Clinical Review

Chimeric antigen receptor T cell therapy for cancer:

BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
clinical applications and practical considerations
Joseph E Maakaron, Marie Hu, Najla El Jurdi
A b s t ra c t

University of Minnesota Twin

Chimeric antigen receptor T cells have revolutionized the treatment of hematological
Cities, Minneapolis, United malignancies during the past five years, boasting impressive response rates and
States
Correspondence to: durable remissions for patients who previously had no viable options. In this
maaka001@umn.edu review, we provide a brief historical overview of their development. We focus on
Cite this as: BMJ 2022;378:e068956
http://dx.doi.org/10.1136/ the practical aspects of a patient’s journey through this treatment and the unique
bmj‑2021‑068956
toxicities and current best practices to manage those. We then discuss the key
Series explanation: State of the
Art Reviews are commissioned registration trials that have led to approvals for the treatment of relapsed/refractory
on the basis of their relevance
to academics and specialists
acute lymphoblastic leukemia (ALL), diffuse large B cell lymphoma (DLBCL), follicular
in the US and internationally.
For this reason they are written
lymphoma, mantle cell lymphoma (MCL), and multiple myeloma. Finally, we consider
predominantly by US authors the future development and research directions of this cutting edge therapy.

Introduction challenging as most antigens expressed by tumors are

The immune system has been recognized to play an
important role in controlling carcinogenesis since the
1950s, when mouse models exemplified a genetic
basis for self-recognition and rejection of non-self.1
Several years later, application of that concept in
allogeneic stem transplantation demonstrated a more
feasible approach to using the immune system to treat
hematological malignancies. Patients who displayed
signs and symptoms of graft-versus-host disease had
lower risk of relapse of leukemia, providing tangible
proof of the role of the immune system in anti-cancer
therapy.2 This concept was further developed by
the infusion of donor lymphocytes to recipients,
successfully eradicating leukemia.3 Adoptive
transfer of lymphocytes was also trialed in patients
with metastatic melanoma, where tumor-infiltrating
lymphocytes were extracted, cultured, and infused
back into the patient, resulting in tumor regression.4
The advent and refinement of gene modification
and manipulation using retroviruses, among other
techniques, allowed for precise modification of the T
cell receptor (TCR) to identify and engage a cognate
receptor.5 This helped further refine adoptive transfer
of anti-tumor immunity to increase specificity and
applicability to other tumor types.6 The co-stimulatory
signal domain necessary for the improved function
and persistence of T cells was eventually combined
with the antigen binding, single-chain, variable,
intracellular domain (CD3ζ) to produce one receptor
capable of antigen recognition and T cell activation
without being HLA-restricted (fig 1).7 8 The result was
a chimeric antigen receptor (CAR).9
A key component of the success of chimeric
antigen receptor T cells (CAR-Ts) is the availability of
a target which is uniformly expressed on tumor cells,
but not on normal tissue. Finding such an antigen is
either transient or are autoantigens.10 Leukemias and
lymphomas of B cell origin uniformly express B cell
antigens, namely CD19, CD20, and CD22.11 CD19 is
expressed earlier on in the B cell maturation pathway
and was therefore selected as a potential target.12 It
is found on normal B cells and B cell aplasia was an
expected off-target effect. However, this phenomenon
is also frequently encountered with other therapies
in B cell malignancies and immunoglobulin
replacement can overcome any deleterious effects.
One postulated benefit of B cell aplasia was that it
would pre-emptively thwart the development of anti-
chimeric CAR antibodies. After proof of concept was
shown in a mouse model,13 individual patient cases
were reported. Patients with chronic lymphocytic
leukemia (CLL), acute lymphoblastic leukemia (ALL),
and B cell non-Hodgkin’s lymphoma (NHL) were
treated with encouraging results.14-18 Larger clinical
trials subsequently ensued and will be the focus of
this review. We will also cover the practical aspects of
managing patients receiving CAR-T therapy.
Incidence and prevalence
CAR-T therapy is approved by the Food and Drug
Administration (FDA) to treat five diseases and is
being investigated in clinical trials for many others;
indeed, there are currently >1000 CAR trials listed on
clinicaltrials.gov. ALL is the most common childhood
cancer and accounts for approximately one quarter of
all childhood malignancies. Almost 3000 new cases
of ALL are diagnosed in children every year in the
US, with an incidence of approximately 3.4 cases per
100 000.19 ALL is rarer in adults, with an incidence
of approximately 1–5/100  000 individuals;
however, it remains the second most common acute
leukemia in this age group.20 The Surveillance,

