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CAR- T cell therapy 373
Leukapheresis
CAR T cells
https://t.me/med1917
Isolation of T
cells
Infusion of
CAR-T back
into host
Figure25.2 Workflow of CAR- T cell manufacturing.
enrich T cell populations such as non- exhausted, TSCM, or
CM have also been preclinically tested and shown to improve
CAR- T cell efficacy (Deng et al.2020; Fraietta et al.2018).
Following enrichment, the cells are activated to promote proliferation and CAR construct integration. Transduction without prior activation for the purpose of maintaining the
naive- like state of the CAR- T cells prior to infusion was examined (Ghassemi etal.2022).
Allogeneic cells isolated from normal donors have also been
explored as a substrate for CAR- T cell production (Benjamin
etal.2020,2022; Razeghian etal.2021; Brudno etal.2016).
Allogeneic cells would, in theory, ease the accessibility, cost,
and manufacture of the therapy by making it an “off- the- shelf ”
product. However, utilizing allogeneic T cells can lead to graft
versus host disease (GVHD) and immune allorejection due to
lack of thymic selection against the opposing donor or recipient’s HLA- type. As such, it is expected that the persistence of
the cells post- infusion will be limited compared to autologous
cells due to rejection by the host T cells. Thus, strategies to
ablate MHC expression on CAR- T cells by removing β2
microglobulin are also being explored (Razeghian etal.2021;
Wang etal.2021). However, the reduction of MHC I expression could facilitate rejection by NK cells, as MHC I inhibits
NK cell function (Ljunggren and Kärre1990). Future research
directions to reduce GvHD from CAR- T cell therapy include
the incorporation of “suicide genes” within the genetic code of
the donor T cells. If GvHD occurs, the activates certain molecule pathways, preventing DNA synthesis and mitotic behavior, resulting in cell death. This research area is actively being
explored, particularly in incorporating suicide genes into
CAR- T cell therapy effectively.
Transfection
of CAR DNA
into HEK293T
Expression,
proliferation,
and
expansion of
Virus
production
and isolation
Transduction
of CAR virus
into T cells
Construct integration method
There are a variety of means to introduce DNA material into
T cells to express the CAR. In all commercially available
CAR- T cell therapies and in most clinical trials, retroviruses
are the method of choice. However, gene delivery using
electroporation- based systems particularly with transposon
and CRISPR Cas9 approaches are also utilized (Dimitri
et al.2022; Eyquem et al.2017; Bishop et al.2019; Barnett
et al.2016; Magnani et al.2020; Kebriaei et al.2016). The
advantages of retroviruses are in their ease of use, safety profile, and maintenance in cell viability, while transposon systems allow a larger transgene insert and CRISPR Cas9 allows
for site- specific editing and integration (Abou- el- Enein
etal.2021). Retrovirus systems involve transfecting the packaging cell line HEK293T with a transgene vector and helper
plasmids encoding capsid proteins, replication enzymes, and
envelope glycoproteins that allow the packaging of transgene
messenger RNA (mRNA) into virus and stable integration
into the genome, following reverse-
transcription. The two
most commonly used retroviruses, historically, are gamma
retrovirus and lentivirus, with the majority of new studies
employing lentivirus. This is primarily due to its safer integration profile and preference for integration in actively transcribed (Ciuffi2008).
Expansion method
Potential modifications of CAR- T- cell expansion include the
activation method, duration of expansion, and cytokine
stimulation. T- cell activation is a required step in transduction with lentivirus and is often utilized to achieve higher cell
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numbers for infusion. Numerous T- cell activation methods
exist including the use of autologous antigen- presenting cells
(APCs), feeder cells/artificial APCs, and antibody- bead conjugates. Feeder cells such as irradiated allogeneic peripheral
blood mononuclear cells (PBMCs) or K562 cells engineered
to express co- stimulatory molecules are excellent mechanisms to expand T cells, but also require the maintenance of
extra culture systems and the fulfillment of additional regulatory guidelines (Suhoski et al. 2007; Maus et al. 2002).
Antibody- bound beads, specifically utilizing CD3 and CD28
antibodies, are the most utilized activation reagents for their
ease of use and potency. They allow simultaneous enrichment and activation of CD3+ T cells and achieve 100–1000
fold expansion over the course of 14days followed by easy
removal of the beads with a magnet. To date, the typical
duration of expansion of CAR- T cells is 8–14 days, as this
duration grants the greatest number of cells for infusion
without restimulation. Shortening the expansion period lessens the differentiation of CAR- T cells, granting the infused
cells greater proliferative capacity, anti- tumor activity, and a
less exhausted phenotype (Zhang et al. 2022; Gattinoni
etal.2011; Cieri etal.2013; Lugli etal.2013; Biasco eta l.2015;
Wang etal.2016; Ghassemi etal.2018).
The use of cytokines or additional reagents in the manufacture of CAR- T cells has become focused on the maintenance of a stem- like naïve profile with the greatest potential
for in vivo expansion and activation. IL- 2in high doses or
over a duration of 10days has the propensity to induce significant cell expansion but promote terminal T cell differentiation and activation- induced cell death (Zhang etal.2018;
Kaartinen etal.2017). Combinations of the cytokines IL- 7,
IL- 15, and IL- 21have been explored for their ability to preserve T cell stemness (Zhou etal.2019; Battram etal.2021;
Alvarez- Fernández et al. 2016; Alizadeh et al. 2019). For
example, IL- 7 and IL- 15 in combination led to increased
proliferation and decreased cell death in vitro as well as
greater engraftment and anti- tumor activity invivo.
Other considerations
While CAR- T cell therapies have demonstrated profound
therapeutic efficacy, the process of CAR production, availability, and cost have significant implication for patient access. Per
infusion, the cost of CAR- T cell therapy is between $373 000
and $475 000 (Fiorenza et al. 2020). In addition, the use of
hospital facilities, medical surveillance, and the treatment of
adverse events brings the cost up an additional $110 000–
$136 000 (Fiorenza et al.2020; Lyman et al.2020). Lentivirus
production typically entails transfecting adherent cell lines
with packaging plasmids and the transgene of interest to
produce the virus. Utilizing adherent cells poses challenges to
scalability due to the need to optimize surface- to- volume
ratios. While this challenge has helped with the development of
fixed- bed bioreactors, their widespread adoption has yet to
occur. Alternatively, suspension packaging cells allow for
greater scalability but are associated with lower productivity.
Lentivirus production requires transfecting packaging cells for
each batch of virus due to cell toxicity associated with the production of vesicular stomatitis virus glycoprotein (VSVG), the
viral envelope. To work around this, stable producer lines with
inducible expression systems (such as Tet- inducible) have been
developed but have also not yet reached widescale adoption.
