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CAR- T cell therapy 383
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ferritin, typically >5000 ng/mL, cytopenias, fevers, elevated
liver enzymes or other organ dysfunction, and presence of
hemophagocytosis in the bone marrow. Treatment is similar
to CRS; however, higher doses of corticosteroids need to be
used.
Immune effector cell- associated neurotoxicity
syndrome
Immune effector cell- associated neurotoxicity syndrome
(ICANS) represents a second recognized complication of
CAR- T therapy. This was previously termed CAR- T- related
encephalopathy syndrome (CRES). Pathophysiology is complex and an active area of research. Like CRS, production
pro- inflammatory cytokines such as IL- 1, IL- 6, INFβ, TNFα,
etc. by the activated CAR- T cells and associated monocytemacrophages is thought to cause disruption of the bloodbrain barrier and accumulation of cytokines in the CNS
causing neuronal injury. The majority of patients with
ICANS have antecedent evidence of CRS. Clinical manifestations include headaches, delirium, lethargy, aphasia, agitation, tremors, seizures and cerebral edema, and coma in
some cases. The most widely used scale for the assessment of
severity of ICANS was established by ASTCT, which includes
the “immune effector cell associated encephalopathy” (ICE)
score (Lee etal.2014). Contrary to CRS, tocilizumab has not
shown to be beneficial in treating ICANS. Conversely, a
trend toward increased incidence and severity of ICANS was
seen in a cohort of patients treated with prophylactic tocilizumab in the ZUMA- 1 trial was noted potentially due to
increased IL- 6 levels produced in the setting of receptor
blockade with greater exposure in the CNS, which tocilizumab does not penetrate. Corticosteroids remain the mainstay of treatment for ICANS. Seizure prophylaxis is also
instituted commonly in patients with ICANS (Sandler
etal.2020; Neelapu etal.2018; Caimi etal.2021).
B- cell aplasia, hypogammaglobulinemia,
andinfections
The current FDA- approved CAR- T therapies target CD19
and BCMA. CD19 is expressed on multiple stages of maturation of B- cells and BCMA is expressed on mature B- cells and
plasma cells along with the malignant cells. B- cell aplasia and
hypogammaglobulinemia represent an on- target off- tumor
effect associated with increased risk for infections. The
impact of lymphodepleting therapy, advanced malignancy
with multiple prior therapeutic regimens, and CAR- mediated
chronic inflammation may contribute to suppression of
T- cell immunity and associated opportunistic infections.
Infection was noted in approximately 30% of patients participating in the registration trials for the currently approved
CARs. Early- onset infections (<30days after CAR- T infusion) often occur in the context of neutropenia and may be
difficult to differentiate from CRS (Morris et al.2022; Lee
etal.2014). These were commonly bloodstream infections,
respiratory, or genitourinary infections. Clostridium difficile
infection has been reported. Viral infections are also common and are typically seen later in the treatment course
(>30days post CARobserved but is not necessarily associated with end- organ
involvement. Fungal infections including pneumonia due to
Aspergillus or Mucormycoses have been noted. Given the suppression of T- cell- mediated immunity and associated lymphopenia, fungal, Varicella Zoster and Pneumocystis
prophylaxis is often administered during the first
6–12months following CAR- T therapy (Caimi et al. 2021;
Wittmann Dayagi et al.2021; Stewart and Henden 2021).
Late opportunistic infections such as cryptosporidium have
been reported in a subset of patients. In addition, episodes of
PML associated with JC viral infection of the CNS have been
noted (Stewart and Henden 2021). Prophylactic immunoglobulin replacement is recommended in patients with
severe IgG deficiency (<400 mg/dL) or for patients with serious or recurrent infections (Ahrendsen etal.2021; Hill and
Seo2020). The etiology of immune compromise and associated risk of opportunistic infection is likely multi- factorial
and the impact of CAR- T cell therapy and chronic inflammatory response has not been fully elucidated.
T infusion). CMV reactivation has been
Cytopenias
Leukopenia/neutropenia, anemia, and thrombocytopenia
are very commonly seen (~50–100%) in patients receiving
CAR- T therapy. While transient marrow suppression
(<30days after infusion) can be attributed to lymphodepleting chemotherapy, patient often experience prolonged
cytopenia or incomplete hematopoietic recovery. Cont ributing
factors include cumulative toxicity related to cytotoxic
therapy, fludarabine- mediated stem cell toxicity, and myelosuppression from inflammatory cytokines related to
CAR-
T and secondary immune activation. Secondary HLH
associated with CAR- T therapy should be considered.