the bmj | BMJ 2022;378:e068956 | doi: 10.1136/bmj-2021-068956 1

 Clinical Review

not published in English and excluded reviews,

BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
editorials, and other articles of a non-interventional
7XPRUFHOO nature. We also excluded irrelevant studies that
contained similar sounding MeSH terms. We then
prioritized interventional studies that reported on
CAR-T therapy in a clinical setting, focusing on phase
2 or later studies with sample sizes larger than 50
patients. Studies that focused on molecular structure
7DUJHWDQWLJHQ
and function in vitro were excluded, except when
HJ&'RU%&0$
they were cited by a clinical study that incorporated
$QWLJHQELQGLQJ
9/ 9+ the results of the experiments. For the toxicities
GRPDLQ
section, we selected the largest case series regarding
each of the known complications and examined the
references from the long term, follow-up studies to
&$57FHOO capture all that is reported in the literature.
PHPEUDQH

&RVWLPXODWLRQGRPDLQ Practical considerations

%%RU&' The advent of CAR-T therapy has revolutionized the
treatment of hematological malignancies and six
$FWLYDWLRQGRPDLQ FDA approved products are now available (table 1, fig
&'
Fig 1 | Structure of a chimeric antigen receptor. CAR=chimeric antigen receptor
Epidemiology, and End Results (SEER) database
recorded an incidence of 1.8/100 000 for the year
2018.21 NHL is more common, with an incidence
of 88/100 000 for adults aged >65 and 20/100 000
when all ages are taken into account.21 Diffuse large
B cell lymphoma (DLBCL), follicular lymphoma,
and mantle cell lymphoma (MCL) are the three most
common subtypes of B cell NHL. Multiple myeloma is
considered rare as it constitutes only approximately
1-2% of malignancies diagnosed annually. The SEER
database reported an incidence of 7.3/100 000 for all
ages in 2018 although, given the extended survival
of multiple myeloma, approximately 150  000
individuals are living with this cancer.21
Since the first approval in 2017, the number of
patients treated with CAR-Ts has steadily increased
and more than 4000 patients had been treated by
2020.22 The number of centers accredited by the
Foundation for the Accreditation of Cellular Therapy
(FACT) to administer CAR-Ts has also increased.
FACT has established standards to ensure the
safe administration of immune effector cells and
reporting/monitoring of patient outcomes.23 As
indications for this treatment are increasing and
experience in administering and managing potential
side effects is becoming more standardized, access to
CAR-Ts is improving and referrals are increasing. The
Center for International Blood and Marrow Research
also hosts a central database to record and report
outcomes and provides regular updates during their
annual conferences.
Sources and selection criteria
We performed a search using PubMed and Medline
databases, using the terms “CAR-T”, “CAR”, and
“Chimeric Antigen Receptor” of all studies published
from January 2000 through April 2022, and identified
>3000 publications. We excluded studies that were
2
2). However, the treatment remains limited to larger
centers that have the expertise and infrastructure
required to successfully administer these products.
The first step is referral to such a center where a
physician specialized in CAR-T delivery obtains a
history and physical examination, and reviews the
records and pathology specimens. If the patient is
deemed eligible and consents to the process, they
undergo testing to objectively evaluate their organ
function.
The next step is to obtain the autologous T cells,
which are manufactured through apheresis. Patients
typically must be chemotherapy and radiation
free for approximately 14 days to ensure optimal
health and an adequate number of lymphocytes.
Several reports have been published regarding
mechanisms of failure of these therapies and
baseline characteristics of the apheresed product,
number of previous therapies, and how the overall
health of the lymphocytes measured by doubling
time is correlated with outcomes.24-26 Early referral,
and appropriate timing and sequencing of therapies
are therefore critical to the success of this process.
After the lymphocytes are collected, they are sent to
designated laboratories tasked with manufacturing,
quality checking, and returning the product to the
treating center. This requires a dedicated team of
expert immunologists and geneticists who co-culture
the product with pro-proliferative cytokines, select T
cells for transfection with a lentivirus or a retrovirus,
and finally check the product for sterility, number,
and function of the CAR-Ts. This entire process takes
three to four weeks, during which the patient might
receive bridging therapy to keep the disease stable
(fig 3).
Once confirmation of successful manufacturing is
received, the patient undergoes another assessment
to ensure no complications have arisen from
either the disease or any bridging chemotherapy
during that time. They are then scheduled to
receive lymphodepleting chemotherapy, typically a
combination of fludarabine and cyclophosphamide
doi: 10.1136/bmj-2021-068956 | BMJ 2022;378:e068956 | the bmj
 Clinical Review