One approach to enhancing access may be the use of automated or semi- automated technologies that allow decentralized CAR- T cell production outside of a clean room
environment and require minimal training (Jackson et al.
2020; Lock et al. 2017; Mock et al. 2016). Unlike centralized
facilities, this manufacturing technology allows on-site treatment of patients and reduction of the ‘vein to vein’ time for
the therapy. Nonetheless, each technology allows for the generation of CAR-T cells for a single patient at a time, thus limiting mass production.
CAR- T disease- specific clinical data
Acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is an aggressive malignancy of lymphoid lineage precursor cells seen in children
and adults. ALL is further sub- divided immunophenotypically into the more common B- cell ALL and the rarer T- cell
ALL. B- ALL is a highly heterogeneous disease with distinct
phenotypes having cytogenetic or molecular abnormalities
which influence the prognosis and choice of treatment.
Prognosis and treatments also differ for adolescents and
young adults (AYAs) as compared to older adults. While
combination chemotherapy is able to achieve a complete or
partial remission in the majority of the cases, there is a high
risk of disease relapse. Pediatric- inspired regimens are
increasingly used for AYAs but are poorly tolerated by older
adult patients. In patients with Philadelphia chromosome
(Ph) positive ALL, incorporation of tyrosine kinase inhibitors (TKIs) has improved the response rates and survival
outcomes significantly (Chalandon et al. 2015; Sasaki
etal.2016). Salvage therapies after relapsed disease have only
a modest response rate/survival benefit (Fielding etal.2007).
Allogeneic hematopoietic stem cell transplantation
(AlloHCT) is the preferred consolidative therapy after remission induction in patients with highpatients with relapsed disease who are eligible; however, it
comes with significant non- relapse morbidity and mortality.
Persistence of minimal residual disease has been shown to be
a highly significant predictor of subsequent relapse after
cytotoxic chemotherapy or transplant. The use of novel biologic agents including antibody drug conjugate (inotozumab
ozogamicin) or a bispecific T cell engager (blinatumomab)
may be effective in consolidating response and eliminating
minimal residual disease.
risk disease or in
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Investigators at the University of Pennsylvania developed
a lentiviral construct encoding anti- CD19 scFv linked with
4- 1BB costimulatory domain and CD3z signaling. In 2013,
the CD19- directed CAR- T cell was administered to two children with advanced ALL, remarkably resulting in complete
remission in both patients (Grupp etal.2013). A subsequent
phase 1- 2a study of the same construct tisagenlecleucel (tisacel), in relapsed/refractory B- ALL conducted on 59 adult
and young adults showed an impressive CR rate of 93%
(Maude etal.2014). Based on these results, a phase 2multisite non- randomized trial (ELIANA) was carried out for
patients with R/R B- ALL in 79 patients in the age group3–23
years. The overall response rate was noted to be 81% with all
responders achieving minimal residual disease (MRD) negativity as measured to be <0.01% by flow cytometry.
A 3- year update from this trial was published in January
2023, which showed that the median event- free survival was
24 months, and the median overall survival (OS) was not
reached but the measured 3- year OS was 63%. The median
duration of response in patients achieving CR was still not
reached. Cellular kinetics assessed showed that median duration of persistence of tisagenlecleucel was 168 days. The
median time to B- cell recovery was 35.3months in responders. The most common non- hematologic adverse event was
cytokine release syndrome (CRS), which occurred in 77%
patients with median time of onset of 3days after infusion
lasting for a median of 8days. About 47% patients of these
needed ICU stay, and 37% patients needed tocilizumab.
Immune effector cell- associated neurotoxicity syndrome
(ICANS) occurred in 40% of patients within 8weeks after
infusion. In most cases, these toxicities were mitigated by
supportive measures and cytokine blockade (Maude
etal.2014; Laetsch etal.2023). Based on these data, tisagenlecleucel was approved for treatment in patients with R/R
B- ALL in patients 25 years of age or less.
An alternative construct involving CD28 signaling was
studied at Memorial Sloan Kettering Cancer Center and
demonstrated complete response rate of 80% in an initial
trial. In a subsequent phase 2multi-
center study of adult
patients with R/R B- precursor ALL of Brexucabtagene autoleucel (KTE- X19, TESCARTUS), the overall complete remission rate (CR + CR with incomplete hematological recovery)
was 71%. The median duration of response was 14.6months
and median OS was 25.4months. Compared with a historical control arm from the SCHOLAR- 3 analysis, the OS was
significantly better (25.4months versus 5.5months) (Maude
et al.2018; Shah et al. 2021). Based on these data, brexucabtagene autoleucel was approved for adult patients with
R/R B- cell precursor ALL.
There has been divergent evidence as to whether CAR- T
therapy alone is sufficient to achieve curative outcomes or
whether it serves as an effective means of cytoreduction and
bridge to allogeneic transplantation. Durable responses have
been observed in a significant subset of patients treated with
cel, but this may reflect the nature of the study popula-
tisation. Several reports have demonstrated long- term survival
in patients undergoing allogeneic transplantation as consolidation following CAR- T cell therapy (Shah et al. 2022;
Summers etal.2018).
B- cell lymphomas
CAR- T therapy has been explored in non- Hodgkin’s lymphoma, a heterogeneous group of lymphoproliferative diseases. Large B- cell lymphoma (LBCL) is the most common
Non- Hodgkin lymphoma (20–30%) characterized by an
aggressive clinical course. Prognostic factors include clinical
factors, cytogenetic abnormalities, and mutational events.
Standard front- line treatment for LBCL includes combination of rituximab (anti- CD20 monoclonal antibody) and
multi- agent chemotherapy (ex. R- CHOP). Cure rate with
R- CHOP alone is about 60% (Lee et al. 2016). However,
about 10% patients have primary refractory disease and
about 30% patients have a relapse after achieving a complete
remission (Coiffier et al. 2002). Salvage chemotherapy followed by autologous stem cell transplantation (Auto CT) has
been considered the standard second- line therapy for
relapsed LBCL and achieves cure in about 30–40% patients
but is limited to fit patients and is ineffective in chemotherapy refractory patients. Patients experiencing an early relapse
(<12 months) had significantly lower 3- year PFS as compared to patients experiencing late relapse (>12 months)
(Sehn and Gascoyne2015). Second or later relapses had dismal outcomes with median overall survival of about
5months (Coiffier etal.2002).