Secondary myelodysplasia and acute myeloid leukemia
have been reported post CAR- T (4–16%) and should be
investigated in patients with prolonged cytopenias (Hill
and Seo2020; Hsieh et al.2022; Cappell et al.2020; Jain
etal.2020). Blood products and thrombopoietin receptor
agonists have been administered as supportive care in this
setting. Conflicting data regarding the impact of G- CSF on
outcomes have been reported in this setting with some concerns expressed regarding worsening of CRS and T cell
suppression while others suggesting mitigation of infection
risk. Hematopoietic stem cell rescue has been utilized as
a means of fostering count recovery in the setting of
prolonged cytopenias as well (Jain et al. 2020; Rejeski
etal.2022; Mullanfiroze etal.2022).
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Coagulopathy
Coagulopathy is seen in about ~50% of patients receiving
CAR- T therapy usually within the first few weeks after infusion. These include elevated - dimer/fibrin degradation
products, decreased fibrinogen, prolonged activated partial
thromboplastin time, and prothrombin time. In a case series,
disseminated intravascular coagulation (DIC) was noted in
association with CRS in about 23% patients (Mullanfiroze
et al. 2022; Johnsrud et al. 2021; Jiang et al. 2019; Wang
etal.2020; Belbachir etal.2021). Mechanisms of coagulopa-
thy related to CAR- T therapy have not been clearly elucidated but are thought to be mediated by pro- inflammatory
cytokines released by the activated CAR- T cell, monocytes,
macrophages causing endothelial and platelet activation
leading to a consumptive coagulopathic state. Transfusion of
fresh frozen plasma and cryoprecipitate to maintain nearnormal coagulation parameters is usually recommended to
prevent bleeding complications (Belbachir et al. 2021;
Brudno and Kochenderfer2016).
In terms of late complications following CAR- T therapy,
the risk of secondary malignancies is reported to be about
4–16% during long- term follow- up. Secondary myeloid neoplasms like myelodysplastic neoplasms and acute myeloid
leukemia have been noted in about 1–6% patients receiving
CAR- T therapy. It remains to be discerned whether these are
related to CAR- T cells or cytotoxic chemotherapy, which
most of these patients receive during some point of treatment (Cappell et al. 2020; Chakraborty et al. 2021).
Additional data on the risk of secondary malignancies will
definitely emerge in the future with longer follow- up in a
larger cohort of patients. In addition, patients with CD19
treatment no longer have remaining B cells, thus lack longterm memory immunocompetency. Other long- lasting
effects include cytopenias, coagulopathy, and autoimmunity
from the treatment, which have been discussed earlier.
CAR- T cells in the tumor
microenvironment
Tumor microenvironment
Chimeric antigen receptor (CAR)- engineered T cell immunotherapy has revolutionized the treatment of immunerelated cancers, such as lymphoma and leukemia, but there
have been noticeable issues with relapse in solid cancers. In
fact, penetrability into tumor microenvironment (TME) has
been shown to be a crucial hindrance to poor differentiation
of the CAR- T cells and the loss of effector function. Another
concept that is seen is resulting T cell exhaustion, which is
phenotypically seen as terminally differentiated immune
cells due to chronic stimulation in the TME, leading to a
non- functional state.
These exhausted T cells are no longer able to selfand functionally impaired, resulting in their inability to
respond to diseases. Currently, exhausted T cells have shown
higher levels of suppressive immune checkpoint inhibitors
(ICRs) such as PD- 1, TIGIT, and CTLA4. Numerous cancer
treatments have shown that deletion or anti- ICR treatments
have been able to prolong the proliferation and efficiency of
CAR- T cells. Still, though checkpoint blockade of these
tumors has improved the short- term efficacy of CAR- T cells,
none of these models are able to show an improvement in the
longevity of the CAR- T cell. Novel targets and stimulation
strategies are crucial in improving the efficacy of CAR- T
immunotherapy.