Table 1 | Summary of registration trials for FDA approved commercial CAR-T products

BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
Trial ELIANA ZUMA-3 ZUMA-1 JULIET TRANSCEND ZUMA-2 ZUMA-5 KarMMA CARTITUDE-1
Product Tisa-cel Brexu-cel Axi-cel Tisa-cel
Liso-cel (JCAR017, Brexu-cel Axi-cel (KTE-C19, Ide-cel Cilta-cel
(CTL019, (KTE-X19, (KTE-C19, (CTL019,
Breyanzi) (KTE-X19, Yescarta) (bb2121, (JNJ-4528,
Kymriah) Tecartus) Yescarta) Kymriah) Tecartus) Abecma) Carvykti)
Construct 19-41BBz 19-28z 19-28z 19-41BBz
19-41BBz 19-28z 19-28z BCMA-41BBz BCMA-
(1:1 CD8:4) 41BBz
Approved B-ALL (refractory R/R B-ALL in R/R LBCL after R/R LBCL after >2 R/R LBCL after >2 R/R MCL in R/R FL after >2 R/R multiple R/R multiple
indication or 2nd/later adults (>18 >2 lines of lines of systemic lines of systemic adults lines of systemic myeloma after myeloma after
relapse) in pts years old) systemic tx in tx in adults tx in adults tx in adults >4 lines of tx >4 lines of tx in
<25 years adults in adults adults
Study type Phase 2 Phase 2 Phase 1/2 Phase 2 Phase 1 Phase 2 Phase 2 Phase 2 Phase 1b/2
Number of patients 92/75 71/55 111/101 165/111 342/268 74/68 146 140/128 97/113
(enrolled/infused) (124 FL; 22 MZL)
Median age, y 11 (range 3–23) 40 (IQR 58 (range 56 (range 22- 63 (IQR 54–70) 65 (range 61 61 61 (IQR 56–68)
28–52) 23–76) 76) 38–79) (range 34–79) (range 33–78)
Prior auto-HCT N/A N/A 21% 49% 33% 43% 24% 94% 90%
Prior allo-HCT 61% 42% - - 3% - - - 8%
Lines of prior tx, 3 (range 1–8) 2 (IQR 2–3) 3 3 (range 1–6) 3 (IQR 2–4) 3 (range 1–5) 3 (range 1–10) 6 6 (IQR 4–8)
median (range 3–16)
Median time to 45 13 (US), 17 (from 54 (from 37 16 (from NR NR 29 (apheresis)
infusion, d (from enrolment) 14.5 apheresis) enrolment) (from apheresis) apheresis)
(EU) (from
apheresis)
Bridging allowed? Yes (87%) Yes (93%) No Yes (92%) Yes (59%) Yes (37%) NR Yes (88%) Yes (75%)
(% received)
Lymphodepleting Flu-Cy or Flu-Cy Flu-Cy Flu-Cy or Benda Flu-Cy Flu-Cy Flu-Cy Flu-Cy Flu-Cy
regimen AraC-Etop
Response rate in 81%/60% 71%/56% 82%/54% 52%/40% 73%/53% 93%/67% 92%/76% 73%/33% 97%/67%
infused (ORR/CR) (94%/80% for FL)
ORR by ITT 66% 55% 75% 34% 61% 85% NR NR NR
PFS (1 y/2 y) 50% (EFS)/- 58% (RFS)/- 44%/38% 35%/33% 44%/- 61%/- 74%/- NR 77%/-
Median PFS (95% NR 11.6 5.8 (3.3-NE) NR 6.8 (3.3–14.1) NR NR 8.8 NE (16.8–NE)
CI), mo (2.7–15.5) (5.6–11.6)
OS (1 y/2 y) 76%/66% 71%/- 59%/51% 49%/40% 58%/- 83%/- 93%/- 78%/- 89%/-
Median OS (95% NR 18.2 NR (12–NE) 12 (7-NR) 21.1 (13.3–NR) NR NR 19.4 NE
CI), mo (15.9–NE) (18.2–NE)
CRS (all 77%/46% 89%/24% 94%/13% 58%/22% 42%/2% 91%/15% -/7% 84%/5% 95%/4%
grades/>G3) (Penn) (Lee) (Lee) (Penn) (Lee) (Lee) (Lee) (Lee) (Lee)