Follicular lymphoma (FL) is the second most common
non- Hodgkin lymphoma arising from germinal center B- cells
commonly associated with translocation involving the antiapoptotic gene, BCL2. It is a heterogenous entity divided
morphologically into indolent low- grade (grade 1 and 2) and
aggressive high- grade (grade 3) diseases based on the relative
prominence of infiltrating centroblasts. Indications for treatment initiation include the presence of high-
grade histology,
constitutional symptoms, or high- volume disease. Patients
who experience prolonged response to primary therapy typically have an indolent course but remain at risk for disease
acceleration due to transformation to an aggressive phenotype. Patients who experience early relapse/progression after
initial therapy characteristically have a more difficult course
with only a transient response to subsequent cytotoxic treatment. Therapeutic options have significantly expanded with
the advent of biologic agents including lenalidomide, copanlisib, and tazemetostat, which may elicit deep responses even
in patients with resistance to standard cytotoxic agents.
AutoHCT may also enhance duration of response in patients
with early relapsed FL (Gisselbrecht etal.2010).
Mantle cell lymphoma (MCL) is a mature B- cell Non-
Hodgkin Lymphoma characterized by overexpression of
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cyclin D1which commonly involves nodal and extra nodal
sites like the gastrointestinal tract. Rituximab- based combination chemotherapy followed by AutoHCT has been pursued in younger, fit patients with aggressive disease. The use
of biologic agents, Bruton tyrosine kinase (BTK) inhibitors
(ibrutinib, acalabrutinib) and lenalidomide have significantly improved outcomes and are highly effective options
for older patients with indolent disease.
While the therapeutic landscape for non- Hodgkin’s lymphoma has dramatically improved in the last decade, curative outcomes remain elusive. The development of recurrent
disease is generally associated with progressive resistance to
cytotoxic and biologic therapy. In contrast, allogeneic transplantation may be uniquely curative for patients with
advanced lymphoma due to immune- based lysis mediated
by alloreactive lymphocytes. Durable remission has been
observed in, approximately, 35%, 50%, and 90% of patients
with large cell lymphoma, mantle cell, and follicular lymphoma, respectively. As outlined, therapeutic efficacy is
counterbalanced by significant treatment- related toxicity.
However, the principle of cell- based treatment for lymphoma
created a powerful precedent for subsequent exploration of
CAR- T cell therapy in this setting.
Tisagenlecleucel, was initially tested amongst 28 adult
patients with R/R DLBCL or FL. Complete remission was
seen in 43% patients with DLBCL and 71% patients with FL
(Smith etal.2018). A subsequent- phase 2 study (JULIET) of
tisagenlecleucel in patients with R/R DLBCL demonstrated
an objective response rate (ORR) of 53% with 39% achieving
a CR. Median overall survival was 11.1months in all patients
and was not reached for patients who had CR at 3 or
6 months. Common toxicities included CRS (57%, 22%
grade 3 or 4), pyrexia (36%) and cytopenias (30–36%).
Neurological events of any grade occurred in about 21%
patients within 8 weeks after infusion (Schuster
etal.2017,2019). A phase 2 study of tisagenlecleucel in adult
patients who had received two or more lines of therapy for
R/R FL (ELARA) included 97 patients between ages
49–64with FL grade 1, 2, or 3A. Amongst the 94 patients
evaluable for efficacy, CR was achieved in 68% patients with
an ORR of 86.2%. Long-
term analysis of the study showed
that at 2 years, median progression- free survival (PFS) was
57.4%, OS was 87.7% and response was maintained in 64.6%
patients. Transgene persistence was detected at a median of
558days in responders. CRS occurred in 49% with 34% of
those needing tocilizumab. ICANS occurred in 4.1% patients
within 8 weeks of infusion (Schuster et al. 2021; Fowler
etal.2022).
Axicabtagene ciloleucel (KTE- C19, YESCARTA) is an
alternative CD19- directed CAR- T cell product with associated CD28 co- stimulation. In the multi- center phase 1 study,
seven patients with R/R DLBCL were treated with axicabtagene ciloleucel (axi- cel) out of which four (57%) achieved
CR and ORR was 71% (Dreyling etal.2022). Based on this
data, ZUMA-
1, a phase 2, multicenter trial studied axi- cel in
101 patients with DLBCL (n = 77), transformed FL (n = 8) or
primary mediastinal B- cell lymphoma (PMBCL) (n = 16)
who had received prior recommended therapies. ORR
achieved was 83% with CR in 58% patients. A 5- year update
of the ZUMA- 1 trial reported a median OS of 25.8months
and 5- year OS 42.6%. Median OS was not reached in patients
achieving a CR. Median duration of response overall was
11.1months, but for patients achieving CR, it was an impressive 62.2months. CRS of all grades occurred in 93% patients,
grade 3 or higher was seen in 11% patients with 43% of those
needing tocilizumab. Grade 3 or higher neurological events
occurred in 28% patients (Locke et al. 2017; Neelapu
etal.2017,2023).
Of note, the presence of CD28 and 41- BB costimulatory
signaling in axi- cel and tiso- cel, respectively, was associated
with a differential pattern of T cell expansion, persistence,
and associated incidence and severity of toxicity. In a retrospective study comparing real- world experience of tisagenlecleucel and axi- cel in patients with R/R DLBCL (DESRCAR- T)
showed improved PFS and OS with axi- cel. 1- year PFS was
46.6% for axi- cel versus 33.2% for tisa- cel (HR 0.61, 95% CI
0.46–0.79), whereas the 1- year OS was 63.5% for axi- cel versus 48.8% for tisa- cel (HR 0.63, 95% CI 0.45–0.88). However,
both CRS and ICANS were more prevalent in patients treated
with axi- cel (Locke etal.2019).
Lisocabtagene maraleucel (JCAR017, BREYANZI) is an
autologous, anti- CD19 CAR- T cell product that uses the
4- 1BB (CD137) costimulatory domain, administered as balanced CD8+ and CD4+ fractions. CD8+ and CD4+ T cells
are selected from leukapheresis and independently manufactured. The TRANSCEND NHL 001 study was a multicenter,
multicohort, seamless design study (dose finding, doseexpansion, dose- confirmation) in which patients with R/R
large B cell lymphoma (de- novo or transformed), high- grade
double- hit or triple- hit B cell lymphoma, PMBCL or FL
grade 3B treated with at least two or more previous recommended lines of therapy were treated with lisocabtagene
maraleucel (liso-
cel). Out of the 269 patients, assessed, 42%
were above age 65 and 10% were above age 75. An ORR was
achieved in 73% patients with CR in 53%. Median duration
of response was 23.1months and median OS was 27.3months.