The biggest limitation to this immune treatment in solid
tumors is the limited penetrability, resulting in less activation
and proliferation of CAR- T cells in the tumor microenvironment. In solid tumors, the TME has various layers of penetrative resistance. The ECM within the TME allows there to
be steric hindrance of the infiltrating immune cells. In addition, there are immunosuppressive cytokines that are
secreted to prevent further activation of the recruited lymphocytes and promoting an exhaustion phenotype. The role
of the TME structure, TME cytokines, and TMEcell exhaustion in the context of CAR- T cells will be discussed in the following sections.
renew
induced T
Cytokine signaling inthe TME
Immunosuppressive microenvironments remain one of the
greatest challenges to CAR- T cell therapy and are considered
the primary cause for the poor clinical efficacy of CAR- T
cells observed in solid tumors to date. Prior to clinical presentation, tumors typically undergo a microevolutionary process in which they have adapted mechanisms to suppress or
avoid killing by the immune system, shifting the balance of
tumor growth versus tumor killing. Due to this process,
tumor microenvironments commonly include immunosuppressive cell types and soluble mediators that discourage
inflammation. Additionally, the physical barriers in solid
tumors such as the tumor stroma limit the infiltration and
motility of CARwith a focus on the strategies being used to overcome them.
Immunosuppressive cell types frequently observed in
tumor microenvironments include T regulatory cells,
M2 macrophages, and myeloid- derived suppressor cells
(MDSCs) (Marofi etal.2021; Enblad etal.2015). These cell
types in addition to tumor cells often secrete molecules that
suppress infiltrating immune populations by inhibiting them
or polarizing them toward an anti- inflammatory phenotype,
in turn yielding more immunosuppressive cells. Well- known
soluble mediators in this category include IL- 10, TGF- β, and
prostaglandin E2. To combat these mechanisms of suppression, researchers have adopted strategies that make CAR- T
T cells. Here we discuss these challenges
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CAR- T cell therapy 385
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cells resistant to their effects or supplement CAR- T cells with
soluble mediators to promote their function. For example,
Newick et al. designed CAR- T cells that expressed the peptide RIAD to prevent CAR- T cell inhibition by prostaglandin
E2 or adenosine (Newick etal.2016). RIAD prevented the
association of protein kinase A with ezrin, thus preventing
the localization of protein kinase A to the immune synapse,
where it could inhibit CAR signaling. CAR- RIAD T cells had
improved effector function and tumor migration in comparison to control CAR- T cells. Similarly, several groups have
demonstrated means of making T cells resistant to or even
stimulated by TGF- β by means of a dominant negative recep-
tor or chimeric switch receptor (Hou et al. 2018; Chang
etal.2018; Bollard etal.2018; Kloss etal.2018).
Examples of strategies that supplement CAR- T cells
include the aforementioned fourth- generation TRUCKS that
include inducible cytokine cassettes downstream of CAR or
TCR signaling to promote the local production of cytokines
such as IL- 7, IL- 12, IL- 15, IL- 18, or IL- 23 at the tumor site
(Chmielewski and Abken2020). These cassettes are usually
driven by an inducible NFAT- responsive promoter.
Preliminary evidence utilizing this strategy has been optimistic but also shows that significant consideration must go
into the context and biology of the cytokine used. For example, when IL- 12- producing TCR- engineered T cells were
used to treat mice in a murine model of melanoma, 1 × 104
IL- 12- engineered T cells were functionally superior to 3 ×
106 control cells (Zhang etal.2011). However, when patients
with metastatic melanoma were treated with IL- 12- secreting
TILs at doses 10–100 times lower than conventional TILs,
patients experienced severe toxicities including high fevers,
liver dysfunction, and hemodynamic instability (Zhang
et al.2015). Nonetheless, a 63% overall response rate was
observed, recapitulating the potency of this strategy.
The physical barriers present in solid tumors are also
thought to constrain CAR- T cell efficacy by limiting infiltration and motility (Marofi etal.2021). To overcome this issue,
one solution is to utilize local rather than the usual systemic
(intravenous) administration of CAR-
T cells. This not only
eliminates the need for trafficking but also decreases the risk
for on- target off- tumor effects. So far, preclinical evidence has
shown superior efficacy of local compared to systemic administration of CAR- T cells in models of lung cancer, breast cancer, brain metastases, and glioblastoma (Adusumilli etal.2014;
Brown etal.2018; Priceman etal.2018). This work resulted in
the initiation of four clinical trials (NCT02414269,
NCT02208362, NCT03389230, NCT03696030). Furthermore,
CAR- T cells have recently been applied with success in an
immunocompetent murine model of resected breast cancer
wherein CAR- T cells were applied in a fibrin glue gel as a
means of clearing the intentionally remaining 25% of residual
breast cancer cells (Uslu etal.2023). The CAR- T cells mixed in
the gel outperformed systemic administration of CAR- T
cells, with a complete response of 100% compared to 40%. An
alternative solution to promote tumor infiltration is to utilize
enzymes to break down the extracellular matrix of tumor
stroma. Caruana et al. (2015) engineered CAR-
T cells to
secrete heparanase, an enzyme that degrades heparan sulfate
proteoglycans, which are primary components of the extracellular matrixetal. In an immunocompromised xenograft model
of human neuroblastoma, Caruana et al. showed the i.p.
