cells can specifically recognize cancer cells and
chiefly comprising of heavy and variable light chain regions lyse them (Maggs et al., 2021).
FIGURE 1 | Structure of CARs and different generations. (A) Highlights the general structure of CARs; they have an extracellular domain containing scFV derived
from antibody variable heavy and light chains, linker, and a hinge/spacer region. All the extracellular structures provide flexibility and improve the binding affinity of the
antigen. A transmembrane domain helps anchor molecules to the T cells, and an intracellular domain containing ITAM motifs, responsible for transmitting activating and
costimulatory signals to T cells, is also present. (B) CARs have witnessed rapid advancement since the first generation, which contained only ITAM (CD3ζ) motifs as
the T cell stimulatory molecule within the intracellular domain. The second generation had one costimulatory molecule, whereas the third generation had two
costimulatory molecules to improve cytotoxicity and robustness of CAR-T cells. The fourth generation was designed based on the second generation but was paired
with cytokine expressors (e.g., IL-12) under the control of NFAT transcription factor; therefore, this generation is referred to as T cell redirected for universal cytokine-
mediated killing (TRUCKs). The fifth generation was also based on the second generation with additional intracellular domains of cytokine receptors (e.g., IL-2Rβ) to
activate JAK and STAT3/5, stimulate cell proliferation, and enhance its persistence.
4 CLINICAL PREPARATION OF CAR-T quality control testing through the entire process (Levine, 2015).
CELLS The first step is collecting leukocytes from the patient
(autologous) or the donor (allogeneic) from the peripheral
Despite various designs and tumor-specific scFVs, the blood via leukapheresis, in which only the leukocytes are
manufacturing process of CAR-T cells remains constant extracted, and the rest of the blood products are returned to
(Wang and Rivière, 2016). In general, the personalized clinical circulation (Brown and Adusumilli, 2016; Zhang et al., 2017).
production of CAR-T cells encompasses several steps followed by Second, T cells are augmented, separated, and washed with
leukapheresis buffer (Zhang et al., 2017; Gomes-Silva and Ramos, This approach has several advantages, such as improved
2018). Third, at the CD4/CD8 composition level, the T-cell integration of the transduced genetic material due to its low
subsets are separated using specific antibody-coated bead promoter activity (Yant et al., 2000), fewer epigenomic changes at
conjugates or markers. The isolated cells are then cultured and the integration site, and reasonably low manufacturing costs
activated by purified allogeneic or autologous APCs or by (Izsvák et al., 2010). The only limitation in this approach is
introducing beads coated with anti-CD3 or anti-CD28 the low rate of transgenic material; however, it was considerably
monoclonal antibodies (or both along with feeder cells and enhanced (Geurts et al., 2003). Nevertheless, the concerns remain;
interleukins) (Guedan et al., 2019). IL-2 is the most common for instance, transient mRNA transfection requires several
growth factor used to induce the rapid growth of T cells (Wang rounds of infusion, the possibility of mutagenesis, and SB
and Rivière, 2016; Guedan et al., 2019). Recently, a study reported transposon remobilization (Beatty et al., 2014). The fifth step
that a cytokine cocktail of IL-2, IL-7, and IL-15 induced better is CAR-T cell expansion using bioreactors, which help cells divide
expansion of CD4 and CD8 CAR-T cells (Coppola et al., 2020). and express CARs on the cell surface (Harrison et al., 2019).
Fourth, different methods have been considered to enable Finally, when the cells reach the clinically required volume, they
nucleic acid delivery to the obtained T cells. Usually, a foreign are reinfused into the patient as a therapeutic agent. The infusion
gene material (RNA or DNA) delivery into human cells can be occurs 48–96 h after lymphodepletion chemotherapy to make
accomplished using viral or non-viral vectors. Viral vectors are room for the infused CAR-T cells (Turtle et al., 2016). The patient
preferable for basic and clinical research because viruses have is then kept under observation for possible adverse effects within
diverse expression characteristics, spend a fraction of time to the first few days of infusion. The process lasts around 3 weeks,
reach clinically desired numbers of cultured T cells, and possess where cell preparation is the most time-consuming phase of
high transfer competency (Zhang et al., 2017; Gomes-Silva and treatment (Zhao and Cao, 2019) (Figure 2).
Ramos, 2018). Viral vectors are used to encode CARs; with their Interestingly, lymphodepletion chemotherapy is a crucial step
reverse transcription potential, vectors convert RNA into before CAR T-cells infusion as it reduces endogenous lymphocyte
permanently integrated DNA in the genome of the obtained numbers, thus increasing hemostatic cytokine availability
T cells. These viral vectors include retroviruses, lentivirus, promoting infused cells survival (Liang et al., 2020).
adenovirus, and adeno-associated virus. The most popular Administration of T-cells to lymphodepleted patients has
ones are genetically engineered retroviruses, more frequently shown superior anti-tumor properties compared to
used than gamma retroviral vectors. During the activation lymphoreplete patients (Bechman and Maher, 2021). There
period, viral vectors are washed out of the culture by dilution have been several benefits to the lymphodepletion regimens,
and medium exchange (McGarrity et al., 2013; Zhang et al., such as the non-myeloablative chemotherapeutic approach;
2017). this regimen results in the removal of endogenous
However, viral vectors present a possible safety hazard. The lymphocytes that act as “cytokines sinks,” which facilitate the
limitations of the viral vectors include tumorigenesis and toxicity accessibility of the infused T-cells to hemostatic cytokines like IL-
caused by the insertion mutation used to generate immune 15, IL-7, and IL-2, which stimulate JAK-STAT-mediated
reactions, and the limited carrier capacity and achieved titers expansion (Gattinoni et al., 2005; Neelapu, 2019). In a
are not sufficient (Wang et al., 2008). Therefore, to overcome the lymphodepleted host, the memory cells proliferate in an
shortcomings of viral vectors, other methods such as mRNA antigen-dependent manner, unlike naïve T cells homeostatic
transfection and non-viral vectors were used in the production of expansion, which occurs in an MHC-dependent manner
CAR-T cells. The most common were transposon-based non- (Gattinoni et al., 2005; Klebanoff et al., 2005). It has been
viral vectors, facilitating safe and consistent DNA transfer into reported that lymphodepletion decreases immunosuppressive
CAR T-cells. The sleeping beauty (SB) transposon system is the cells, such as myeloid-derived suppressor cells (MDSCs) and
currently used substitute for viral-based vectors. It has been used regulatory T cells (Tregs), while enhancing the APC cells’
to prepare CD19+ CAR T-cells with antitumor properties in vivo functionality and availability (Bechman and Maher, 2021).
and in vitro (Singh et al., 2015; Chicaybam et al., 2019). In 2014, Immunosuppressive networks are negatively affected by
an optimized protocol (GMP-compliant) was suggested to utilize lymphodepleting agents such as tryptophan metabolizing
the production of modified CAR T-cells by electroporation with enzyme and indoleamine dioxygenase (IDO) (Hanafi et al.,
CAR-encoding RNA, which helps in overcoming several 2014; Ninomiya et al., 2015). Lymphodepletion also exerts
drawbacks of classic viral transfection such as viral certain positive effects on the microbiome. It enhances the
contamination, low time-efficiency, higher resource translocation of microbes from the gastrointestinal tract, which
consumption, and off-target effects (Krug et al., 2014). In lead to immunostimulatory impacts through Toll-like receptor
2019, the optimized protocol was used in producing ligation, resulting in an augmented release of IL-1β (Viaud et al.,
genetically modified CAR T-cells against melanomas; the CAR 2013; Lee et al., 2019). According to imaging studies, post
T-cells were electroporated and expanded with mRNA that lymphodepletion, the tumor-trafficking properties of
encoded CAR targeting CSPG4, a surface protein highly adoptively infused cytotoxic T-cells were enhanced (Pittet
expressed in most melanomas. The results showed that a high et al., 2007). In a clinical trial (NCT03939026), which
dosage of modified CAR T-cells could lyse 80% of melanoma cells evaluates the safety and efficacy of certain lymphodepletion
after 20 h; the authors suggested a future expansion of their study regimens, the phase I results suggest that fludarabine as a
to a full clinical trial (Wiesinger et al., 2019). component in the lymphodepletion regimen is critical and
FIGURE 2 | Clinical production of CAR T-cells. The peripheral blood is withdrawn from the patient (autologous) or it can be obtained from the peripheral blood of a
healthy donor (mononuclear cells), induced pluripotent stem cells (iPSC), or umbilical cord blood (allogeneic). The targeted T-cells are obtained by leukapheresis. Then,
the T cells are separated and purified from other leukocytes using anti-CD3/CD28-coated beads; this process is followed by activation of the cells. Then, the genetic
material encoding chimeric receptors is introduced into the T-cells via several known methods (such as mRNA transfection), viral vectors (e.g., lentivirus), or
sleeping beauty (SB) transposons. The engineered T-cells expressing CARs are then expanded in a bioreactor. The patient receives chemotherapy for decreasing white
cells blood count; after 48–96 h, the CAR T-cells are reinfused into the patient, followed by close monitoring for a few days to observe any adverse effects.
FIGURE 3 | CAR T-cell action: (A) CAR T-cells recognition of targeted antigen. (B) Chimeric antigen receptor binding to tumor-antigen. (C) Initiation of the antitumor
(cytolytic) effects where the activated T-cells downstream the killing signaling by secreting granzymes and perforins, pro-inflammatory cytokines due to immune cell
invasion, as well as initiating the expression of TRAIL and FasL pathways.
contributes to the efficacy of the procedure. Moreover, using a combination is required for optimization in certain types of
combination of fludarabine and cyclophosphamide (Flu/Cy) cancer and attenuation of the exerted toxicities of these agents.
regimen is beneficial in multiple tumors; however, this Although the benefits of lymphodepletion are undeniable, there
have been certain limitations, such as the short-lived span of large B-cell lymphoma (r/r DLBCL) (Thudium Mueller et al.,
lymphodepletion and the consequent immune restoration phase 2021).
accompanied by a compensatory overshoot of both MDSCs and
Tregs as indicated by preclinical and clinical studies (Bechman 5.1.2 Acute Myeloid Leukemia
and Maher, 2021). Acute myeloid leukemia (AML) results from genetic alterations in
The mechanism of action of CAR T-cell involve the binding of precursor cells that affect the growth and differentiation of
CARs to a targeted antigen present on tumor cell surface via scFV hematopoietic cells, resulting in the accumulation of immature
recognition domain, which elicit anti-tumoral effects through the myeloid cells in the bone marrow and peripheral blood. These
secretion of inflammatory cytokines (e.g., IL-2, IFN-γ, and TNF- cells are incapable of turning into mature hematopoietic cells.