CRS of all grades occurred in 42% patients with grade 3 or
more in 2%. Neurological events occurred in total of 30%
patients with grade 3 or more in 10% patients (Bachy
etal.2022; Abramson etal.2022).
Based on these encouraging findings for CD19- directed
CAR- T therapy for advanced lymphoma, several studies were
conducted to compare the efficacy of CAR- T as second- line
therapy in comparison to autologous stem cell transplant for
patients at time of first relapse. In the ZUMA- 7international
phase 3 trial, patients were randomized 1:1 to receive axi- cel
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versus auto- HCT. After a median follow- up of 24.9months,
treatment with axi- cel led to more responses (83% versus
50%), improved 2- year EFS (41% versus 16%, HR 0.40, 95%
CI 0.31–0.51) and 2- year OS (61% versus 52%) (Abramson
etal.2020). Similarly, a phase 3 randomized, open label study
comparing liso- cel with standard of care in 184 adult patients
randomized 1:1 between liso- cel and standard of care transplant, the primary end point of event- free survival was significantly improved in the liso- cel group compared to
standard of care, 10.1months versus 2.3months with an HR
0.35 (95% CI 0.23–0.53). Median OS was not reached in the
liso- cel group compared to 29.9months in standard of care
group. Adverse events were similar to the TRANSCEND
study and no new safety signals were identified (Locke
etal.2022; Abramson etal.2023). The TRANSFORM study
supported the use of liso- cel as a second- line treatment in R/R
LBCL. In contrast, a similar study comparing tiso- cel to
autologous transplantation did not demonstrate better outcomes for patients undergoing CAR- T cell therapy. A
matching- adjusted indirect comparison between liso- cel and
axi- cel as second- line therapy in R/R LBCL showed comparable efficacy of the two CAR- T products, whereas lower rates
of all grade CRS and ICANS were seen with liso- cel as compared with axi- cel likely due to the CD28 costimulatory
domain used in axi- cel (Kamdar etal.2022).
A phase 2 study of tisagenlecleucel in adult patients who
had received two or more lines of therapy for R/R FL
(ELARA) was carried out based on the background of 71%
CR rate noted with tisagenlecleucel as mentioned above.
This study included 97 patients between ages 49 and 64with
FL grade 1, 2 or 3A. Amongst the 94 patients evaluable for
efficacy, CR was achieved in 68% patients with an ORR of
86.2%. Long- term analysis of the study showed that at 2
years, median PFS was 57.4%, OS was 87.7% and response
was maintained in 64.6% patients. Transgene persistence was
detected at a median of 558days in responders. CRS occurred
in 49% with 34% of those needing tocilizumab. ICANS
occurred in 4.1% patients within 8weeks of infusion (Fowler
etal.2022; Dreyling etal.2022).
Brexucabtagene autoleucel (KTE-
X19, TESCARTUS) is a
CD19 directed CAR- T cell therapy expressing CD28with a
manufacturing process that selective depletes circulating
CD- 19 expressing malignant cells to minimize exhaustion of
anti- CD19 CAR- T cells during the ex vivo manufacturing
process. In a multi- center, open- label, phase 2 study (ZUMA-
2), brexucabtagene autoleucel was studied in patients with
therapy including Bruton’s tyrosine kinase (BTK) inhibitors.
Amongst the 68 treated patients, the ORR was 91% with a
CR rate of 68%. A 3- year follow- up of the ZUMA- 2 study
published reported a median PFS 25.8 months, OS
46.6 months, and a median duration of response of
28.2 months. Outcomes were equivalent in patients with
poor prognostic features including TP53 mutations, Ki-
67
>50%, etc. CRS of all grades occurred in 91% patients with
grade 3 or higher occurring in about 15%. Fifty- nine percent
of those needed treatment with tocilizumab. Neurological
events occurred in total of 63% patients with grade 3 or
higher in 31% (Maloney etal.2021; Wang etal.2020).
Chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a common mature B
cell neoplasm that typically expresses CD5, CD19, and CD23.
Small lymphocytic lymphoma (SLL) is a similar disease predominantly confined to the lymph nodes. CLL/SLL is categorized as an indolent B- cell non- Hodgkin lymphoma typically
with a prolonged asymptomatic phase. However, a subset of
patients progress to symptomatic phase rapidly and have an
adverse outcome. Some of the high- risk features that portend
treatment resistance and poor prognosis include del(17p),
TP53 mutations, IGHV unmutated status, etc. BTK inhibitors
(ibrutinib, acalabrutinib, zanubrutinib), anti- CD20 antibodies (rituximab and obinutuzumab) and apoptotic pathway
targeting BCL- 2 inhibitor, venetoclax, have largely replaced
previously used cytotoxic therapies like fludarabine and
cyclophosphamide and improved outcomes. Despite these
advancements, CLL is considered incurable and disease
relapse is inevitable (Zenz et al 2010; Hallek and AlSawaf2021; Shadman2023). CAR- T therapy has been studied in this context. Similar to other B cell lymphomas, CAR- T
cells targeting the CD19 antigen were first used at the
University of Pennsylvania in two patients with relapsed/
refractory CLL with both achieving sustained complete
remission (Porter etal.2011; Melenhorst etal.2022) A larger
study at the same institute included 32 evaluable patients with
relapsed/refractory CLL who were treated with CD19/4- 1BB
CAR- T cells. The complete and overall response rate were
only 28% and 44%, respectively. The median PFS in all
patients was a dismal 1month, while in those achieving a CR,
it was 40.2months (Frey etal.2020). Another phase 1/2 study
included 24 relapsed/refractory CLL patients who were
treated with CD19/4-
1BB CAR- T cells; the 4- week overall
response rate was 71%, however, with a CR rate of 21% and
high incidence of all grade CRS (83%) and ICANS (33%)
(Turtle et al.2017). More recently, the results of TRANSCEND
CLL 004, a multi- center phase 1/2 study of lisocabtagene
maraleucel in 117 patients with CLL previously treated with
BTKi showed a CR rate of 18% with a median duration of
response of 35.5months in patients achieving CR. The overall
response rate was 47%. Grade 3 CRS was noted in 9% and
ICANS in 19% patients. Majority of patients in this study also
had received venetoclax indicating a rather difficult- to- treat
population (Siddiqi etal. PMID 37295445).