administration of CAR- T cells secreting heparanase led to significantly improved survival and a greater than 40- fold average increase in the percentage of infiltrating CAR- T cells.
Lastly, to improve trafficking of CAR- T cells to tumors when
administered systemically, some have engineered the expression of chemokine receptors such as CCR2b, CXCR1, or
CXCR2 (Jin etal.2019; Liu et al.2020; Whilding etal.2019;
Craddock et al.2010). In each of these studies, this strategy
was successful in improving anti- tumor responses when the
cognate chemokine was present in the tumor microenvironment. Overall, the assessment of these strategies in clinical
studies and the development of new strategies to improve
tumor infiltration will be necessary next steps for the field of
CAR- T cell therapy.
TME structure
The solid tumor exhibits several physical attributes that
can impair CAR- T function. These inhibitions can lead to
various physical attributes that result in a diverging structure from healthy tissue. TME structures arise from the
necessities that the developing tumor require, for example,
vascularization for nutrients (Nia etal.2020). While there
is heterogeneity among tumor types, there are common
patterns for TME structure that have been observed.
Carter etal. model the TME with complex layers that can
be divided into the tumor core, which is surrounded by the
cancer cells. Interwoven within this region, there are
cancer- associated fibroblasts and local immune cells that
have been compressed into a cancer cell membrane.
Moving further outside of the tumor, there are aligned collagen fibers, which, after reaching a certain density of
about a 5-
μm margin, prevent the invasion of lympho-
cytes. The integrin- dependent migration factors are
directly blocked by the ECM and are further sterically
inhibited with increased angiogenesis.
The ECM contributes to the intense complexity of the
tumor (Simsek and Klotzsch2022). The collagen fibrils are
aligned and have intense crosslinking, which results in the
increase in stiffness. In this way, the matrix prevents access
of the CAR- T cells (as well as chemotherapeutics) to the
tumor core. A specific feature of the TME that can impact
CAR- T cells is desmoplasia. Desmoplasia is the deposition
of ECM, particularly collagen, fibroblasts, fibronectin, and
other matrix proteins by the stromal tissue. The deposition
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of the ECM components leads to significant changes in the
tissue heterogeneity and elasticity, including angiogenesis
and compression of the tumor region due high interstitial
fluid pressure. Desmoplasia acts not only as a physical barrier, but also a biochemical deterrent to immunotherapy
(Obaid et al.2022). In addition, high levels of TGF- beta
and CTGF (connective tissue growth factor) result in an
overproduction of matrix proteins. Desmoplasia induces
several biological signaling cascades that contribute to
resistance of therapeutics, such as MMP- 9 for angiogenic
switch and remodeling of the matrix (Whatcott etal.2012).
Immune treatments that consider the formation of this
stromal layer are a new direction that could augment the
efficacy of CAR- T therapies.
The core of the tumor is characterized by diverse arrangement of immune, cancerous, and non- cancerous cells.
Generally, a basal level of killing does occur from the infused
CAR- T lymphocytes in core, but the cytotoxic capacity is
limited by the pressure and the compression of the cancerous
membrane (Carter etal.2021). The lymphocytes have continual access to the cancer cells that results in the release of
perforin and granzymes after recognition of the cancer antigen complex; however, chronic stimulation can lead to the
exhaustion of these infused CAR- T cells. In addition, the
core of the tumor proliferates and the high interstitial fluid
pressure creates a high concentration of suppressive
chemokines and cytokines that further impede the CAR- T
cells, similarly to traditional cytotoxic T cells. Thus, there are
increased quantities of exhausted and immunosuppressed
cells to contribute to the dense mix of cells within this layer.
3D models, such as organoids, could lead to better in vitro
models to test CAR- T cell invasion into these various layers
(Nia etal.2020).