α), cytolytic effector function via perforin and granzyme CAR-T cell therapy in AML did not show the same success as
(Benmebarek et al., 2019), TNF-related apoptosis-inducing seen in ALL, and the target of CAR T-cells in AML was CD123
ligand (TRAIL), which binds to death receptors (e.g., DR4 and and CD33; the latter was used in treating a patient and showed a
DR5) on tumor cells cell surface to activate graft-versus tumor significant reduction in tumor volume in the bone marrow;
effect (donor T-cells) (Watanabe et al., 2021). Also, tumor cell however, 9 weeks post-infusion, the patient experienced a
apoptosis can be initiated via the activation of caspase 8 and the relapse (Wang et al., 2015). Furthermore, the use of anti-
formation of death-inducing signaling complex (DISC) leading to CD123 CAR-T cells as a potential treatment of AML showed
cell death mediated by mature caspase 3 subsequent cleavage of inadequate potency in “on-target-off-tumor” since CD123 is also
over 500 cellular substrate as a result of Fas and Fas ligand (FasL) expressed in normal tissues (e.g., endothelial tissue) and
pathway activation (Waring and Müllbacher, 1999; Nagata and monocytes in relatively low levels compared with AML
Tanaka, 2017) (Figure 3). (Tettamanti et al., 2014). Therefore, other antigens have been
investigated as new targets, including Lewis-Y (LeY) and
CLEC12A antigens, and anti-LeY CART-cells were used in
5 CLINICAL APPLICATIONS OF CAR-T patients who eventually developed disease progression.
CELLS In contrast, the CD33was used as anti-CLEC12A-CD33 CAR
T-cells, showed complete remission in a 44-year-old female
5.1 Hematological Malignancies patient with refractory AML (Ritchie et al., 2013; Morsink
5.1.1 Acute Lymphoblastic Leukemia et al., 2019). In AML the application of CAR T cell therapy is
CAR-T cells are primarily used in hematological malignancies limited by the absence of an AML-specific antigen. AML cells can
such as Acute lymphoblastic leukemia (ALL), characterized by a express several cell surface antigens such as CD34, CD33, CD123,
rapid proliferation of naïve cells in the bone marrow. CAR-T cells and many more. moreover, these antigens are also expressed by
showed efficacy in treating ALL, especially the engineered T cells healthy Hematopoietic stem and progenitor cells (HSPCs) and
against CD19, as CD19 is a highly expressed biomarker of the their lymphoid and myeloid progenitors (Cummins and Gill,
B-cell lineage, responsible for B-cell malignancy of ALL. CD19 is 2019). However, CAR-T cells are unable to distinguish between
a transmembrane glycoprotein involved in B-cell activation and is malignant and normal cells, unlike CD19 CAR T-cells, their
expressed throughout the developmental stages of B cells (Wang complete elimination of the normal and malignant B cells
et al., 2012). Another potential target in B-ALL is the light chain resulting in B cell aplasia is considered clinically benign and
of immunoglobulin CD20 (Gill et al., 2016; Jain and O’Brien, manageable by intravenous immunoglobulin infusion; however,
2016). Conversely, T-cell malignancy of ALL (T-ALL) showed this is not the same in targeting myeloid antigens shared with
limited efficacy when the engineered CAR T-cells targeted CD19; normal myeloid progenitor as their elimination could be fatal due
therefore, another target (anti-CD5) showed effective elimination to bleeding complications and neutropenic infections (Mardiana
of a specific T-cell line expressing CD5 (Mamonkin et al., 2015). and Gill, 2020). The aggressiveness of this disease and its ability to
Anti-CD4 CAR-T cells are potential targets showing promising develop resistance against treatments requires substantial efforts
results against T-cell lymphoma (CD4 positive) models in vivo to achieve remission. CAR T-cell therapy is a promising
and in vitro (Pinz et al., 2016). Clinical trials evaluating technology; however, the lack of leukemia-specific cell surface
multitargeted CAR-T cell therapy against ALL, such as single antigens could present a problem in designing CAR T-cells
engineered CAR-T cells targeting both CD19 and CD22 and a against AML (Mardiana and Gill, 2020). HSPCs frequently
combination of CAR-T cells with anti-CD19 and anti-CD20 to share antigens with AML. CAR T-cells expansion is threatened
target each antigen independently, have yielded encouraging by AML blasts or prior exposure to chemotherapy that damages
results (Huang et al., 2018). KYMRIAH
which is a second generation CAR-T cell product (4-1BB
™
(tisagenlecleucel), T cells. In addition, the AML’s ability to evade the immune
system by inducing various immunosuppressive mechanisms
costimulatory domain) directed against CD19 antigen, was makes it challenging to achieve desired outcomes (Mardiana
approved by the Food and Drug Administration (FDA) for and Gill, 2020).
ALL in 2017 based on multicenter clinical studies, which
established an overall remission rate of 81% in children and 5.1.3 Chronic Lymphocytic Leukemia
young adults with relapsed/refractory acute B-cell acute Chronic lymphocytic leukemia (CLL) results in excessive mature
lymphoblastic leukemia (r/r B-cell ALL), and a best overall lymphocytes in the blood, bone marrow, and lymphoid tissue
response rate of 52% in adults with relapsed/refractory diffuse (Kipps et al., 2017). The use of CD19 as a target in the case of CLL
by producing anti-CD19 CAR-T cells has shown remarkable which is a CD19 directed second generation CAR-T (CD28 co-
results in patients with complete remission and minimal stimulatory domain) cell product for the treatment of NHL.
residual disease, and anti-CD19-CD28ζ CAR-T cells have
shown promising results, according to the data from the 5.1.5 Hodgkin’s Lymphoma
National Cancer Institute (Porter et al., 2011, 2015; Hodgkin’s lymphoma (HL) is a common lymphoma derived
Kochenderfer et al., 2015). Pharmacokinetics plays an essential from B cells. Hodgkin and Reed-Sternberg cells are rarely
role in enhancing the outcomes and safety of CAR-T cell found in the tissues derived from mature B cells that lose their
treatments, especially when it comes to the individual phenotype and co-express unusual hematopoietic cell markers
persistence of treatments, as it is considered the main goal in (Küppers et al., 2012). HL cells highly express CD30; therefore, it
achieving the desired long-term antitumor effects (Norelli et al., was considered an ultimate target by engineered CAR-T cells, and
2016). In a recent study (NCT01747486), 42 patients (18 years clinical trials showed encouraging results where patients
and above) with CLL were treated with autologous CD19 CAR diagnosed with HL exhibited complete remission after anti-
T-cells and 38 patients were infused with anti-CD19 CAR T-cells. CD30 CAR-T cell therapy, wherein other patients either
Twenty-eight patients randomly received a low dose of (5 × 107) developed stable disease or relapse; however, the observations
and high dose of (5 × 108), and 24 were evaluable for response of anti-CD30 CAR-T cells did not show any toxicities or adverse
assessment. After a short time, ten patients revived the high dose events (Ramos et al., 2017; Wang et al., 2017).
while eight were evaluable for response assessment. Follow-up
ranged from 2 to 75 months; results showed that higher doses 5.1.6 Multiple Myeloma
effectively induce a complete remission (CR) without excessive Multiple myeloma (MM) is also a B-cell malignancy of long-lived
toxicities (Frey et al., 2020). One of the inevitable issues in CLL plasma cells, which play a significant part in the immune defense
treatment is the antigen-negative relapse that has been system by producing antigen-specific immunoglobulins; in the
threatening CAR T-cell therapy’s success in CLL patients case of malignancy, these cells excessively produce a specific
(Mancikova and Smida, 2021). The proportion of remissions immunoglobulin (containing two heavy chains and two light
in patients with CCL post CAR T-cell therapy remains the lowest chains) and additional light chains, which can be detected in the
compared to the spectrum of B-cell tumor patients. Current data blood. They are used to diagnose and monitor MM (Bird and
are crucial for utilizing the clinical effects, and ibrutinib Boyd, 2019). Disease management was compromised because of
administration and partial reversing of the exhausted the unavailability of an ideal target. Syndecan 1 (CD138) was the
phenotype of CAR T-cells in CLL patient seem substantially target for the treatment of MM. This surface protein was
promising. The genetic modification (insertion) of transgenic expressed on both plasma cells and normal cells (epithelial),
vector in the recipient T cells with systems such as CRISPR/Cas9 causing “on-target-off-tumor” toxicity. Nonetheless, Chinese
may contribute to treatment efficacy. The low quality of non- clinical trials using CD138 as a target achieved stable disease
functional CAR T-cells derived from treated CLL patients could in 4/5 patients (Heffner et al., 2012). Another target is the B-cell
be improved using allogeneic CAR T-cells. The antigen-negative maturation antigen (BCMA), which is thought to be involved in
relapse could be alleviated using bispecific CARs targeting two all stages of B-cell differentiation and maturation and is highly
antigens presented on the tumor cell surface. Suitable biomarkers expressed in myeloma cells; therefore, it is considered a better
must be identified and used as targets to design treatment and target in CAR-T cell therapy (Ali et al., 2016). A phase 1 clinical
avoid infusion failure (Mancikova and Smida, 2021). trial showed preliminary results regarding BCMA (anti-CD269)
CAR-T cell therapy; one patient achieved complete remission for
5.1.4 Non-Hodgkin’s Lymphoma more than 3 months, whereas another patient showed an
Non-Hodgkin’s lymphoma (NHL) consists of a group of outstanding partial response to therapy. Additionally, a
neoplasms with various degrees of malignancy occurring in correlation was established between high treatment efficacy
lymphocytes, lymphoid tissue, and histocytes at any stage of and higher doses. However, the higher the dosage, the more
their development. These heterogeneous lymphoproliferative adverse events were seen, such as cytokine release syndrome,
malignancies have a greater chance of dissemination to regardless of the use of BCMA or CD138 in therapy (Yang X.
extranodal sites and are less predictable than Hodgkin’s et al., 2019). The expression levels of CD19 in the plasma cells
lymphomas (HL) (Singh et al., 2020). Anti-CD19 CAR-T cells were low, but they were observed to be slightly higher in
have shown remarkable results in treating chemo-resistant malignant cells and showed remission in a 43-year-old patient
lymphomas. Patients with refractory diffuse large B-cell using CTL019 cells and CD19 as a target in MM. Cytokine release
lymphoma (DLBCL) had complete remission for more than syndrome did not develop, and following several days of infusion,
2 years (Neelapu et al., 2017a; Schuster et al., 2017; Tiberghien CTL019 cells were detected in the bone marrow and blood
et al., 2017). CD22 is expressed in progenitor and differentiated (Garfall et al., 2015). BCMA CAR T-cells were designed with
B cells and is highly expressed in B-cell lymphomas and leukemia. signaling domain (CD3ζ) and CD28 (costimulatory domain) in a
Anti-CD22 showed promising results in four out of nine patients study (NCT02215967) conducted with 24 patients with MM; the
with a negative minimal residual disease and complete remission cytotoxicity observed was minor post an infusion of a minimum
(Fry et al., 2015). Anti-CD20 and anti-CD23 CAR-T cells have dose (0.3–3.0 × 106 cells/kg). The objective response rate (ORR)
also been used to treat NHL (Till et al., 2012; Zou et al., 2018). In was 20%. The anti-tumor function with 81% ORR, while severe
2017, the FDA approved YESCARTA (axicabtagene ciloleucel), cytokine release syndrome (CRS) was reported in higher dosage
of CAR T-cells (9 × 106 cells/kg) (Brudno et al., 2018). Bispecific cells using lentivirus gene transfer, the MSLN-CAR molecules
CAR T-cell (LCAR-B38M) was designed to target VHH1 and were highly expressed on the surface of NK-92, which led to the
VHH2 epitopes of BCMA in a multicenter study (NCT03090659) killing of MSLN+ OC cells such as SKOV3 and OVCAR3 in vitro
on patients with MM. The findings included 88% ORR and 68% (Cao et al., 2020).
CR. The adverse events included leukopenia, thrombocytopenia,
CRS, and pyrexia (Zhao W.-H. et al., 2018). In 2021, the FDA 5.2.3 Lung Cancer
approved ABECMA (idecabtagene vicleucel) for MM. ABCEMA Lung cancer is one of the most diagnosed cancers worldwide and
is a second generation CAR-T cell product directed against the is considered one of the leading causes of death. Several antigens
BCMA tumor antigen. have been targeted to treat this cancer, including epidermal
growth factor receptor (EGFR), which is highly expressed in
5.2 Solid Tumors the epithelium and epithelium-derived tissues compared with
5.2.1 Renal Cancer normal lung tissues. Because the receptor provides significant
Renal cancer (RCC) is one of the most diagnosed cancers in affinity for binding sites in lung carcinomas, it is one of the most
both men and women worldwide. RCC development is therapeutic targets of CAR-T cells. Second-generation EGFR-
associated with several factors, including chronic kidney CAR-T cells with CD137 co-stimulatory domain showed
disease, smoking, hypertension, and obesity (Rossi et al., feasibility and safety in treating refractory/relapsed non-small
2018; Capitanio et al., 2019). For many years, surgical cell lung cancer (Feng et al., 2016). Another candidate target was
intervention was the most effective treatment for RCC, HER2, as it exhibited good therapeutic outcomes in refractory/
known for its chemoresistance. Later, other treatments such recurrent HER2+ sarcomas without any respiratory distress
as cytokine and tyrosine kinase inhibitors (TKIs) were syndrome (RDS) signs. However, RDS was observed 15 min
approved, and when RCC showed possible immunological after cell infusion in one patient diagnosed with metastatic
sensitivity, other immunotherapies were approved as well colon cancer to the lung and liver, plausibly because of an
(Schepisi et al., 2020). CAR-T cell therapy of RCC targets autoimmune reaction. Generally, the safety and efficacy of this
carboxy-anhydrase-IX (CA-IX) as an antigen, which anti-HER2 CAR-T cell in lung cancer depends on the levels of
participates in the catalysis of carbon dioxide hydration HER1 in patients and might be compromised because of RDS
(Bagley and O’Rourke, 2020; Bagley and O’Rourke, 2020) (Morgan et al., 2010).