Overall, CAR- T cell therapy in CLL has not achieved suc-
cess similar to B- ALL or other B cell lymphomas and remains
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an investigational therapy. The overall and complete response
rates are noted to be lower and less durable compared to
B- ALL and B cell lymphomas. T- cell dysfunction due to an
exhaustion phenotype induced by persistent antigenic
stimulation is considered to be a major source of CAR- T
resistance in CLL. CLL is also characterized by an immunosuppressive microenvironment consisting of tumor macrophages, myeloid- derived suppressor cells, and other cells,
which cause inactivation of T cells by inducing inhibitory
immune checkpoints like CTLA- 4 and PD- 1. CLL- cellderived extracellular vesicles have been shown to induce a
state of CAR- T cell exhaustion by expression of PDL- 1. Most
treatments used in CLL also cause impaired T- cell function.
This leads to an inadequate number of functional T cells to
be available for CAR- T manufacturing (Cox et al. PMID
33388419; Yang etal. PMID 34489116). Use of BTK inhibitor, ibrutinib, was shown to decrease expression PD- 1 on T
cells and increased CAR- T cell expansion in vivo (Fraietta
et al. PMID: 26813675). In a phase 2 study, patients were
treated with ibrutinib 2weeks prior to leukapheresis until
3months after CAR- T infusion. Compared to patients who
did not receive ibrutinib, decreased incidence of grade 3 CRS
and improved response rates were noted (88% versus 56% p
= 0.06) (Gauthier et al. Blood 2018, supplement), demonstrating a technique of improving outcomes. There are multiple CAR- T clinical trials assessing newer generation
constructs, alternative targets as well as combinational therapy in CLL; however, a positive large- scale clinical trial is still
eagerly awaited.
Multiple myeloma
Multiple myeloma (MM) is a plasma cell neoplasm accounting for approximately 10% of all hematological malignancies
defined by presence of clonal bone marrow plasmacytosis,
monoclonal gammopathy, and clinical manifestations that
may include anemia, hypercalcemia, renal insufficiency, lytic
bone lesions, and recurring infections. Prognostic factors
predictive of poor outcome include cytogenetic abnormalities such as p53 deletion, translocation t(4;14), or t(4;16) and
mutational profiling associated with drug resistance.
Significant advances in the field include immunomodulatory
drugs (IMIDs), proteosome inhibitors (PIs), and anti CD38monoclonal antibodies. In eligible patients, high- dose
chemotherapy with autologous hematopoietic stem cell rescue remains an important therapeutic tool. However, despite
these significant advances, patients ultimately develop a progressively resistant disease.
B- cell maturation antigen (BCMA) is selectively expressed
by malignant and normal plasma cells and terminally differentiated B- cells and has served as a critical target for CAR- T
cell engager therapy targeting MM (Wang et al. 2023;
Rajkumar2022; Avigan and Rosenblatt2014). Idecabtagene
vicleucel (bb2121, ABECMA) is an autologous anti-
BCMA
CAR- T cell product incorporating an anti- BCMA scFv,
CD3z, and the 4- 1BB co- stimulatory domain. A phase 1
study of idecabtagene vicleucel (ide- cel) of 33 patients with
R/R MM showed an objective response rate of 85% with 45%
achieving CR (Russell and Avigan2023). A subsequent phase
2 study (KarMMa 2) reported on 128 patients treated with
ide- cel who had previously received at least 3 regimens
including a PI, IMID and an anti- CD38mAb. At a median
follow- up of 13.3 months, 73% patients had an objective
response with 33% having CR or better. Median PFS was
8.8months. While CRS of any grade was seen in 84% patients,
grade 3 or higher was observed in only 5%. Neurological
events of any grade or grade 3–4were noted in 18% and 3%,
respectively. Low levels of CAR- T cells were noted in circulation in 36% patients 12months after infusion. A rising soluble BCMA level corresponded with disease progression in
this study (Raje etal.2019). Subsequently, a phase 3, international, open- label, randomized control trial of ide- cel versus
standard regimens in RR MM (KarMMa- 3) was conducted.
After a median follow- up of 18.6months, the primary end
point of PFS was 13.3months in the ide- cel group versus
4.4months in the standard- regimen group (HR 0.49, 95% CI
0.38–0.65). ORR was 71% with CR 39% in the ide- cel group
versus ORR 42% with CR 5% in the standard- regimen group.
Data for OS has not matured by the time this chapter was
written (Munshi etal.2021). Ide- cel was approved as fourth
line or higher therapy for MM demonstrating a high level of
response but with a median time to progression of approximately a year and no clear evidence of a plateau suggestive of
curative outcomes in a subset of patients.
Ciltacabtagene autoleucel (CARVYKTI, cilta- cel) is an
autologous anti- BCMA CAR- T cell product expressing two
BCMA- targeting single- domain antibodies, a CD3z signaling domain and a 4- 1BB costimulatory domain. LCARB38M, its antecedent CAR- T product, was studied in a phase
1 clinical trial (LEGEND- 2) demonstrating deep, durable
responses (Rodriguez-
Otero et al. 2023). In a subsequent
phase 1b/II study of cilta- cel (CARTITUDE- 1), with a
median follow- up of 27.7months, the overall response rate
was 97.9% and 82.5% of patients achieved a stringent CR.
The median duration of response, PFS and OS were not
reached and the PFS and OS at time of analysis was 54.9%
and 70.4%, respectively. Patients with high- risk disease had a
shorter duration of response, PFS and OS rate. CRS of all
grades and grade 3–4was observed in 95% and 4%, respectively. Neurological toxicity of all grades occurred in 21% of
patients with grade 3 or higher seen in 9% (Zhao etal.2018;
Berdeja etal.2021). Several patients were observed to have
late neurologic toxicity with features of movement disorders
with associated mortality. A phase 2 and 3 study of cilta- cel
in earlier stages of MM is currently being conducted
(Martin etal.2023). A nonrandomized case- control analysis
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comparing cilta- cel and ide- cel from the CARTITUDE- 1
and KarMMa trial reported improved ORR, CR rate, median
duration of response, and PFS with cilta- cel (Cohen etal.2021).
A potential mechanism for immune escape following
CAR- T cell therapy in myeloma is the emergence of BCMA
negative variants. As such, investigators have sought to identify additional therapeutic targets. G protein- coupled receptor, class C, group5, member D (GPRC5D) was noted to be
somewhat selectively expressed on plasma cells in MM.
MCARH109 is a second- generation CAR- T cell therapy with
human B- cell- derived GPRC5D scFv, CD3z, and the 4- 1BB
costimulatory domain. A phase 1 study of MCARH109was
conducted at Memorial Sloan Kettering Cancer Center in 17
patients with RR MM having received 3 or more lines of
treatment, some also with prior anti- BCMA therapy. ORR
was recorded to be 71%. About 70% of patients who received
anti- BCMA therapy achieved a response. CRS of all grades
was seen in 88% patients and only one patient had grade 4.