The “heart” of the tumor core can be theorized as a cancer “stem cell.” However, whether these cells can be identified has posed an ongoing question among scientists. Since
the early 2000s, several research groups have discussed cells
of a multipotent phenotype that arise from within the
tumor in literature. For example, in GBM tumor tissues, a
multipotent sphere has been shown to arise externally
around the primary tumor tissue, which results in tumorigenesis and the development of heterogeneity within the
tumor genotype (Ignatova et al. 2002). Cells with these
stemlike phenotypes have been theorized as the cause of
therapeutic failure (Wee etal.2016). These cells were identified in the GBM mouse model based on the ABCG2 assay
but expressed stem cell markers and high tumorigenicity,
corresponding with self-
renewal, resistance, and multilineage differentiation. CAR- T therapy is expected be an
important modality to eliminate CSCs, due to the lack of
MHC restriction (Cui etal.2021). Many of these markers
expressed on the CSCs are promising novel antigens, such
as ABC transporters and anti- apoptotic proteins, that fol-
low signaling pathways (NOTCH) (Masoumi etal.2021).
These cancer stem cells demonstrate enhanced resistance
to not only traditional cancer treatments, such as chemotherapy and radiation, but also CAR-
T therapy. CSCs have
higher rates of tissue invasion and are theorized to progress
the cancer (Deleyrolle etal.2011). This self- renewal ability
could describe the tumor mechanism of relapse despite
immunotherapy. Though the therapeutic effect of CAR- T
cells leads to an initial shrinking of the tumor area, the inability to reach the CSCs that reside in the core, due to the
sterics of the TME, results in the continuing oncogenic
mutation of the stem cells and the self- renewing CSCs to
reestablish the tumor. This leads to the question of if a more
effective target for these CSCs that can be directly accessed
by the CAR- T cells. If so, CAR- T cell therapy could become
a more potent therapy by affecting the root of most cancer
types, including solid tumors.
Therapeutic approaches to mitigate the effects
of the TME
While the TME seems to be severely inhibitory to immunotherapy, several new synergistic approaches to circumvent
these attributes are being developed. One notable approach
is immune checkpoint inhibitors, discussed earlier, that has
proven to be effective in melanoma and NSCLC (Anderson
etal.2017). Yet, solid tumors, such as pancreatic (PDAC)
or ovarian cancers, can prove to be largely resistant and
provide anti- T cell activity. Glucose is a common fuel
source for both cancers and proliferating T cells, and the
hypoxic environment stifles the growth of these cells. There
has been evidence that photodynamic therapy, which uses
reactive oxygen species in hypoxic regions, can disrupt
cancer growth, while also rescuing the metabolic function
of the T cells. Another school of thought is to use local
treatments, rather than specific targets, such as nanoparticles or T cells. Since immunospecific targeting has fewer
off-
target effects, the limitation is penetration of these molecules into the tumor body. Thus, by combinatorically
treating with chemotherapeutics, there may be more neoantigens expressed and slowing of cancer growth that
would lower CAR- T exhaustion and prolong the length of
efficacy and penetrability of the immunotherapy. There are
numerous strategies employed to combat the TME that
have been discussed, referenced in Table 25.3 (RomaRodrigues etal.2019). The factors that govern CAR- T- cellintrinsic mechanisms of resistance are also closely tied to
the design of CARs and the methods of CAR- T cell manufacturing that have already been discussed (see “CAR
structure and function” and “CAR-T cell manufacturing”
sections). Broadly speaking, these strategies include further engineering CAR- T cells or utilizing synergistic combination therapies to accent CAR- T cell therapy.
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CAR- T cell therapy 387
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Table25.3 Effective TME strategies
Treatment
strategy TME attribute Mechanism
beta inhibition ECM Reduction in collagen
TGF-
secretion and
desmoplasia,
leading to better
treatment
Checkpoint
blockade
De- acidification pH and hypoxia Reversal of glycolysis;
VEGF inhibition Angiogenesis Tumor receives less
Cytokine
treatment (IL-
Immunosuppression Immune checkpoint
inhibitors allow
cytotoxicity to
progress (CTLA4)
tumor cells benefit
in low pH over
immune cells
nutrients, reduces
growth, and lowers
interstitial pressure
1R)
Chronic
inflammation
Antagonist against
IL- 1, to reduce
inflammation, less
neoplasia
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