and is considered a critical antigen in RCC; however, it is Further antigens were considered, including MSLN, since it is
also found in other normal tissues of gastric mucosa expressed in 69% of lung adenocarcinoma (1/5 patients) and not
epithelium, small intestine epithelium, duodenum, and the in normal lung tissues and reduced tumor burden in mouse
biliary tree where it is expressed moderately (Yeku et al., models (Carpenito et al., 2009; Kachala et al., 2014). The NSCLCs
2017). The expression of CA-IX can be induced under were found to overexpress transmembrane glycoprotein MUC1
hypoxic conditions in various tissues (Tafreshi et al., 2014). and Prostate Stem Cell Antigen (PSCA), a
The first generation of CA-IX/CART-cells toward RCC was glycosylphosphatidylinositol (GPI)-anchored cell surface
associated with high cytokine secretion due to cytotoxicity (Li antigen; therefore, they were preferred to be used in
et al., 2018). combination as potential targets for MUC1-CAR-T cells and
anti-PSCA-CAR-T cells, which showed excellent efficacy
5.2.2 Ovarian Cancer compared with using a single antigen (Wei et al., 2017).
Novel therapeutics are constantly required in Ovarian cancer Carcinoembryonic antigen (CEA) is overexpressed in nearly
(OC) as it is known for its high recurrence levels post-surgery and 70% of NSCLCs (Berinstein, 2002); however, patients who
multi-agent chemotherapies. CAR-T cells are a novel therapy. In received anti-CEA CAR T-cell treatment had transient acute
the context of ovarian cancer, they target tumor-associated respiratory toxicity, possibly because of the expression of
glycoprotein 72 (TAG72); humanized TAG72-specific CAR-T CEACAM5 on lung epithelial cells (Thistlethwaite et al.,
cells exhibited cytokine production and cytotoxic activity in OC. 2017). The tyrosine kinase-like orphan receptor 1 (ROR1) was
In contrast, it also showed proliferation reduction and increased used as a target; however, toxicity concerns are growing since it
mouse viability in mouse models (Murad et al., 2018). Another was also expressed in normal tissue. Therefore, to overcome this
target was mucin 16 (MUC16), which causes OC progression issue, selectivity of the target was improved by engineering CAR
depletion after intraperitoneal and intravenous injection in T-cells with synthetic Notch (synNotch) receptors specific for
mouse models, making it one of the potential targets, and an EpCAM or B7-Homolog 3 (B7-H3), a member of the B7 family of
in-vitro study using Her-2 CAR-T cells on human OC cell line immune checkpoint molecules, which is expressed on ROR1+
(SKOV3) expressing Her-2/neu reported growth suppression tumor cells but not on ROR1+ stromal cells, resulting in the
potential (Chekmasova et al., 2010). The antigen mesothelin regression of tumor cells without causing toxicity (Srivastava
was targeted by anti-Meso CAR-T cells, which inhibited et al., 2019). The costimulatory role of CD80/CD86 makes it a
proliferation and increased mouse viability. Additionally, 5T4- suitable target for immune intervention, and upon binding to
specific CAR-T cells and FRα-specific CAR-T cells exhibited CTLA4 (CTLA4-CD80/CD86), T cells are downregulated via
inhibitory effects against OC cellular growth and progression various mechanisms. In several NSCLC cells, the mRNA
(Zuo et al., 2017; Owens et al., 2018). In the dual design of CAR-T expression of CD80/CD86 was detected in normal tissues,
cells targeting both CD19 and mesothelin (MSLN-CAR NK-92) risking autoimmunity reactions; hence, new strategies are
encouraged to overcome this risk by using CD80/CD86 CAR-T model, explicit control of the tumor growth was observed without
cells and enhancing its selectivity (Wroblewski et al., 2001; Egen exhibiting any toxicity. On the other hand, in healthy mouse
et al., 2002). models, cytotoxic effects were observed, which might be due to
the retroviral vectors used that might have affected the abundance
5.2.4 Breast Cancer of CAR T-cells (Risma and Jordan, 2012b; Chaudhary et al., 2012;
Breast cancer (BC) is one of the leading causes of death in women, Byrd et al., 2018). Another intriguing target is the human
wherein 1.5 million women are diagnosed with BC worldwide endogenous retrovirus family K (HERV-K) antigen, highly
each year. BC is diagnosed during routine screening or expressed in basal BC cells, similar to TNBC. Importantly, it is
incidentally, and it could reach the lymph nodes and absent in nearly all normal human tissues. The anti-K CAR
metastasize to other organs such as the brain (Sun et al., 2017; T-cells experimented with in-vivo BC mouse models showed
Seely and Alhassan, 2018). One of the most attractive targets for slow tumor growth. The MDA-MB-231 cell line showed great
CAR T-cell therapy is triple-negative breast cancer (TNBC). This lysis post-exposure to anti-K CAR T-cells prepared from cells
type of breast cancer lacks estrogen (ER), progesterone, and obtained from patients with BC (Zhao et al., 2011; Wang-
epidermal growth factor (EGFR) receptors (Harrer et al., Johanning et al., 2012; Krishnamurthy et al., 2015; Zhou et al.,
2019). The targeted receptors for CAR T-cell treatment 2015, 2016; Johanning et al., 2017).
include folate receptor alpha (FRα); as a result, the anti- FRα
CAR T-cells killed in vitro TNBC cells. This antitumor activity 5.2.5 Prostate Cancer
correlates with the FRα antigen levels in the cells (Song et al., The second most frequently diagnosed malignancy in men is
2016). The MUC1 antigen is associated with different tumor prostate cancer (PrC) and the fifth leading cause of death
invasiveness and metastatic behavior, including breast cancer, worldwide. According to GLOBOCAN 2018, the number of
making it a potential treatment target (Zhou et al., 2019). Integrin newly reported diagnoses in 2018 reached 1,276,106 cases
αvβ3 is another tumor antigen expressed in different tumors, worldwide, with a higher incidence in developed countries
including BC tumors, and stimulates tumor cell survival and (Rawla, 2019). Prostate-specific membrane antigen (PSMA)
metastasis (Felding-Habermann et al., 2001). Tyrosine-protein has been used as a target by CAR T-cells in studies (in vivo
kinase Met (c-Met) is a cell surface molecule expressed in almost and in vitro) and causes the proliferation and differentiation of
50% of breast tumors. After an intratumoral injection of c-Met PSMA+ cells (Maher et al., 2002; Gade et al., 2005). In mouse
CAR mRNA, the tumors were excised and analyzed via models of metastatic PrC, diabetes, and severe combined
intratumoral injection immunohistochemistry, revealing immunodeficiency, the use of PSMA CAR T-cells eradicated
inflammatory and necrotic responses (Tchou et al., 2012; Zhao metastatic PrC cells. The second generation CAR T-cells
et al., 2017). The ROR antigen was also used as a CAR T-cell (containing co-stimulator CD28) offer a novel immune-
target in BC, eliminating multiple layers of tumor cells deep in the targeted approach for metastatic PrC since it showed a better
tumor tissues above and beneath the basement membrane eradication effect than the previous generation (Ma et al., 2014;
(Wallstabe et al., 2019). Recent clinical trials have targeted Zuccolotto et al., 2014). The anti-PSMA CAR T-cell dosage and
several antigens against BC, including HER2, MUCI, CEA, protocols for metastatic PrC patients is being investigated in
CD70, CD133, ROR1, and NKG2D ligands (Williams et al., phase 1 clinical trials, in addition to the possible use of dual-
2017). The cell surface antigen mesothelin was found to be targeted CAR T-cells targeting PSMA and transforming growth
overexpressed in 67% of TNBC samples and is considered a factor-β (TGFβ) and their safety in another phase 1 clinical trial
potential target because of its involvement in the activation of (Slovin et al., 2013; Kloss et al., 2018). The prostate stem cell
intracellular pathways including MAPK, NFlB, and PI3K, antigen (PSCA) is also an attractive target for CAR T-cell therapy;
resulting in tumor cell proliferation and resistance to apoptosis the first generation of CAR T-cells with the scFV of 7F5
(Morello et al., 2016; Tchou et al., 2017). CSPG4 is a tumor antibodies exhibits antitumor effects in mice. In another study
glycoprotein found in 72.7% of TNBC lesions and believed to be that used the 4-1BB co-stimulator, the activation of T cells was
associated with tumor cell survival and recurrence; it was better than that by the CD28 co-stimulator (Hillerdal et al., 2014;
primarily detected in TNBC stem cells responsible for Priceman et al., 2018). As a potential strategy, combined CAR
resistance and relapse. Using anti-CSPG4 CAR T-cells in T-cell therapy uses low-affinity PSCA CAR T-cells and high-
TNBC metastasis and progression can also be diminished; it affinity PSMA CAR T-cells to eliminate double-positive CAR
can attack more than one target, including stromal cells, primary T-cells in PrC (Feldmann et al., 2017). A different approach is to
TNBC cells, and cancer-associated fibroblasts, which are use diabodies (bispecific antibodies; BITEs) that simultaneously
considered to be crucial for maintaining the TME (Wang bind to specific T-cell receptor-associated molecules on the T-cell
et al., 2010; Cooney et al., 2011; Harrer et al., 2019). surface (e.g., CD3ε) and to a tumor-specific antigen expressed on
Disialoganglioside GD2 is a BC stem cell antigen expressed in the cancer cell surface (e.g., CD19; PSMA). The simultaneous
35.5% of metastatic TNBC and is considered an engagement of BITEs with both CD3 and the specific antigen
immunotherapeutic target, and anti-GD2 CAR T-cells have resulted in tumor cell lysis via the activation of cytotoxic T-cells.
been reported to show cytolytic activity in GD2+ cell lines BITEs have also been reported to be overexpressed in tumor
(Seitz et al., 2020; Xia et al., 2020). The TEM8 marker was tissues compared to normal ones (Stone et al., 2012; Stieglmaier
found to be overexpressed in the vasculature of solid tumors. et al., 2015; Yang et al., 2016). These novel antibodies were
When anti-TEM8 CAR T-cells were used in the TNBC mouse evaluated in combating cells by targeting PSMA (Baum et al.,
2012; Friedrich et al., 2012; Feldmann et al., 2017). In animal receptor group 2, member D (NKG2D), and MSLN. Other
models, these novel antibodies failed to block the proliferative possible biomarkers that hold immense potential in GC
activity of cancer; they only caused delayed tumor growth, which include actin-related protein 2/3 (APR 2/3), desmocollin 2
suggests that the use of diabodies as a single treatment would not (DSC2), B7H6 ligand, neuropilin-1 (NPR-1), cancer-related
achieve a sturdy cellular memory response (Hillerdal and Essand, antigens CA-72-4 and CA-19-9, and anion exchanger 1 (AF1)
2015). However, in murine xenograft PrC models, the humanized (Zhang Q. et al., 2016). The use of anti-PSCA CAR T-cells on
bispecific antibody MOR209/ES414 caused tumor growth BGC-823, MKN-28, and KATO III GC cell lines and xenograft
inhibition and improved survival. PSMA expression was GC mouse models showed antitumor cytotoxicity post CAR
reduced only in transferred and adaptive human T cells. In a T-cells peritoneal injection in mouse models resulted in tumor
recent study on xenograft models, BITE targets CD3 in T cells and progression restriction (Wu et al., 2020).