Neurological toxicity was seen in one patient (Martin
etal.2021). A larger, multicenter phase 1 study is currently
being conducted for further assessment of safety and efficacy. Additionally, signaling lymphocyte- activation molecule 7 (SLAMF7), a target expressed on myeloma cells is also
being tested clinically in the CARAMBA trial in the European
Union (Mailankody etal.2022). A combination of BCMA/
GPRC5D targeting CAR- T is also being tested to address
antigen escape (NCT05431608). Multiple other targets are
being currently investigated either alone or in combination
with BCMA. A dual antigen (BCMA/CD38) targeting
CAR- T showed 87% response rate with a similar toxicity
profile (Prommersberger et al. 2021). Similarly, a CD- 19/
BCMA dual targeting CAR- T showed 92% response rate
with a median PFS of 18.3months (Mei etal.2021). A proliferation inducing ligand (APRIL) is a natural high- affinity
ligand for BCMA and transmembrane activator and calciummodulator and cyclophilin ligand interactor (TACI). A dual
BCMA- TACI targeting third- generation CAR- T (AUTO2)
with CD28, OX40, and CD3z domains showed a response
rate of about 43% (Wang etal.2022). FcRH5has also come
up as an important target undergoing therapeutic exploration (Popat etal.2019).
To address the problem of long wait times, feasibility of
novel approaches like production of “off-
the- shelf” allogeneic anti- BCMA CAR- T cells are being investigated
(Jiang et al. 2023). To avoid specialized facilities and
workers, changes in CAR- T cell protocols as well as automated or semi- automated technologies are needed that
allow decentralized CAR- T cell production outside of a
clean room environment and require minimal training.
The CliniMACs prodigy, developed by Miltenyi and capable of isolating, transducing, and expanding cells in a
completed automated fashion in a clean room environment, is one rare example of such technology that lowers
the production time to a few days by not expanding the
cells after CAR expression (Table25.2).
Sources of CAR- T resistance
There has been an increased understanding of the sources of
CAR- T resistance. Emergence of antigen negative variants as
a means of immune escape has been observed including biallelic loss of BCMA. Transient downregulation of antigen
expression has also been noted at the time of relapse
(Mailankody etal.2023). One strategy to enhance density of
antigen expression has been via the use of Gamma Secretase
Inhibitors that prevent the cleavage of surface BCMA preserving target expression on the malignant cell (Samur
etal.2021). Alternatively, the use of combinatorial approach
targeting multiple antigens has been explored in patients
with non- Hodgkin lymphoma including bi- cistronic constructs directed against CD22, CD20, and CD19 (Chen
etal.2022; Wang etal.2014; Zhang etal.2017).
Another mechanism of resistance is the development of
T- cell exhaustion and lack of persistence. The nature of
costimulatory signaling may provide for enhanced activation
and persistence including signaling via the OX40 and STING
pathways. A unique approach has been the use of costimulatory CAR constructs in which binding to a common antigen
in the tumor microenvironment (TME) such as CD38leads
to enhanced costimulatory signaling in the absence of offtarget killing (Shah et al. 2020). The T cell substrate for
CAR- T production appears critical in determining the associated functional properties. Generation of CAR- T from
patients with multiply relapsed disease has shown poorer
outcomes potentially due to a more suppressed starting population. Analysis of relapsed patients with multiple myeloma
by single cell transcriptomics reveals heightened levels of terminally differentiated and exhausted T cells and few naïve
and stem cell memory cells associated with better in vivo
expansion (Katsarou etal.2021; Pilcher et al.2021). There
has been some evidence that prolonged exvivo stimulation
via CD3/CD28ligation results in greater exhaustion in the
CAR product and efforts are now being explored in shorter
production time to preserve stimulatory capacity invivo. In
addition, on/off switches for CARtion are being explored to avoid hyperstimulation over a
chronic period with resultant exhaustion (Pilcher etal.2021;
Jan etal.2021).
We have demonstrated that durable response following
CAR- T therapy may be dependent on the generation of secondary immune stimulation of the native repertoire, epitope
spreading, and maintenance of immune surveillance following elimination of the CAR- T component (Jan etal.2021;
Karagkouni et al.2023). An alternative strategy to enhance
CAR- T efficacy is via targeting the TME to modulate the
T activation and stimula-
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Table25.2 Key trials evaluating FDA- approved CAR- T cell products
Sr. no Trial/NCT Phase Intervention Target Patient population Efficacy
Lymphoid malignancies
1 ELIANA
NCT02435849
2 BELINDA
NCT03570892
3 ZUMA- 7
NCT03391466
4 ZUMA- 2
NCT02601313
5 Zuma- 3
NCT02614066
6 TRANSCEND NHL 001
NCT02631044
7 TRANSFORM
NCT03575351
Myeloma
8 KarMMa- 3
NCT03651128
9 CARTITUDE- 1
NCT03548207
II Tisagenlecleucel CD-
III Tisagenlecleucel versus salvage
chemotherapy+AutoHCT
III Axicabtagene ciloleucel versus
salvage chemotherapy+AutoHCT
II Brexucabtagene autoleucel CD- 19 R/R MCL OR 93%; CR 67%
II Brexucabtagene autoleucel CD- 19 R/R B- ALL OR 71%; CR 56%; mOS
I/II Lisocabtagene maraleucel CD-
III Lisocabtagene maraleucel versus
salvage chemotherapy+AutoHCT
III Idecabtagene vicleucel versus
standard of care
I/II Ciltacabtagene autoleucel BCMA R/R myeloma OR 97%; sCR 67%
19 R/R B- ALL OR 81%; CR 60%
CD- 19 R/R aggressive B- cell
lymphomas
CD- 19 R/R LBCL mEFS 8.3months versus
19 R/R LBCL OR 73%; CR 53%
CD- 19 R/R LBCL mEFS Not reached months
BCMA R/R myeloma mPFS 13.3months versus
mEFS 3months versus
3months (p = 0.61); OR
46.3% versus 42.5%
2months (p < 0.001);
OR 83% versus 52%
18.2months
versus 2.4months (p <
0.001); ORR 87%
versus 49%
4.4months (p < 0.001);
ORR 71% versus 42%;
CR 39% versus 5%
R/R: relapsed or refractory; Bresponse; CR: complete response; sCR: stringent complete response; mOS: median overall survival; mEFS: median event- free survival; mPFS:
median progression- free survival; BCMA: B- cell maturation antigen.
immunosuppressive milieu. The use of checkpoint inhibition
has been explored in patients following suboptimal response
to CAR- T therapy or at the time of relapse (Karagkouni
etal.2023; Li etal.2018; Zah etal.2020). Similarly, institution of lenalidomide has been examined in this setting (Zah
etal.2020; Ping etal.2022). The use of viralvaccines has been studied to amplify response. We have
developed a personalized cancer vaccine in which patientderived tumor cells are fused with autologous dendritic cells
(DCs) such that a broad array of tumor antigens are presented in the context of DC- mediated co- stimulation. In preclinical models, we have shown that vaccination with DC/
tumor fusions enhance CAR- T activation, persistence, and
killing of antigen positive and negative variants (Ping
etal.2022; Cheloni etal.2021).