(Grading system)
ICANS/ 40%/13% 60%/25% 64%/28% 21%/12% 30%/10% 63%/31% -/19% 18%/3% 21%/9%
neurotoxicity (all
grades/>G3)
AraC=cytarabine; Benda=bendamustine; B-ALL=B cell acute lymphoblastic leukemia; CI=confidence interval; CR=complete response; Cy=cyclophosphamide; FL=follicular lymphoma;
Flu=fludarabine; Etop=etoposide; HCT=hematopoietic stem cell transplantation; ICANS=immune effector cell associated neurotoxicity syndrome; IQR=interquartile range; ITT=intention-to-treat;
LBCL=large B cell lymphoma; MCL=mantle cell lymphoma; MM=multiple myeloma; MZL=marginal zone lymphoma; NE=not estimable; NR=not reported; ORR=overall response rate; OS=overall
survival; pts=patients; R/R=relapsed/refractory; tx=treatment.

over three days. This is a critical step to eliminate
cytokine sinks and other homeostatic signals that
allow adequate expansion of the cells.104 This
is typically carried out in the outpatient setting.
The cells are then infused after a two day rest
period. Institutions have different criteria for
whether the patient is hospitalized for this part of
the treatment. It is also highly dependent on the
actual pharmacokinetics of the cells given and
reimbursement guidelines.105 Following infusion of
the cells, the patient needs to be closely monitored
for treatment related adverse events. During this
time, their medical needs are typically addressed
by the cellular therapy team. It is very important to
minimize the use of corticosteroids unless necessary.
Toxicities
CAR-T treatment has toxicities like all novel immuno-
oncological treatments. The difference between
CAR-Ts and other immunological treatments is
that the main toxicities of CAR-Ts are intended
on-target effects and are thus reversible when the
CAR-Ts are removed, either pharmacologically or
by the recipient’s immune system. They are also
different to traditional chemotherapy toxicities in
that there are no dose adjustments for certain high
risk features such as frailty or poor organ function.
For most patients, it is a single infusion followed by
close monitoring and management. The bulk of the
knowledge regarding how to evaluate, treat, and
prevent these toxicities is based on CD19 CAR-Ts,
which are widely used.
Cytokine release syndrome (CRS)
When CAR-Ts encounter their cognate antigen
the signal is transmitted downstream leading to
activation of a cascade, resulting in release of
inflammatory cytokines, proliferation of the CAR-Ts,
and recruitment of other cells including monocytes
and macrophages. This systemic inflammatory
response can cause endothelial damage and
vascular leakage in multiple organs and tissues,