PSMA in PrC cells. The results revealed their antitumor potential
(Hernandez-Hoyos et al., 2016; Bailis et al., 2019). An additional 5.2.8 Colorectal Cancer
target of PrC is the epithelial cell adhesion molecule (EpCAM; Colorectal cancer (CRC) incidence has reached 1.85 million cases
also known as CD326), a known stem cell antigen present in worldwide. The mortality rate has reached more than 850,000
several tumors, including PrC (Gires et al., 2009; Ni et al., 2012). deaths per year, making it the third most common cause of death
Recently in Europe, EpCAM-CD3 was approved for the among cancer-related deaths (Biller and Schrag, 2021). The
treatment of malignant ascites. Using it as a TAA, it was targeted antigens in CRC are NKG2D, CEA, EGFR, MUC1,
developed to produce anti-EpCAM CAR T-cells capable of HER2, and CD133 (Li et al., 2021). The membrane-bound
combating PC3M cells overexpressing EpCAM, thereby guanylyl cyclase2C (GUCY2C) has been used as a CAR T-cell
extending the survival of under-expressing EpCAM PC3 cells. target. It showed antitumor activity in both human and syngeneic
However, further investigation of its efficacy in metastatic PrC is xenograft CRC mouse models and is expressed in the intestinal
needed (Deng et al., 2015). apical surface, epithelial cells, and a proportion of the
hypothalamic neurons (Magee et al., 2016, 2018). Anti-
5.2.6 Liver Cancer EpCAM CAR T-cells used against CRC cells and models
Liver cancer is a global health burden, with an estimated >1 exhibited cytotoxic lysis of the targeted cells that secreted
million cases by 2025. The most frequently diagnosed type of liver cytotoxic cytokines, including IFN-γ and tumor necrosis
cancer is hepatocellular cancer (HCC), contributing ~90% of all factor-alpha (TNF-α), resulting in tumor growth and
diagnosed cases. Many risk factors play a role in the progression development in xenograft mouse models (Zhang et al., 2019).
of various diseases, such as hepatitis B and C infection, non- The tumor-associated glycoprotein 72 (TAG-72) was used as a
alcoholic steatohepatitis associated with diabetes mellitus, or CAR T-cell target in CRC. It was infused in patients via the
metabolic syndrome (Llovet et al., 2021). The glypican-3 hepatic artery and intravenously. The CAR T-cells were
(GPC3) cell surface has been targeted in CAR T-cell therapy confirmed in the blood, and trafficking to the tumor tissue
against the HCC xenograft mouse model and proved effective was confirmed by tumor biopsy. The results showed antitumor
(Gao et al., 2014; Jiang Z. et al., 2016). Other targets are being effects of the anti-TAG-72 CAR T-cells. However, the metastatic
investigated, including MUC 1, CEA, and epithelial cell adhesion deposits were resistant to these cells and escaped the immune
molecules (Chen et al., 2018; Katz et al., 2019). A different target is attack (Hege et al., 2017). Doublecortin-like kinase 1 (DCLK1),
the deletion-mutation form of EGFR (known as EGFRvIII), involved in the epithelial-mesenchymal transition (TME) and
expressed in a wide range of cancer tissues, including HCC tumor progression, is a novel target for CRC immunotherapy and
tissues. It was identified as a suitable target by CAR T-cells in anti-DCLK1 CAR T-cells resulted in cytotoxicity and secretion of
an in vivo model (female BALB/cA-nude mice) and an in vitro IFN-γ after incubation with CRC cells in two. Higher secretion
SMMC7721 cell line (expressing high levels of EGFRvIII). The levels were observed in three-dimensional cultures (Sureban et al.,
researchers used CAR T-cells by applying the transposon system 2019).
(piggyBac), and the results showed antitumor effects in both in
vivo and in vitro models (Ma et al., 2020). 5.2.9 Pancreatic Cancer
Pancreatic cancer (PaC) incidence has increased over the past few
5.2.7 Gastric Cancer years, comprising 2% of all diagnosed malignancies and 5% of
Gastric cancer (GC) is the fourth most commonly diagnosed type cancer-related deaths. Early diagnosis of PaC is challenging, and
of cancer and the second cause of cancer-related death. Each year, symptoms are not detectable at the early stages of the disease up
the number of diagnosed patients is 990,000, of which 738,000 die to the advanced and metastatic settings. Most patients relapse,
(Machlowska et al., 2020). Different CAR T-cell targets against and the 5-year survival rate is 2% (Zhao and Liu, 2020). CXCR2-
GC have been investigated, including folate receptor 1 (FOLR1) expressing CAR T-cells migrate more efficiently toward
(Kim M. et al., 2018). HER2 is also a target in GC, and anti-HER2 interleukin-8 (IL-8) and IL-8 containing TME, leading to a
CAR-T cells showed antitumor effects in MKN1 cells and mouse higher antitumor activity against αvβ6-expressing PaC
xenografts derived from a GC cell line with HER2 expression xenografts (Whilding et al., 2019). B7-H3, also known as the
(Song et al., 2017). Several markers with diagnostic and functional CD276 antigen, was targeted by CAR T-cells in pancreatic
importance have been studied as targets in GC, such as claudin adenocarcinoma in vitro and a metastatic xenograft mouse
18.2 (CLDN 18.2), EpCAM, MUC1, CEA, EGFR2, natural-killer model, which proved efficacy (Du et al., 2019). Anti-CD133
CAR T-cells showed inhibitory activity against potential stalker scorpion venom [(DeBin et al., 1993). CLTX was found to
metastatic cells in HCC, colorectal carcinoma, and pancreatic selectively bind to primary tumor cells, while it is hardly detectable
carcinoma in phase I clinical trial (Wang et al., 2018). Other in different types of normal brain tissues (Lyons et al., 2002). CLTX
known antigens are being investigated for PaC CAR T-cell directed-CAR T-cells were generated to target glioblastoma, which
therapy, such as MUC-1 (Qu et al., 2004), fibroblast activation exhibited antitumor activity in orthotopic xenograft mouse
protein (FAP) (Tran et al., 2013), PSCA (Wu et al., 2020), CEA models (Wang D. et al., 2020). NKG2D receptors are expressed
(Gansauge et al., 1996), mesothelin (Argani et al., 2001), CD24 in glioblastoma stem-like cells (Flüh et al., 2018; Yang D. et al.,
(Jacob et al., 2004), and HER-2 (Komoto et al., 2009). 2019). Chemotherapy or radiotherapy upregulates the expression
of the NKG2D ligand in glioblastoma cells; therefore, the
5.2.10 Brain Cancer combination of radiotherapy and anti-NKG2D CAR T-cells led
The burden of the brain and central nervous system cancers is to the prolonged survival of immunocompetent mice grafted with
high. However, they occur rarely and comprise approximately intracranial glioma cells (Weiss et al., 2018). In human
1.5% of all diagnosed cancers, 80% of all adult primary brain differentiated glioblastoma cells and cancer initiation cells, and
cancers are gliomas, and the relative 5-year survival rate is 22% in subcutaneous tumor models showed cellular eradication after CAR
brain cancer (Sandler et al., 2021). Various targets of CAR T-cells T-cell therapy; however, NKG2D-ligands on normal tissues are
in brain cancer have been studied, including EGFRvIII, which has expressed under distress, which may result in human toxicity
several limitations, including adverse events such as dyspnea and (Yang D. et al., 2019). In preclinical studies, various targets,
hypoxia in patients. Another potential end is that the heterogenic such as carbonic anhydrase (CAIX), CD70, chondroitin sulfate
expression of this target in glioma tumors might lead to the proteoglycan 4 (CSPG4), erythropoietin-producing hepatocellular
accumulation of resistant variants able to escape CAR T-cell carcinoma A2 (EphA2), and trophoblast cell surface antigen 2
therapy (Goff et al., 2019; Rutkowska et al., 2019). In a human (TROP2) (Maggs et al., 2021).
pilot study where IL-13Rα2 was used as a target for CAR-T cells
in treating glioblastoma via multiple intracranial infusions, the 5.2.11 Malignant Pleural Mesothelioma
treatment was well-tolerated and antitumor activity was observed Malignant pleural mesothelioma (MPM) is an incurable, rare,
in patients (Brown et al., 2015). A study on HER2 as a target and aggressive type of cancer that initiates at the serosal surfaces,
showed that the third generation HER2-specific CAR-T cells with including pleura, pericardium, peritoneum, and the vaginalis (in
enhanced activity combined with PD-1 blockade successfully males), as a result of asbestos exposure, with an approximate
eliminated glioblastoma cells (Shen et al., 2019). Additionally, survival of 8–14 months (Andujar et al., 2016; Carbone et al.,
HER2-specific CAR T-cells were infused in 17 patients. The 2019; Klampatsa and Albelda, 2020). In the United States, the
infusion was well-tolerated, no dose-limiting toxicities were incidence rate reached 3,200 diagnosed cases/year (Jane Henley
observed, and CAR T-cell persistence was detected for up to et al., 2013), while in Europe, the cases are constant and are
12 months after infusion. No disease progression was observed expected to have an increased trend between 2020 and 2025
during 24–29 months of follow-up (Ahmed et al., 2017). B7-H3 (Carbone et al., 2019). MPM has three main histological
was targeted against glioblastoma in mouse models, and anti-B7- mesothelioma subtypes: sarcomatoid, biphasic, and epithelioid
H3 Car T-cells led to significant tumor regression and extended (Yang et al., 2008). The disease is characterized by a significant
survival (Tang et al., 2019). B7-H3 mRNA exists in all normal therapeutic resistance and poor prognosis (Klampatsa and
tissues, but the microRNAs inhibit its translation; however, Albelda, 2020). Preclinical studies using mRNA
conditions such as inflammation might elicit B7-H3 expression electroporation exhibited potent anti-tumor effects (Zhao
in these tissues, making them a target of anti-B7-H3 CAR T-Cells et al., 2010). In light of this, an initial study focusing
(Xu et al., 2009). The inducer of extracellular matrix (NCT01355695) on toxicity assessment was conducted using
metalloproteinase, known as CD147, is responsible for the T-cells with transient expression of second-generation murine
degradation of the extracellular matrix, allowing for tumor anti-mesothelin CAR containing CD3ζ and 41BB signaling
growth, invasion, and metastasis (Xiong et al., 2014). CD147 domains (Maus et al., 2013; Beatty et al., 2014); in phase I
expression in glioma is significantly higher than that in normal safety trial none of the patients exhibited “on-target, off-
tissues, and its expression is correlated with patient prognosis tumor” toxicity post-infusion, and there was no evidence of
(Yang et al., 2013; Li et al., 2017a). A phase 1 clinical trial was clinical responses (Beatty et al., 2014; Klampatsa et al., 2017).
performed to evaluate the anti-CD147 effect in recurrent However, an immediate anaphylactic reaction was observed in
glioblastoma patients; however, low levels of this antigen in one of the patients post a delayed infusion of mesothelin CAR
several normal tissues despite high levels in malignant tissues T cell, which was linked to the immunogenicity of the murine SS1
sparked concern (Riethdorf et al., 2006; Liao et al., 2011; Tseng scFV used in the construction of CAR (Maus et al., 2013). After
et al., 2020). GD2 is also expressed in glioblastoma patient the safety confirmation of the transient CAR mesothelin
samples and cell lines (Golinelli et al., 2018). Anti-GD2 CAR expression, a second phase I clinical trial (NCT02159716) was
T-cells exhibited cytotoxic activity against neuroblastoma cell conducted on 15 patients with mesothelioma, ovarian, and
lines in vitro and subcutaneously grafted cell lines in mouse pancreatic cancer; the used CARs were expressing the same
models and successfully eliminated orthotopic patient-derived second-generation murine-based anti-mesothelin constructed
diffuse midline glioma xenograft models (Prapa et al., 2015; using a lentiviral transduction vector (Haas et al., 2019). In
Mount et al., 2018). Chlorotoxin (CLTX) is found in the death this trial, two doses of T-cells were administered, and some
response. Also, the CAR T-cells persisted and lasted for up to

42 weeks in the pleural fluid (Adusumilli et al., 2019).