Treatment after CAR- T failure is not well delineated and
likely to have poor outcomes. There is a paucity of data and
recommendations in this setting. In non- Hodgkin lymphoma,
salvage cytotoxic chemotherapy may provide short- term
ALL: B cell acute lymphoblastic leukemia; AutoHSCT: autologous hematopoietic cell transplantation; OR: overall
disease control. Treatment with PD-
1 inhibitors, ibrutinib,
immunomodulatory drugs has been tried with variable success (Cheloni etal.2021; Byrne etal.2019; Fraietta etal .2016;
Chow etal.2019). One study showed median OS of 8 months
directed cancer
after post-CARet al. 2023). Bispecific T- cell engaging antibodies have
T relapse (Chow etal.2019; Alarcon Tomas
emerged as an appealing therapeutic option in this patient
population (Alarcon Tomas et al.2023; Falchi et al.2023;
Van Oekelen etal.2023). In multiple myeloma, post CAR- T
relapses can be treated with T- cell engaging therapies like a
subsequent CAR- T or bispecific antibody as well as transplant based approaches which have shown durable responses
(~22months) despite multiple prior lines of therapy (Falchi
et al. 2023; Van Oekelen et al. 2023). Ultimately, rapid
advancements in the composition of the CAR- T cells to
target resistance via antigen loss, immune exhaustion, and
influencing tumor microenvironment possess a unique
opportunity to achieve long- term responses or cure in
patients with relapsed lymphomas and multiple myeloma.
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To target a less evolved, low- volume disease clone, efforts are
underway to move CAR- T therapy in earlier lines of
treatment.
CAR- T- cell exhaustion
T- cell exhaustion is a dysfunctional state of T cells that results
from repeated activation through the TCR. Exhausted T cells
lose the capacity to respond to antigen stimulation and have
decreased proliferation and effector function. Chronic CAR
signaling leads to a similar state in CAR- T cells with all the
hallmarks of exhaustion including induction of inhibitory
checkpoint receptors (Gomes- Silva et al. 2017; Long et al.
2015; Lynn et al. 2019). Inhibition of checkpoint receptor
signaling via knockout, knockdown, or antibody blockade
has been tested for its ability to augment CAR- T cell therapies. Knockout or antibody blockade of PD1in combination
with CAR- T cells resulted in mixed responses in both preclinical studies and early clinical data that is attributed to
beneficial functions of PD1in T cell activation or compensatory mechanisms such as expression of TIGIT (Kalinin
et al.2021; Chong et al. 2017; Chong et al. 2017; Heczey
etal.2017; Cherkassky etal.2016; Jacobson etal.2018,2020;
John etal.2013). Knockdown of PD1was also tested in combination with knockdown of TIGIT, TIM3, CTLA4, or
LAG3, and the combination knockdown of TIGIT and
PD1 in particular led to a synergistic effect in vivo (Lee
et al.2022). Our group has demonstrated a 33% improvement in mouse survival in a xenograft model of lymphoma
when TIGIT blockade was combined with CAR- T cells (see
Chapter 4) (Jackson et al. 2022). Similarly, blockade of
TIM3in an acute myeloid leukemia (AML) xenograft mouse
model showed a 100% complete response rate compared to
45% with CAR- T cells alone (Kenderian et al. 2016).
However, neither short hairpin RNA (shRNA) knockdown
of CTLA4 or CRISPR Cas9knockout of LAG3 demonstrated
functional improvements of CAR- T cells (Condomines
etal.2015; Zhang etal.2017).
Additional methods of alleviating CAR-
T cell dysfunction
include proof- of- concept studies in which signaling components in CAR- T cells were modified to improve their effect.
For example, two independent groups demonstrated means
by which CAR expression or signal transduction could be
attenuated pharmacologically in order to provide resting
periods between CAR stimulations (Weber etal.2021; Wu
etal.2015). Others have beneficially modified CAR signaling occurring downstream of 4- 1BB and CD28 by engineering the expression and recruitment of Lck or Src homology 2
domain- containing protein tyrosine phosphatase 1 (SHP- 1)
so as to either increase or decrease phosphorylation or
dephosphorylation (Sun etal.2020). Similarly, a group demonstrated that in CAR- T cells, the overexpression of c- Jun so
as to promote greater rates of c- Jun and c- Fos dimerization
led to a reduction in CAR-
T cell exhaustion (Lynn etal.2019).
As a greater understanding of the formation of T cell exhaustion is gained, it is likely that more strategies geared toward
alleviating T cell exhaustion will reach the clinic.
Exhaustion in the tumor microenvironment also contributes to the dysfunction of the CAR- T cells in immunotherapy. The TME layers have a variety of cells, which include
cancer cells and immunosuppressive cells. These immunosuppressive cells secrete various inhibitory cytokines, such as
IL- 10 and TGF- beta that prevent immune cell proliferation
and differentiation (Siebzehnrubl etal.2013). The proliferative cytokines, such as IL- 2 are also shown to be significantly
decreased in concentration (Zhang etal.2020). T cells are no
longer able to differentiate into effector populations that are
crucial in clearance of the tumor. In addition, the few effector T cells that remain are chronically exposed to the antigen
in the cancer core, without any further lymphocyte recruitment, due to physical and chemical inhibition, and become
exhausted and lose cytotoxic capabilities. The terminal differentiation and low persistence of lymphocytes is a key
component of cancer immune evasion (Jiang etal.2015).
Epitope shedding
One of the most notable challenges of CAR- T therapy is a
loss in target antigen recognition due to modulation or loss
of epitope expression. CAR- T cell killing of epitopeexpressing cells introduces a strong selection pressure to promote microevolution of the tumor cell population toward
epitope- negative derivatives. In CD19 CAR- T cell therapy,
these derivatives are then able to drive patient relapse in
approximately 10–20% of patients between 3 and 6months
of treatment (Maude et al. 2014; Shah and Fry 2019; Lee
et al.2015; Gardner et al. 2017; Park et al. 2018). Known
mechanisms of epitope shedding include deleterious mutations, lineage switching (in leukemia), disruption of CD19
transport to the cell surface, and alternative splicing (Braig
etal.2017; Fischer etal.2017; Sotillo etal.2015). Strategies
to circumvent epitope shedding primarily include targeting
multiple antigens (sequentially or simultaneously), promoting bystander effects/epitope spreading in which antigennegative cells are killed by endogenous immune cells, or
targeting essential proteins such as oncogenes.