5.3 HIV Infection

The human immunodeficiency virus (HIV) infects crucial cells in
the human immune system, such as DCs, macrophages, and T
helper cells (CD4+ T cells) (Cunningham et al., 2010). The
deterioration of CD4+ T cells below critical levels renders the
body susceptible to opportunistic infections (OIs) and the
advancement of acquired immunodeficiency syndrome (AIDS)
(Okoye and Picker, 2013). HIV-specific CD8+ cytotoxic T
lymphocytes (CTLs) play an essential role in recognizing viral
antigens presented by HLA class I and killing the infected cells,
resulting in limited viral replication in vivo; however, CTLs fail to
provide sustainable HIV replication control without the use of a
combination antiretroviral therapy (cART) (Jones and Walker,
2016). The CTL responses still fail to clear the virus from the
body, even when using cART to delay disease progression and
increase life expectancy. HIV remains an incurable disease, and
one of the main reasons behind the failure of the immune system
to clear out HIV infection is the reduction or absence of HIV viral
antigen expression on infected yet latent CD4+ T cells that act as
viral reservoirs (Churchill et al., 2016). Viral reservoirs have been
FIGURE 4 | HIV reservoir eradication. The “kick and kill” strategy is used
to eliminate latently infected cells (reservoir); the “kick” part of this strategy
targeted by one strategy known as “kick and kill” or “shock and
depends on latency reversal agents (LRAs), which induce the virus via kill.” This approach suggests the induction of the virus from the
transcriptional reactivation of the incorporated provirus within the latent cells to promote HIV eradication via cell death or by
infected cell. The infected CD4+ T-cell then starts producing and assembling immune surveillance, which clears the viral reservoir (Kim Y.
the virus. Upon leaving the cell membrane, the engineered CD8+ CAR T-cell
et al., 2018). However, this approach has been investigated in
will detect the expressed viral antigens; then, the “kill” action occurs via the
secretion of perforin and granzymes, sending the cell into apoptosis. clinical trials using latency reversal agents (LRAs), and the results
are not promising (Rasmussen et al., 2014; Spivak et al., 2014;
Søgaard et al., 2015). CAR T-cells are a promising approach for
cohorts used a lymphodepleting agent (cyclophosphamide). targeting and killing HIV-expressing cells (Kuhlmann et al.,
Although cyclophosphamide improved CART-meso expansion 2018) for multiple reasons: 1) long-term immune surveillance
but did not enhance persistence beyond 28 days, the best provided by CAR T-cells: the effector function of peripheral-
overall response reported was stable disease in 11/15 patients derived CAR T-cells has been reported to be maintained for
(Haas et al., 2019). A third clinical trial (NCT03054298) was 6 months (Kalos et al., 2011; Kochenderfer et al., 2012; Maude
conducted using an active, fully human anti-mesothelin CAR et al., 2014). Moreover, hematopoietic stem cell (HSPC)-derived
and cyclophosphamide, administered via intravenous and CAR T-cells persist longer and provide constant production of
intrapleural routes, respectively, to enhance the overall CAR T-cells as observed in HIV/AIDS animal models (Zhen
persistence and efficacy of CAR T-cells. In addition, researchers et al., 2017). Additionally, HSC-based CAR T-cells were found in
at Memorial Sloan Kettering Cancer Center are conducting a several lymphoid tissues in the gut, bone marrow, and several
mesothelin-targeting CAR T cell trial to treat malignant pleural lymph nodes, all of which represent the main replication sites in
disease, including MPM (NCT02414269) based on preclinical non-human primate (NHP), infected models, with simian-
studies of an orthotopic MPM mouse model. The study human immunodeficiency virus (SHIV) (Zhen et al., 2017).
demonstrated that intrapleural administration of mesothelin Moreover, the long-lived immunological memory provided by
CAR T-cell therapy was potent and had long-lasting antitumor CAR T-cells can be reprogrammed and differentiated into central
efficacy (Adusumilli et al., 2014). The phase I/II clinical trial used memory or effector T cells (Kawalekar et al., 2016). 2) The
CAR with human-derived anti-mesothelin scFV and CD3Z/CD28 trafficking capability of CAR T-cells to various types of tissues,
signaling domain transduced by a retroviral vector; the CARs were including the central nervous system, is considered a potential
administered via the intrapleural route in patients with primary harbor for latent HIV (Marban et al., 2016). Penetration of the
and secondary pleural malignancies, with MPM patients being the blood-brain barrier has been a difficult task for drugs; however,
main target population. A subset of the MPM patients had a evidence of anti-CD19 CAR T-cell trafficking to brain tissues and
subsequent administration of PD-1 checkpoint inhibitor cancer cell elimination supports the concept that CAR-T cells
(Pembrolizumab) to assess its efficacy in maintaining the may effectively target HIV reservoirs in the brain tissues (Grupp
prolonged activity of CAR T-cell therapy. Of the 27 patients et al., 2013; Maude et al., 2014). Homing receptors can be added
who received cyclophosphamide, CAR T-cell therapy, and three to CAR T-cells to increase their presence in the B cell follicle,
doses of Pembrolizumab, 63% achieved either partial or complete which is another important HIV reservoir difficult for CTLs to
FIGURE 5 | The number of clinical trials. Several clinical trials have been investigating various malignancies as recorded by ClinicalTrials.gov. Based on the data up
to January 2022, the number of these clinical trials is rising. The figure shows the number of CAR T-cell therapy clinical trials for hematological malignancies, solid tumors,
and HIV infection (total = 789). (A) Hodgkin’s lymphoma = 15 studies. (B) Acute myeloid leukemia = 35 studies. (C) Chronic lymphocytic leukemia = 74 studies. (D)
Multiple myeloma = 114 studies. (E) Non-Hodgkin’s lymphoma = 153 studies. (F) Acute lymphoblastic leukemia = 157 studies. (G) Human Immunodeficiency Virus
= 6 studies. (H) Prostate Cancer = 10 studies. (I) Brain Cancer = 12 studies. (J) Renal Cancer = 12 studies. (K) Colorectal Cancer = 15 studies. (L) Ovarian Cancer = 16
studies. (M) Lung Cancer = 22 studies. (N) Gastric Cancer = 19 studies. (O) Breast Cancer = 19 studies. (P) Pancreatic Cancer = 28 studies. (Q) Liver Cancer = 29
studies. (R) Malignant pleural mesothelioma = 4 studies.
target (Haran et al., 2018). 3) The ability of CAR T-cells to target certain impediments, such as limited in vivo expansion,
antigen in an MHC-independent manner helps in targeting HIV- susceptibility to apoptosis, and cytotoxicity (Heuser et al.,
infected cells and avoids viral downregulation of MHC-1 that 2003; Zhao et al., 2009). CAR T-cells were optimized into the
leads to immune escape (Collins et al., 1998; Goulder and Walker, second generation by adding costimulatory domains 4-1BB,
1999; Wonderlich et al., 2011). The HIV CAR T-cell therapy resulting in 50-fold more compelling in vitro suppression of
targeted the primary HIV cellular receptor CD4, infused with HIV replication than the previous generation (Leibman et al.,
CD3ζ signaling domain (CD4ζ) (Mitsuyasu et al., 2000; Walker 2017). In vivo studies showed that second generation CAR T-cells
et al., 2000; Deeks et al., 2002). The reason behind choosing CD4 had superior expansion in response to the antigen, provided
as the reactive antigen in anti-HIV CAR T-cell design is its protection to CD4+ T-cells against HIV infection, and CD4
extensive targeting of all HIV isolates. Additionally, the binding reduction was decreased compared to the CARs without
sites of CD4 on the envelope protein are well preserved (Wang costimulatory molecules (Leibman et al., 2017). The
et al., 2019). The first generation CD4-based CAR-T cells have costimulatory domain 4-1BB is superior in reducing viral
been tested in several clinical trials on HIV patients (Mitsuyasu rebound than the CD28 domain after antiretroviral therapy
et al., 2000; Walker et al., 2000; Deeks et al., 2002). The results (ART) and 4-1BB-induced T-cell perseverance in the absence
showed a lack of durable control over viral replication; however, of the antigen (Zhang et al., 2007; Leibman et al., 2017).
no treatment-associated toxicities were observed, and the Developing third generation CARs with multiple costimulatory
persistence of modified cells continued for more than 10 years molecules enhanced effector function, survival, and proliferation.
(Mitsuyasu et al., 2000). The first generation of CAR T-cells had It also enhanced tumor targeting and killing (Savoldo et al., 2011).
TABLE 1 | CAR T-cell clinical trials with recorded results from ClinicalTrials.gov.
Condition Enrollment Status Antigen Phase Results NCT
B- cell lymphoma 43 Active, not Anti-CD19 CAR T-cells Phase I/ Complete remission (CR) of an (NCT00924326)
recruiting phase II assortment of the B-cell
malignancies with durability for up to
≥3 years post 51% of anti-CD-19
CAR T-cell treatment with remission
of 9 years and going. The adverse
events were infrequent
Metastatic melanoma and renal 24 Terminated Anti-VEGFR2- CAR T-cells Phase I/ Adverse events registered Grade 3 (NCT01218867)
cancer phase II of 4 toxicity with a presentation of
hypoxia, nausea, vomiting,
hyperbilirubinemia, elevation in
aspartate transaminase, and alanine
transaminase. The study was
terminated due to the absence of
observed impartial responses
Metastatic cervical, pancreatic, 15 Terminated Anti-mesothelin CAR T-cell Phase I/ Adverse events were evident in this (NCT01583686)
lung, ovarian, and mesothelioma phase II study, including anemia,
cancers constipation, thrombocytopenia,
lymphocytopenia, and hypoxia. The
study was terminated due to low
and inadequate accrual
Malignant gliomas 18 Completed Anti-EGFRvIII CAR T-cells Phase I/ The pilot clinical trial failed and led to (NCT01454596)
phase II severe adverse events such as
hypoxia, dyspnea, and multi-organ
failure. In addition, the CAR T-cell
intervention had no significant
impact on the glioblastoma and
resulted in its progression
Refractory B-cell malignancies in 53 Completed Anti-CD19 CAR T-cells Phase I The feasibility and safety of this (NCT01593696)
children and young adults treatment were evident. The anti-
leukemic activity was remarked in
chemoresistance patients. High
responses rate was observed post-
infusion in patients. Central nervous
system (CNS) trafficking and
clearance were detected in two
cases. Minimum cytokine release
syndrome was CAR T-cells
expansion correlated. Toxicities
were reversible
Relapsed or refractory CD19 42 Completed Anti-CD19 CAR T-cells Phase II Anti-leukemic activity and long (NCT01747486)
positive chronic lymphocytic persistence of tranced cells were
leukemia (CLL) and small seen in patients. Upon further
lymphocytic lymphoma (SLL) investigation, findings suggest that
patients who achieved complete
response showed an increased
mass of the Anti-CD19 CAR T-cells
mitochondria, which contributed to
cells expansion and persistence
Adult B-cell Acute Lymphoblastic 82 Terminated JCAR015 Anti-CD19 CAR Phase II The clinical trial failed to achieve (NCT02535364)
Leukemia (B-ALL) T-cells significant results as five patients
suffered from cerebral edema as an
adverse event, resulting in death,
and the study was terminated for
safety reasons
B-cell Malignancies (B-Cell 27 Active, not Anti-CD19 CAR T-cells. (Hu19- Phase I Patients had shown CR. This study (NCT02659943)
Lymphoma, Non-Hodgkin’s recruiting CD828Z) suggested that enhancing the CAR
Lymphoma) T-cells design resulted in less
neurotoxicity and CRS associated
with low or mild cytokine production
levels
(Continued on following page)
TABLE 1 | (Continued) CAR T-cell clinical trials with recorded results from ClinicalTrials.gov.
Multiple myeloma 6 Terminated Anti-CD19 CAR T-cells. Post Phase II No mortalities were reported. The (NCT02794246)
autologous stem cell serious adverse events were 1/6
transplantation (ASCT) patients suffered from CRS and
upper respiratory tract infection
(URI). The study was terminated due
to administrative reasons
B-cell Acute lymphoblastic 1 Terminated Anti-CD19 CAR T cells Phase II The patient died. The severe adverse (NCT02935543)
leukemia in adults events mentioned were paresthesia,
encephalopathy, and gastric
necrosis. The results were not
discussed further, and the study was
terminated due to admirative reasons
Glioblastoma and gliosarcoma 3 Terminated Anti- EGFRvIII CAR T-cells Phase I The mortalities were 3/3. The (NCT02664363)
adverse events were confusion and
generalized muscle weakness in 1/
3. The study was terminated
because the funding was not
sufficient
Multiple myeloma 12 Terminated AUTO2 (APRIL CAR T-cells) Phase I/ The study mortalities were 6. Some (NCT03287804)
phase II patients have severe adverse
events, including Acute myocardial
infarction (AMI), pyrexia, lung
infection, decreased neutrophil
count, hypocalcaemia, metaplastic
breast carcinoma, headache, and
dyspnea. The study was terminated
as the preliminary efficacy post-
treatment was insufficient to
guarantee further development
B Cell Acute Lymphoblastic 23 Completed AUTO3 (CD19/22 CAR T-cells) Phase I/ The mortality rate was 61.6% (NCT03289455)
Leukemia (ALL) phase II among patients who received high
infusion doses; serious adverse
events were anemia, febrile
neutropenia, thrombocytopenia,
pyrexia, cellulitis, encephalopathy,
and seizure
Relapsed/refractory B-cell 26 Active, not Anti-CD20/19-CAR T-cells Phase I The results of this study suggest (NCT03019055)
malignancies recruiting that the favorable infusion dosage is
2.5 × 106 cells/kg providing low
toxicity and high efficacy in city
profile and sustained efficacy at a
dose of 2.5×106 cells per kg for
relapsed, refractory B cell non-
Hodgkin’s lymphoma (NHL) and
chronic lymphocytic leukemia (CLL)
patients
Relapsed/Refractory Multiple 17 Active, not KITE-585 CAR T-cells Phase I The overall mortality rate was (NCT03318861),
Myeloma recruiting 62.5%, and the adverse events
were chest pain and hypoxia
Advanced Lung Cancer 1 Terminated Anti-PD-L1 CAR T-cells Phase I The patient developed severe CRS, (NCT03330834),
which caused interstitial pneumonia
disease. The study was terminated
due to serious adverse events
Acute Myeloid Leukemia (AML) 8 Terminated Anti-CD44v6 CAR T-cells Phase I/ The patients had adverse events of (NCT04097301)
Multiple Myeloma (MM) phase II pyrexia, anemia, neutropenia. The
study was terminated due to low
patient recruitment and a lower-
than-expected proportion of
myeloma and leukemia expressing
CD44v6. The study failed to be
completed in a clinically relevant
time frame
(Continued on following page)
TABLE 1 | (Continued) CAR T-cell clinical trials with recorded results from ClinicalTrials.gov.
CD19+ Diffuse Large 12 Completed Anti-CD19 CAR T-cells Phase I/ Serious adverse events included (NCT02650999)
B-cell Lymphomas Follicular phase II optic disorder, fever,
Lymphomas Mantle Cell hyperbilirubinemia, CRS, sepsis,
Lymphomas hypercalcemia, delirium, acidosis,
hypoxia, pleural effusion, non-
cardiac related chest pain, and rash
DLBCL Neurotoxicity Syndromes 25 Terminated Evaluation of the Safety and Phase II Patients had febrile neutropenia, (NCT03954106)
Efficacy of Defibrotide in the atrial fibrillation, myocardial
Prevention of Chimeric Antigen infarction, asthenia, pyrexia, CRS,
Receptor-T-cell-associated decreased appetite, neurotoxicity,
Neurotoxicity tumor lysis syndrome, transient
ischaemic attack, confusion state,
pleural effusion, pulmonary
embolism, and hypotension. The
study was terminated because
unplanned interim assessment on
the first 20 efficacy evaluable
patients was unlikely to meet the
primary endpoint
Relapsed or Refractory 17 Completed Anti-GD2 CAR T-cells, (1RG – Phase I Hypotension, capillary leak (NCT02761915)
Neuroblastoma CART) syndrome, neurological symptom,
headache, hyponatremia, pyrexia,
tachycardia, febrile neutropenia,
and coagulopathy. Only 12 patients
were subjected to therapy as two
were withdrawn due to progressive
disease, one died, and one
withdrew the consent for the trial
Myeloma-Multiple Myeloma, 13 Completed Anti-SLAMF7 CAR T-cell Phase I Serious adverse events included (NCT03958656)
Plasma-Cell CRS sinus tachycardia and fever
Using the third generation CARs with CD3z-CD28-4-1BB as pre-clinical trials have shown promising results (Seif et al., 2019).
multiple domains, targeting the envelope glycoprotein GP120 The number of clinical trials of CAR-T cell therapies is increasing,
(gp120) and anti-gp120 CAR T-cells in HIV infection showed and their observations are constantly changing, as it is a very
increased effectiveness in lysing Env-expressing cells in vitro attractive field of research with remarkable potential (Figure 5).
compared to CD4ζ CAR T-cells (Liu et al., 2016). Targeting However, according to ClinicalTrials.gov, only 21 studies had
HIV reservoirs by immune surveillance is difficult because of the results in January 2022 (Table 1).
ability of the virus to persist in various reservoirs and the lack of It is worth of mentioning that CAR T-cells potentials were
viral antigen expression in infected cells. The “kick and kill” recently applied against cardiac fibrosis (heart tissue stiffening
strategy cause the transcription reactivation of the latently and scarring). Rurik et al. were capable of designing an
persistent provirus leading to viral antigen expression, making immunotherapy strategy to generate transient CAR T-cells
it detectable by the immune surveillance in ART-treated patients. able to identify fibrotic cells in the heart through injecting
The ‘kick” strategy can be achieved by potent latency reversal CD5-targeted lipid nanoparticles encompassing the needed
agents (LRAs). Clinical studies in animals showed that LRA was mRNA to reprogram T lymphocytes, therapeutic CAR T-cells
well tolerated in vivo and induced HIV expression (Marsden were successfully generated inside the body (In vivo). The heart
et al., 2017). Although LRAs induce the virus killing by the disease in mouse model was analyzed and revealed that this
immune system, it is insufficient, and reservoir eradication is approach has indeed succeeded in fibrosis reduction and cardiac
inefficient (Thorlund et al., 2017). The CAR T-cells can exhibit function restoration (Rurik et al., 2022).
the “kill” response in this strategy along with LRAs; this
combination is necessary for effective reservoir eradication
(Bashiri et al., 2018) (Figure 4). The kill action in the human 6 FDA APPROVED CAR T-CELLS
system shows that CTLs, either CD8+ or CD4+, induce apoptosis THERAPIES
by cytolytic perforin and granzyme (Yasukawa et al., 2000).
CAR T-cell therapy has been considered a potential treatment 6.1 Axicabtagene Ciloleucel (YESCARTA™)
against other infectious diseases such as those caused by The first Food and Drug Administration (FDA) approved CAR
opportunistic fungi, hepatitis B virus (HBV), hepatitis C virus
(HCV), and cytomegalovirus (CMV), and the data gathered from
T-cell therapy, axicabtagene ciloleucel (YESCARTA ) from Kite
Pharma approved in 2017, comprises autologous genetically
™
modified T cells designed to produce CAR protein targeting lymphodepleting chemotherapy. The clinical trial had 68
CD19 expressing normal and malignant cells (Papadouli et al., eligible patients out of 115, and the outcomes were 50% ORR
2020). It is used to treat adult large B-cell Lymphoma after two or with a 32% CR rate. With a median follow-up time of 9.4 months,
more lines of systemic therapy, including DLBCL, high-grade patients with the best overall response CR had longer DOR than
B-cell lymphoma, primary mediastinal large B-cell lymphoma, that of patients with PR. Patients with CR estimated median DOR
and DLBCL arising from follicular lymphoma. The approval of of (10.0 months) was not reached, while the estimated median
this drug was based on a single-arm multicenter clinical trial DOR among PR patients was 3.4 months. The most common
(ZUMA-1; NCT02348216) conducted on 108 patients diagnosed adverse events in 20% of the patients included CRS, pyrexia,
with aggressive B-cell non-Hodgkin’s lymphoma. The selection nausea, infections-pathogens unspecified, fatigue, diarrhea,
criteria were occurrence of refractory disease post a recent headache, edema, and hypotension. The recommended dose of
therapy or relapse post autologous hematopoietic stem cell tisagenlecleucel for adults with r/r DLBCL was 0.6–6.0 × 108
transplantation within a year. The patients underwent CAR-positive viable T-cells (Schuster et al., 2019).
lymphodepletion before receiving a single infusion of
axicabtagene ciloleucel. The efficacy was evaluated in 101
patients as follows: ORR 72%, with a complete remission rate 6.3 Brexucabtagene Autoleucel
(CR) of 51%, the duration of response (DOR) was longer in (TECARTUS™)
patients with CR than in patients with partial remission (PR). The
median DOR was not reached after 7.9-months (median follow-
Accelerated approval of brexucabtagene autoleucel (TECARTUS )
was granted by FDA in July 2020; this immunotherapy comprises
™
up). The estimated DOR was 2.1 months. Most common grade 3 autologous genetically modified T cells (CD19-directed) for the
(with incident ≥10%) adverse events occurred including fever, treatment of adult patients with r/r mantel cell lymphoma (MCL)
febrile neutropenia, encephalopathy, CRS, hypoxia, and (Wang M. et al., 2020). The clinical trial behind the approval was a
hypotension; 25% exhibited severe adverse events, including multicenter, single-arm, and open-label (ZUMA-2; NCT02601313)
neurotoxicity, CRS, serious infections, and prolonged trial. Seventy-four patients diagnosed with MCL were subjected to
cytopenia. In some patients, CRS and neurotoxicity were fatal. this study. These patients previously received anthracycline or
The FDA approved axicabtagene ciloleucel with bendamustine-containing chemotherapy, anti-CD20 antibody, and
recommendations of mitigation strategy and risk evaluation. Bruton tyrosine kinase inhibitor. After completing lymphodepleting
The recommended dosage was 2 × 106 viable CAR-positive chemotherapy, patients received a single infusion of brexucabtagene
T cells/kg of body weight, following lymphodepletion autoleucel. Sixty out of 74 patients evaluated for efficacy in a
chemotherapy by (Flu/Cy) (Neelapu et al., 2017a). In March minimum duration of 6 months follow-up showed 87% ORR,
2021 (Yescarta, axi-cel), the FDA approved another directed with a CR rate of 62%. The estimated DOR was not reached
CD19 T-cell therapy to treat adult r/r follicular lymphoma (0–29.2 months) after a median DOR of follow-up (8.6 months).
after two lines of therapy. The approval was based on Among all 74 patients who underwent leukapheresis, the ORR was
collected data from a single-arm, open-label phase II clinical 80%, and CR was 55%. The most common adverse reactions with
trial (ZUMA-5; NCT03105336). The clinical trial had 81 grade 3 or higher (≥10%) included hypoxia, encephalopathy,
participants. The results were: ORR 91%, with CM of 60%, the leukopenia, anemia, neutropenia, thrombocytopenia, hypotension,
median DOR was not reached within a year of CM rate of 76.2%, hypophosphatemia, hypertension, hyponatremia, pyrexia, infection-
patients who underwent leukapheresis (n = 123) experienced a pathogen unspecified, lymphopenia, hypocalcemia, and pneumonia.
ORR of 89% with CM rate 62%. CRS (grade ≥ 3, 10%) occurred in Due to the fatal or life-threatening neurotoxicity and CRS, the FDA
88%, and neurotoxicity occurred in 51% of all patients with non- approval came with risk evaluation and mitigation strategies. The
Hodgkin’s lymphoma (Colombo et al., 2021). recommended dose of brexucabtagene autoleucel was a single IV
infusion of (2 × 106 – 2 × 108)CAR-positive viable T-cells/kg body
6.2 Tisagenlecleucel (KYMRIAH™) weight post lymphodepleting chemotherapy of (Flu/Cy) (Wang M.
The second FDA approved CAR T-cell therapy, tisagenlecleucel et al., 2020).
™
(KYMRIAH ) from Novartis pharmaceuticals approved in
2018, is a genetically modified autologous T-cell
In 2021 brexucabtagene autoleucel was approved to treat adult
patients with r/r B-cell precursor ALL based on the data gathered
immunotherapy (CD19 directed) for adult patients with r/r from a phase II clinical trial (ZUMA-3; NCT02614066) (Shah
large B-cell lymphoma post two or more lines of systemic et al., 2021). The study had 125 participants diagnosed with r/r
therapy, including high-grade B-cell lymphoma DLBCL, and B-cell precursor ALL. Patients received a single infusion of
DLBCL arising from follicular lymphoma. The approval was brexucabtagene autoleucel post completion of lymphodepleting
based on phase II of a single-arm, open-label, multicenter chemotherapy. The outcomes included CR within 3 months post-
clinical trial (JULIET; NCT02445248) conducted on adults infusion. Fifty-four patients were evaluable for efficacy, 28
with r/r DLBCL and DLBCL arising from follicular lymphoma achieved CR within 3 months with a median follow-up of
(Schuster et al., 2019). The criteria included a condition that the 7.1 months, the CR median duration was not reached, and the
subject must at least undergo two prior therapy lines with CR duration for more than half of the patients was estimated to
rituximab and anthracycline or have relapsed after autologous exceed 12 months. In 92% of patients, CRS occurred (≥grade 3,
hematopoietic stem cell transplant. Patients had a single 26%); neurotoxicity occurred in 87% (≥Grade 3, 35%); most
tisagenlecleucel infusion after the completion of common adverse events were hypotension, CRS, encephalopathy,
fever, chills, headache, rash, edema, nausea, tachycardia, febrile 28%. Approximately 65% of patients had CR for at least 12 months.
neutropenia, musculoskeletal pain, hypoxia, diarrhea, tremor, The most common adverse events included CRS, neurotoxicity,
constipation, infection with an unspecified pathogen, vomiting macrophage activation syndrome, prolonged cytopenia. Moreover,
and decreased appetite. The recommended dose was a single IV infection, fatigue, hypogammaglobulinemia, and musculoskeletal pain
infusion of brexucabtagene autoleucel (1 × 106–1 × 108) of CAR- were designated as common side effects. Idecabtagene vicleucel was
positive viable T-cells/kg body weight preceded by (Flu/Cy) approved with recommendations of risk evaluation and mitigation
lymphodepleting chemotherapy (Shah et al., 2021). strategies. The healthcare facility that houses this therapy must be
specially certified to recognize and manage neurotoxicity and CRS.