In B- cell- derived leukemias and lymphomas, additional
antigens to be targeted include CD20, CD22, and CD123.
Preclinical experiments utilizing co- transduced CD19 and
CD22 CAR- T cells or combination CD19 and CD22 CAR- T
cells have been promising, with invivo testing showing the
ability to eliminate patient- derived xenografts with or without prior CD19 CAR- T cell therapy (Qin et al. 2018).
Accordingly, this strategy is now being evaluated in several
ongoing clinical trials (NCT03330691; NCT03241940;
NCT03233854; NCT03448393; NCT03289455). Likewise,
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bispecific CD19- and CD20- directed CAR- T cells have
achieved clinical success with a 92% complete response rate
in 22 patients (Shah etal.2020). The difficulties in targeting
multiple tumor- specific- antigens lie in the identification of
tumor- related antigens and the added risk of on- target offtumor toxicities. A method proposed to alleviate this risk
was to use a CAR system in which two targeted antigens
must be present in order to instigate cytotoxicity (Roybal
etal.2016). This however reverses the advantage of targeting
two antigens to prevent antigen escape.
As an alternative to targeting multiple antigens, scientists
can design strategies to promote epitope spreading, a phenomenon in which endogenous T cells are recruited to eliminate antigen- negative tumor cells due to the release of
neoantigens by tumor cell lysis and promotion of a proinflammatory microenvironment. In a syngeneic mouse
model of malignant mesothelioma, Klampatsa etal. demonstrated that as few as 10% antigen- negative cells were sufficient to avoid tumor elimination in an otherwise curable
disease with treatment of mesothelin- directed CAR- T cells.
CAR- T cells combined with anti- PD- 1, anti- CTLA- 4, or
anti- transforming growth factor β (TGF- β) antibodies; ago-
nistic CD40 antibodies; or an indoleamine 2,3- dioxygenase
inhibitor were all insufficient to achieve tumor elimination.
Of the strategies tested, only pre- treatment with a nonlymphodepleting dose of cyclophosphamide resulted in
tumor elimination with up to 25% mesothelin- negative cells.
Thus, Kampatsa et al. simultaneously demonstrated the
necessity of bystander effects and the difficulty to achieve
them (Klampatsa et al. 2020). As essential tumor- specific
extracellular proteins are quite rare to identify in large percentages of patients, one recently developed strategy is to
develop CARs that recognize intracellular- derived tumorspecific peptides presented in the context of MHC
(Yarmarkovich etal.2021). Here, Yarmarkovich etal. demonstrated CAR- T cell killing of neuroblastoma cells when
presenting a peptide derived from the neuroblastoma
dependency gene PHOX2B on HLAor HLA- B*14:02. While limited to specific HLA allotypes
like engineered αβ TCR T cells, the strategy nonetheless
could significantly expand the repertoire of targets for
CAR- T cells.
A*24:02, HLA- A*23:01,
Toxicities of CAR- T therapy
Although CAR- T therapy has significantly changed the outcomes of relapsed/refractory malignancies (See table 25.2),
treatment- related toxicities remain a major source of morbidity and occasional mortality. The incidence and severity of
CAR- associated toxicity may differ based on the nature of the
CAR- T construct (scFv, signaling, and costimulatory
domains), dose, conditioning lymphodepleting chemotherapy
and, in some cases, disease burden. As an example, CARproducts using CD28 as the costimulatory domain induce
more rapid T cell expansion potentially associated with
increased incidence of grade 3- 4 cytokine release syndrome.
T
Cytokine release syndrome
Cytokine release syndrome (CRS) is a common toxicity associated with CAR- T therapy. Rapid activation and expansion
of the CAR- T cell population results in production of inflammatory cytokines such as tumor necrosis factor alfa (TNF- α)
and interferon gamma (IFN- γ), secondary stimulation of
monocytes, macrophages, and release of interleukin (IL) 1β,
IL- 6, IL- 12, nitric oxide (NO) generating the clinical syndrome. Peak incidence of CRS varies based on the CAR- T
construct and dose. Of note, early onset of CRS may be associated with greater severity and risk for mortality (Van
Oekelen etal.2023; Giavridis etal.2018; Norelli etal.2018).
The common terminology criteria for adverse events
(CTCAE) v5 defines CRS as “a disorder characterized by
fever, tachypnea, headache, tachycardia, hypotension, rash
and/or hypoxia caused by the release of cytokines.” Common
routine laboratory abnormalities include elevated C- reactive
protein, serum ferritin, and low fibrinogen. Different systems have been developed for the grading of CRS (Norelli
et al. 2018; Lee et al. 2014); however, the current widely
adopted consensus criteria for grading of CRS is established
by the American Society of transplantation and Cellular
therapy (ASTCT), which classifies CRS into four grades of
increasing severity (Lee et al.2014). Management of CRS
generally depends on the severity. Mild CRS (grade 1 and
some grade 2) is usually managed with antipyretics, antihistamine, intravenous fluids, nasal oxygen supplementation.
Severe CRS (most grade 2, grades 3, and 4) can be treated
with tocilizumab, which blocks the interaction of IL- 6with
its native receptor. The addition of corticosteroids is considered for patients with severe or persisting CRS. There are no
randomized trials of comparing tocilizumab and glucocorticoids either in combination or alone. Immunosuppressive
therapy to address CRS has not been clearly associated with
blunting CARtion in high- risk patients has not been fully established.
There are multiple ongoing studies assessing the utility of
targeting other inflammatory pathways (IL- 1, IL- 6, GMCSF) to mitigate CRS (Lee etal.2014,2019; Hay etal.2017;
Morris et al. 2022; Sterner et al. 2019; Chen et al. 2016).
Secondary hemophagocytic lymphohistiocytosis (HLH)/
Macrophage activation syndrome (MAS) has also been
described in the literature to be prevalent in about 3.5%
patients receiving CAR- T therapy (Chen etal.2016; Sandler
etal.2020). However, given overlapping features with CRS,
HLH/MAS can be difficult to diagnose. High suspicion
should be maintained in the setting of rapidly rising serum
T efficacy. The role of prophylactic interven-
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