FDA called for a post-marketing observational study conducted by the
6.4 Lisocabtagene Maraleucel manufacturer involving the patients treated with idecabtagene
(BREYANZI™) vicleucel (Munshi et al., 2021).
In February 2021, lisocabtagene maraleucel (BREYANZI )
from Juno Therapeutics was approved by FDA for the
™
treatment of adult patients with r/r large B-cell lymphoma 6.6 Ciltacabtagene Autoleucel
after two or more lines of systemic therapy, including high-
grade B-cell lymphoma, DLBCL, primary mediastinal large
(CARVYKTI ™)
The most recently FDA approved CAR T-cell therapy, in February
™
B-cell lymphoma, DLBCL arising from indolent lymphoma,
2022, is ciltacabtagene autoleucel (CARVYKTI ) from Janssen
and follicular lymphoma grade 3B (Abramson et al., 2020).
Biotech, Inc. This drug was approved for the treatment of r/r
Lisocabtagene maraleucel is a CD19- directed CAR T-cell
multiple myeloma post four or more prior lines of therapy
immunotherapy comprised of autologous genetically
including an anti-CD38 monoclonal antibody, an
modified T cells that produce CAR protein able to identify
immunomodulatory agent (IMiD), and a proteosome inhibitor (PI).
and eradicate CD19-expressing normal and malignant cells. The
It is a genetically modified autologous CAR T-cell therapy directed by
immunotherapy efficiency was evaluated in a single-arm, open-
B-cell maturation antigen (BCMA). In a multicenter study
label, multicenter trial (TRANSCEND, NCT02631044); 192
CARTITUDE-1 (NCT03548207) ciltacabtagene autoleucel safety and
patients underwent lymphodepleting chemotherapy before
efficacy of were evaluated in 97 patients with r/r multiple myeloma who
infusion. The outcomes included 73% ORR, with a CR rate
presented disease progression post their last chemotherapy regimen;
of 54%, and the median time of first response was 1 month; 104/
82% of the patients had received four or more prior lines of
192 patients had CR, which lasted at least 6 months (65%), and
antimyeloma therapy. The dosage of ciltacabtagene autoleucel given
some patients (62%) had a remission that lasted at least
to patients was falling within the range of 0.5–1.0 × 106 viable CAR-
9 months. The DOR was 16.7 months in patients who
positive T-cells/kg body weight. According to the International
achieved CR; and the patients with PR had 1.4 DOR.
Myeloma Working Group Uniform Response Criteria for Multiple
Adverse events included CRS in 46% of the patients (grade 3
Myeloma, the efficacy was evaluated by an Independent Review
or higher, 4%); neurotoxicity occurred in 35% (grade 3 or
committee based on the overall ORR and DOR response. The ORR
higher, 12%). Three patients encountered fatal neurotoxicity.
97.9%, and a median DOR of 21.8 and 12 months median duration of
Other grade 3 or higher adverse events were prolonged
follow up. Most commonly observed adverse reactions of ciltacabtagene
cytopenia (31%) and infections (19%). Due to the fatal and
autoleucel were CRS, fatigue, hypogammaglobulinemia, pyrexia,
life-threatening neurotoxicity and CRS, the FDA approval came
musculoskeletal pain, nausea, infection, diarrhea, coagulopathy,
with recommendations of risk evaluation and mitigation
encephalopathy, headache, vomiting, and constipation. Moreover,
™
strategies. The recommended regimen was a single dose of
recommended dosage of (CARVYKTI ) ranges from 0.5–1.0 × 106
50–110 × 106 CAR-positive viable T-cells with a ratio of 1:1
to a maximum dose of 1 × 108 viable CAR-positive T-cells/kg of body
™
of CD4 and CD8 components, intravenous (IV) infusion
weight per single infusion. The approval of (CARVYKTI ) is restricted
following (Flu/Cy) lymphodepletion (Abramson et al., 2020).
by a risk evaluation and mitigation strategy necessitating healthcare
facilities that houses this therapy and their associated clinicians to be
6.5 Idecabtagene Vicleucel (ABECMA™)
™
specially certified to recognize and manage neurotoxicity and CRS. FDA
On March 2021, idecabtagene vicleucel (ABECMA ) from Bristol
called for a post-marketing observational study conducted by the
Myers Squibb was approved as the first cell-based immunotherapy for
manufacturer involving the patients treated with ciltacabtagene
adult patients with r/r multiple myeloma after four or more preceded
autoleucel (Berdeja et al., 2021).
lines of therapy, including an anti-CD38 monoclonal antibody, an
immunomodulator, and a proteasome inhibitor (Munshi et al., 2021).
It is an autologous genetically modified B-cell maturation antigen
(BCMA)-directed CAR T-cell therapy. In a multicenter study 7 LIMITATIONS AND SOLUTIONS FOR CAR
(NCT03361748), a total of 127 patients with r/r multiple myeloma T-CELLS
were included to evaluate the safety and efficacy of the idecabtagene
vicleucel; all patients received three (88% had received four or more) The CAR T-cell technology has immense potential. Current
lines of antimyeloma therapies. In addition, 100 had received clinically approved CAR T-cell therapies are KYMRIAH for ™
idecabtagene vicleucel with a dosage range of 300–460 × 106 of ™
ALL and DLBCL; YESCARTA for DLBCL and follicular
CAR-positive T-cells. The results showed a 72% ORR and a CR rate of lymphoma; TECARTUS ™
for mantle cell lymphoma;
BREYANZI® for DLBCL and follicular lymphoma; and limitation of “on-target-off-tumor” toxicity as the on-target
ABECMA® for MM. Unfortunately, all these approved CAR-T activity is focused on the malignant tissue, and the normal
cell products exert serious but clinically manageable adverse tissue interaction is disregarded (Sterner and Sterner, 2021).
effects such as cytokine release syndrome and neurotoxicity Inducible CAR-T cell products based on engineered synthetic
(Zhao Z. et al., 2018; Zheng et al., 2018). Notably, the delay in Notch receptors are also being explored to mitigate the on-target
approving CAR T-cell therapies targeting other diseases has the off-tumor associated toxicities (Roybal et al., 2016).
following structural limitations.
7.3 Trafficking and Tumor Infiltration
7.1 Tumor Antigen Escape One of the significant inadequacies in using CAR T-cell therapy
Single antigen-targeting CAR-T cells might face tumor resistance in solid tumors is the ability of these cells to traffic and infiltrate
after the initial high response rate. The decline in response and the tumor because both immunosuppressive TME and physical
increase in resistance is due to partial or complete loss of target barriers of tumor such as stroma restrain mobility and diffusion
antigen expression. Tumor cells escape killing by encouraging of CAR T-cells. The proposed approach uses the local
mutations in the antigen-coding gene, leading to the administration as the delivery route, which disregards the need
downregulation of expression of alternative antigens that lack for the cells to traffic to the disease site (Sterner and Sterner,
the antigen epitopes targeted by CAR T-cells (Majzner and 2021). Another strategy developed to overcome the trafficking
Mackall, 2018; Sterner and Sterner, 2021). One strategy to issue is the addition of chemokine receptor expression on CAR
overcome this hurdle is to design T cells equipped with two or T-cells that match and respond to chemokines expressed by
more CARs to target multiple TAAs, suggesting that the escape targeted tumors (Whilding et al., 2019). The physical barrier
mechanism would require mutation of several genes instead of of the stroma mainly comprises an extracellular matrix with a
one by engineering CARs with multi-specific targets such as primary component of heparin sulfate proteoglycan (HSPG).
bicistronic CAR T-cells, tandem CAR T-cells, co-administered Upon its degradation, CAR T-cells can reach the tumor
CAR T-cells, or co-transduction CAR T-cells. However, finding (Zhang B.-L. et al., 2016). Engineered CAR T-cells with
more than one TAA in one tumor targeted by CAR T-cells may heparinase expression have been shown to degrade HSPG,
prove challenging in some malignancies, with respect to safety leading to enhanced tumor infiltration and elimination
and effectiveness (Hegde et al., 2013; Jackson and Brentjens, (Caruana et al., 2015). Likewise, fibroblast activation protein
2015). In addition, the use of lymphodepleting agents before the (FAP) was also targeted by CAR T-cells in animal models,
adoptive T-cell transfer can enhance epitope spreading, leading to which increased cytotoxic function by reducing the number of
more specific antigen recognition (Cui et al., 2009). Additionally, tumor fibroblasts (Wang et al., 2014).
combining CAR T-cell therapy with checkpoint inhibitors
(Gargett et al., 2016; Li et al., 2017b; Heczey et al., 2017; 7.4 Immunosuppressive Microenvironment
Adusumilli et al., 2021), radiation (Weiss et al., 2018), vaccines In the TME, several tumor-infiltrating cells contribute to
(Slaney et al., 2017; Tanaka et al., 2017), other immune agonists immunosuppression, including MDSCs, regulatory T cells
(Khalil et al., 2016; Majzner et al., 2017) might also contribute to (Tregs), and tumor-associated macrophages (TAMs) (Quail
epitope spreading and immune escape restriction (Majzner and and Joyce, 2013). These infiltrates and tumor cells contribute
Mackall, 2018). to the production of tumor-supporting growth factors,
chemokines, and cytokines, and the antitumor immunity
7.2 On-Target Off-Tumor declines because of immune checkpoint proteins such as
One of the most observed toxicities in CAR T-cell therapy is the CTLA-4 or PD-1. Weak CAR T-cell responses could be
“on-target-off-tumor,” where the normal tissues express the same regarded as a poor T-cell expansion and limited persistence
targeted antigen on the malignant tissues at variable levels, period, indicating that the development of T-cell exhaustion is
leading to a direct attack from CAR T-cells against the normal prompted by co-inhibitory pathways (Yin et al., 2018).
tissues and eventually resulting in toxic effects that can be Consequently, the combination of CAR-T cells with
detrimental (Sun et al., 2018). To overcome this roadblock, immunotherapy and checkpoint blockade is thought to be the
using affinity-tune CARs to recognize tumor cells that have next cutting-edge immunotherapy approach because it provides
increased density of surface antigens and preventing the two major elements to secure strong immune responses: CAR
involvement with normal tissues that express low-density T-cells provide tumor penetration and PD-1/PDL1 blockade to
surface antigens has been suggested (Zhao et al., 2009). This guarantee sustained and persistent T-cell function (June et al.,
strategy can be executed by altering the binding region of scFV via 2018; Grosser et al., 2019). Recently, CAR-T cells have been
mutagenesis or via the recombination of both heavy and light engineered to be robustly resistant to TME immunosuppressive
chains (Carter et al., 1992; Drent et al., 2017). Another potential factors such as TFG-β-mediated inhibitory signals (Kloss et al.,
avenue for solid tumors is to target tumor-restricted post- 2018). Furthermore, CAR T-cell engineering includes the
translational modifications, such as overexpression of addition of immunostimulatory signals such as stimulatory
truncated O-glycans such as Tn (GalNAca1-O-Ser/Thr) and cytokines capable of increasing survival, proliferation, and
sialyl-Tn (STn) (NeuAca2–6-GalNAca1-O-Ser/Thr) (Steentoft antitumor activity while re-equalizing TME (Chmielewski
et al., 2018). Another suggested approach is CAR T-cell local et al., 2014). Various studies have been investigating numerous
administration to the disease site, which might contribute to the cytokines to create “armored CARs.” The studies that focused on
proinflammatory cytokines apart from concentrating on Management of ICANS aims to reduce the inflammatory
inhibitory signals have depended on IL-12 secretion (Koneru response, which could be achieved by using Siltuximab (IL-6
et al., 2015), expression of IL-15 (Krenciute et al., 2017), and the antagonist), which prevents continuous IL-6 translocation across
redirection of immunosuppressive cytokine signaling (e.g., IL-4) the blood-brain barrier (Gust et al., 2017). A high dose of
towards proinflammatory cytokines (Mohammed et al., 2017). corticosteroids shows sound central nervous system (CNS)
penetration (Neelapu et al., 2017b). The use of levetiracetam
7.5 CAR T-Cell-Associated Toxicities or other antiepileptic agents can also be considered an option for
T-cell therapy has been one of the most groundbreaking tools in treating severe neurological dysfunction as prophylaxis for
cancer treatment; however, toxicities and associated fatalities seizures (Pehlivan et al., 2018). Additional studies are required
have limited this approach’s applications. To date, the to understand the mechanism underlying ICANS manifestation,
characterization of the toxicities associated with CAR T-cell associated risk factors, and optimal management required for
therapy has been broadly studied in patients receiving FDA- CAR-T cell infusion.
approved CAR T-cell therapy such as anti-CD19 CARs (Sterner HLH is a rare condition characterized by fever, hyperferritinema,
and Sterner, 2021). Several factors determine the occurrence and splenomegaly, hypertriglyceridemia, coagulopathy, and cytopenia
intensity of (CRS), hemophagocytic lymphohistiocytosis (HLH), due to improper immune activation and cytokine release (Risma and
macrophage activation syndrome-like activation (MAS-L) (HLH/ Jordan, 2012a). In patients with low-grade CRS, HLH can occur;
MASL), and immune effector cell-associated neurotoxicity however, severe CRS might evolve into HLH. Thus, clinicians must
syndrome (ICANS), including tumor type, specific target, and pay attention to this condition to prevent fatal outcomes HLH/MAS
CAR design (Roex et al., 2020). post CAR T-cell therapy in association with CAR T-cell induced
The most frequent acute toxicity associated with CAR T-cell toxicities (CARTOX) score, which includes serum ferritin levels
therapy is the CRS; the cytokines involved are produced either by >10.000 ng/ml and one of the following: oliguria grade ≥3 or
the infused CAR T-cells or by the CAR T-cell-responding elevated serum creatinine grade ≥3, pulmonary edema, elevation
immune cells such as macrophages. These cytokines include in serum bilirubin, aspartate aminotransferase or alanine
TNF-α, several interleukins such as IL-6, IL-2, -IL-2α, IL-8, aminotransferase grade ≥3, and incidence of hemophagocytosis
IL-10, and IFN-γ, which were elevated in the patient’s serum. bone marrow (Mei et al., 2018). Management of HLH/MAS as
Also, patients with severe CRS experience high-grade pyrexia, mentioned in CRS and ICANS with anti-IL-6 agents and
which can develop into an uncontrolled systemic inflammatory corticosteroids can be used. However, if the condition persists
response with circulatory shock requiring vasopressors, vascular for almost 48 h, other interventions, such as intrathecal cytarabine
leakage, disseminated vascular clots, tachycardia, hypotension, and etoposide, especially in neurotoxicity-associated HLH
hypoxia, and multi-organ system dysfunction. The severity of the (Neelapu et al., 2017b).
CRS was correlated with the type of cytokines detected in the Several recommendations have been proposed to attenuate the
serum (Brudno and Kochenderfer, 2016; Shimabukuro- toxicities resulting from CAR T-cells: 1) to ensure that the
Vornhagen et al., 2018). Organ dysfunction can be reversed in therapeutic efficacy is valid and no toxic overshooting of
most patients once CRS signs are recognized and managed early cytokines is occurring by monitoring the CAR T-cell activation
(Morris et al., 2021). Management of CRS using supportive care threshold post-infusion. Activation of CAR T-cells is influenced by
includes antipyretics, blood components transfusion, intravenous several factors, including tumor antigen expression levels on
fluids, vasopressors, monoclonal antibodies (tocilizumab) used malignant cells, the affinity of the antigen-binding domain to
against the IL-6 receptor, and steroids in high-grade CRS. Both target epitope, tumor burden, costimulatory elements of CARs
tocilizumab and steroids can control CRS in most cases. However, (van der Stegen et al., 2015; Milone and Bhoj, 2018); 2) to
resistant CRS can also develop where the symptoms persist achieve low affinity of the antigen-binding domain to ensure
regardless of supportive treatments in a minority of patients, selectivity for tumors with high expression levels of targeted
putting them at a high mortality risk (Yang X. et al., 2019). antigen; 3) hinge-region and transmembrane region modifications
ICANS is another common toxicity occurring after CAR T-cell and optimization to control cytokine secretion levels and keep them
infusion and is associated with treatment-related morbidity. within the therapeutic window as seen in anti-CD19 CAR T-cells
However, the exact mechanism underlying the manifestation where no CRS or ICANS were observed (Ying et al., 2019); 4)
of neurologic toxicity remains indistinct. CAR T-cell facilitated costimulatory domain can be customized based on tumor burden,
inflammation-causing endothelial activation and disruption of tumor antigen binding domain engagement, antigen density, and
the blood-brain barrier may play a central role (Holtzman et al., toxicity concerns. Evidence suggests that 4-1BB costimulatory
2021). ICANS manifestation begins with toxic encephalopathy, domains show lower toxicity risk, lower T-cell expansion levels,
aphasia, dysphasia, impaired motor function, and drowsiness. In higher T-cell endurance. In contrast, CD28 costimulatory domains
severe cases, more severe symptoms occur, such as seizures, are associated with CAR T-cell onset rapid activation and
motor weakness, cerebral edema, and coma, most patients consequent exhaustion. These properties make 4-1BB domains
experiencing ICANS had earlier CRS that had subsided. more preferable in cases of high disease burden or/and high
Therefore, CRS could be considered an early sign of ICANS. tumor antigen density, and in cases of low surface antigen
Concurrence between ICANS and CRS occurs less frequently. density or/and low-affinity antigen-binding domain CARs with
ICANS is also reversible in patients who do not develop CD28 costimulatory domains are more preferable (Salter et al.,
permanent neurological deficits (Morris et al., 2021). 2018); 5) CARs immunogenicity can be decreased by modifying
hinge region and/or transmembrane domain, which also contributes (Figure 2). Despite the advantages of allogeneic CAR T-cells,
to CAR T-cell persistence improvement (Jonnalagadda et al., 2015; some limitations prevent their use in the CAR T-cells field. The
Sommermeyer et al., 2017); 6) neutralization of GM-CSF to first limitation is the graft-versus-host disease (GVHD) and the allo-
overcome CRS and neurotoxicity, tyrosine hydroxylase inhibition rejection produced by the host immune cells, which would hinder
by metyrosine or deletion of this enzyme in a myeloid cell-specific the cells’ anti-tumor activity (Martínez Bedoya et al., 2021). Changes
manner resulted in catecholamine and cytokine levels reduction within the design of the allogeneic CAR T-cells could overcome the
(Staedtke et al., 2018), use of IL-1 antagonists to reduce GVHD; these changes include the employment of genetic
neuroinflammation (Giavridis et al., 2018); 7) use of “off-switch” engineering tools such as Zinc finger nucleases (ZFN),
or suicide gene strategies to encourage selective elimination of CAR transcription activator-like effector nucleases (TALEN), and
T-cells at the commencement of adverse events under a secondary CRISPR/Cas9, which can be utilized in knocking-out T-cell
agent control. However, the slow onset of antibody-mediated receptor (TCR) and in attenuating the GVHD. Strategies to
depletion limits the efficacy of this approach, especially in mitigate allorejection are being evaluated; chemo-resistant CAR
patients who require immediate reversal during acute and T-cells are also being repeatedly tested through several rounds of
severe cytokine toxicities; therefore, faster switches such as administration to allow more profound or prolonged lymphopenia
inducible cas9 were developed and proved to deplete 90% of (Poirot et al., 2015; Valton et al., 2015). Overcoming the limitations
CAR T-cells within 30 min (Di Stasi et al., 2011; Jones et al., of both autologous and allogeneic CAR T-cells is a great challenge
2014). Engineering CAR T-cells with CD20 full-length expression but not impossible in such a fast-growing field.
or CD 20 mimotopes, which deplete CAR T-cells post rituximab
treatment (Philip et al., 2014), use of switch off CARs (SWIFF-
CARs) (Juillerat et al., 2019). The most significant limitation in 8 CONCLUSION
utilizing the suicide gene strategy is the sudden cessation of therapy
in rapidly progressing diseases, making this strategy a last resort. The employment of adaptive immunity in treating chronic and
However, recently, the use of TKIs, which inhibit proximal TCR malignant diseases has been the focus of many studies over the
signaling kinases and suppress T cell activation (dasatinib), provide past few decades. The CAR T-cell revolution has changed the
temporary inhibition of CAR T-cells. CAR T-cell activity would landscape of conventional therapies used in cancer and has
resume after toxicity has subsided (Sterner and Sterner, 2021). provided new opportunities to test these technologies against
Additional studies are required to overcome all toxicities without other diseases. However, CAR T-cell therapy has few limitations,
affecting the activity and persistence of CAR-T cells. slowing its widespread clinical application as a routine treatment. To
overcome these limitations, various in vivo and in vitro studies have
7.6 Autologous Vs. Allogeneic suggested innovative strategies to enhance the efficacy of CARs
Although most of the clinical studies testing CAR T-cells depended against blood cancers and solid tumors. Several factors have been
on autologous T-cells, these therapies presented several limitations. designated as necessary in CAR T-cell design, including tumor
The patient’s cell generation is a cost-time-consuming process that antigen expression levels on malignant cells, the affinity of the
holds a risk of manufacturing failure (Zhao J. et al., 2018). antigen-binding domain to the target epitope, tumor burden, and
Additionally, it might result in a delayed availability of treatment, costimulatory elements of CARs. However, there is still a need to
which could be problematic for patients with aggressive and highly elucidate and resolve the issues associated with this intriguing
proliferative diseases (Depil et al., 2020). The patients usually receive technology. Therefore, further development of eccentric strategies
lymphodepleting chemotherapy, which might affect the quality and to reduce CAR T-cell therapy limitations while maintaining
quantity of the starting autologous T cells (Ceppi et al., 2018); in antitumor efficacy, cellular persistence, and expansion will be
contrast, allogeneic CAR-cells (derived from healthy donors) offer necessary to magnify the clinical applications of this therapy.
fully functional cells in high amounts allowing multiple generations Notably, “off-the-shelf” CAR-T cell products with CRISPR-Cas9
of “off-the-shelf” CAR T cells products (Zhao J. et al., 2018; Depil genome-edited changes to manage toxicities and persistence will
et al., 2020). The heterogenic nature of tumor cell antigen expression hold much promise. Additionally, the utilization of synthetic biology
and the immune evasion mechanisms developed by tumor cells and cell engineering technologies might break the barriers impeding
require CAR T-cells with multiple antigen specificities (Walsh et al., allogeneic CAR T-cells from being used as universal CAR T-cells,
2019). This issue could be overcome by allogeneic T-cells capable of which could be pivotal in enhancing therapeutic outcomes and
generating several CAR T-cells products with various antigen overall patient survival.
specifiers (multivalent), unlike autologous T-cells that are known
to be capable of generating (monovalent) CAR T-cells (Martínez
Bedoya et al., 2021). Allogeneic CAR T-cells can be obtained from AUTHOR CONTRIBUTIONS
several sources such as mononuclear cells from the peripheral blood
of healthy donors that are capable of providing high numbers of All authors listed had made a considerable, comprehensive, and
fitter cells than the ones derived from the patients’ blood as they have perceptive contribution to the work and approved it for publication.
been subjected to radio- or chemotherapy (Depil et al., 2020). AA, SA, and YA were involved in the study’s design. The manuscript
Umbilical cord blood is another source. Furthermore, adult was drafted by AA, SA, YA, TA, SA, MA-S, and HA. SA and AA
somatic induced pluripotent stem cells (iPSC) can be produced collaborated on the manuscript’s review and editing. The final
by introducing specific transcription factors (Papapetrou, 2016) manuscript was read and approved by all authors.
ACKNOWLEDGMENTS support received from the core research grant of the

Science and Engineering Research Board (CRG/2020/
We thank Taif University and King Faisal Medical 002294) and the extramural grant of the Indian Council of
Complex (KFMC) for their contributions and facilitation Medical Research (ICMR) (GIA/2019/000274/PRCGIA
during the research. Also, TA acknowledges the funding (Ver-1)).
Baum, V., Bühler, P., Gierschner, D., Herchenbach, D., Fiala, G. J., Schamel, W. W., et al.
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published: 22 June 2022

Chimeric Antigen Receptor T-Cells: An

response. Also, the CAR T-cells persisted and lasted for up to

5.3 HIV Infection

Condition Enrollment Status Antigen Phase Results NCT

Condition Enrollment Status Antigen Phase Results NCT

Condition Enrollment Status Antigen Phase Results NCT

ACKNOWLEDGMENTS support received from the core research grant of the

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