the bmj | BMJ 2022;378:e068956 | doi: 10.1136/bmj-2021-068956 3

Clinical Review

BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
$[LFHO<HVFDUWD
DSSURYHGIRUDGXOW
55)/DIWHUWZROLQHV
0DUFK
$[LFHO<HVFDUWD
DSSURYHGIRUDGXOW
55KLJKULVN/%&/
$[LFHO<HVFDUWD 7LVDFHO.\PULDK %UH[XFHO7HFDUWXV /LVRFHO%UH\DQ]L DIWHURQHOLQH
DSSURYHGIRUDGXOW55 DSSURYHGIRUDGXOW55 DSSURYHGIRUDGXOW DSSURYHGIRUDGXOW55
$SULO
/%&/DIWHUWZROLQHV /%&/DIWHUWZROLQHV 550&/ /%&/DIWHUWZROLQHV
2FWREHU 0D\ -XO\ )HEUXDU\

     

7LVDHO.\PULDK ,GHFHO$EHFPD &LOWDFHO&DUY\NWL

DSSURYHGIRU DSSURYHGIRUDGXOW55 DSSURYHGIRUDGXOW55
SHGLDWULF$<$55 00DIWHUIRXUOLQHV 00DIWHUIRXUOLQHV
%$//DIWHUWZROLQHV 0DUFK )HEUXDU\
$XJXVW

Fig 2 | Timeline of CAR-T FDA approvals in the US. B-ALL=B cell acute lymphoblastic leukemia; LBCL=large B cell lymphoma; MCL=mantle cell
lymphoma; MM=multiple myeloma; R/R=relapsed/refractory
resulting in CRS.1 The clinical syndrome generally
begins with high fevers and can progress to systemic
inflammation with capillary leak, hypotension,
hypoxia, and organ failure. It is characterized by
high levels of interferon-ɣ, tumor necrosis factor-α,
interleukin-1, and interleukin-6 (IL-6).27 28
The incidence, timing, and severity of CRS depends
on the CAR-T product, as different CAR constructs
have different expansion and proliferation kinetics;
however, CRS of any grade uniformly occurs in
more than 50% of patients with all products.
Earlier pivotal trials used different severity grading
systems and made treatment recommendations
based on grade, which makes counseling, cross-
product comparisons, and management more
difficult. Moreover, staff at centers designated to
administer CAR-Ts need to undergo risk evaluation
and mitigation training. Standardization of all
toxicity assessment scores and treatment guidelines
would make these processes easier. More recently,
in an effort to harmonize reporting and treatment
guidelines, the American Society for Transplantation
and Cellular Therapy (ASTCT) released a consensus
grading system (tables 2, 3).29
The standard management consists of IL-6
antagonists with or without corticosteroids when
the severity warrants interrupting the cascade,
in addition to supportive care with fluids,
4
%UH[XFHO7HFDUWXV
DSSURYHGIRUDGXOW
55%$//
2FWREHU
antipyretics, or vasopressors if needed. Other more
investigational agents that have shown promise for
the treatment of CRS include the tyrosine kinase
inhibitor dasatinib and IL-1 receptor antagonist
anakinra.30-32 The care team needs to always keep
a broad differential in mind as these patients are
often severely immunocompromised, and it might
be difficult to differentiate a fever of an infectious
source from fevers related to CAR-T therapy.
Procalcitonin can be a useful tool in these situations
(especially for bacterial infections) as it appears to
lag behind in the case of CRS, but more validation
is needed.33 Rarely, an exaggerated form of CRS can
lead to clinical manifestations of hemophagocytic
lymphohistiocytosis syndrome.34 35 This requires
prompt diagnosis and management, including
treatment with immunosuppressants and anti-
inflammatory medications similar to CRS.
Immune effector cell associated neurotoxicity
syndrome (ICANS)
Neurotoxicity and encephalopathy can also occur
with CAR-T therapy. While CRS has been extensively
studied and a clear description of implicated
cytokines and established treatments exist, the
exact pathophysiology of ICANS is less clear. The
current working hypothesis is that endothelial injury
caused by the inflammatory milieu of the tumor,
doi: 10.1136/bmj-2021-068956 | BMJ 2022;378:e068956 | the bmj
 Clinical Review

BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
 &$57FHOOVDWWDFNFDQFHU &ROOHFW:%&IURPSDWLHQWšV
FHOOVPRQLWRUIRUVLGHHƷHFWV
VXFKDV&56,&$16
'HDWKRIFDQFHUFHOOV
 *LYHO\PSKRGHSOHWLQJ
FKHPRWKHUDS\DQGLQIXVH
&$57FHOOVEDFNLQWRSDWLHQW
 *URZDQGH[SDQG
PLOOLRQVRI&$57FHOOV
Fig 3 | Summary of the CAR-T manufacturing and treatment process. CAR=chimeric antigen receptor; CRS=cytokine release syndrome;
ICANS=immune effector cell associated neurotoxicity syndrome; WBC=white blood cells. Adapted from “CAR-T Cell Therapy Overview,” by
BioRender.com (2021)
lymphodepleting chemotherapy, and high-grade
CRS leads to a breakdown in the blood-brain barrier,
allowing influx of pro-inflammatory cytokines into
the cerebrospinal fluid. This subsequently leads
to activation of resident pericytes and microglial
cells, leading to the observed clinical syndrome
of encephalopathy. Similar to CRS, it can vary in
severity from a simple headache, tremor, or word-
finding difficulties, at its mildest, to confusion,
aphasia, seizures, brain edema, and death in the
most severe forms.36-38 ICANS is mostly reversible;
however, recent clinical observations point to a small
the bmj | BMJ 2022;378:e068956 | doi: 10.1136/bmj-2021-068956
EORRGOHXNDSKHUHVLV
DQGLVRODWH7FHOOV
7FHOO
(QJLQHHU7FHOOV
ZLWK&$5JHQH
&$57FHOO
subset of patients who might experience subtle,
prolonged, neurological manifestations including
cognitive dysfunction.39 Treatment is predominantly
with corticosteroids in addition to supportive care
(antiepileptics and intensive care unit (ICU) level
care/intubation if needed).
Infectious complications
Patients undergoing treatment with CAR-Ts have
varying and complex risk factors that can weaken
their humoral and cellular immune responses. In a
real world study reporting on 60 consecutive patients
5
Clinical Review

Table 2 | American Society for Transplantation and Cellular Therapy consensus grading for cytokine release syndrome

BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
CRS parameter Grade 1 Grade 2 Grade 3 Grade 4
Fever* Temperature ≥38 °C Temperature ≥38 °C Temperature ≥38 °C Temperature ≥38 °C
 with
Hypotension None Not requiring vasopressors Requiring a vasopressor with or without Requiring multiple vasopressors (excluding
vasopressin vasopressin)
 and/or†
Hypoxia None Requiring low-flow nasal cannula‡ Requiring high-flow nasal cannula‡, facemask, Requiring positive pressure (eg, CPAP, BiPAP,
or blow-by nonrebreather mask, or Venturi mask intubation and mechanical ventilation)
Organ toxicities associated with cytokine release syndrome (CRS) may be graded according to Common Terminology Criteria for Adverse Events v5.0, but they do not influence CRS grading.
*Fever is defined as temperature ≥38 °C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy, such as tocilizumab or steroids, fever is no
longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.
†CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with a temperature of 39.5 °C, hypotension requiring one
vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS.
‡Low-flow nasal cannula is defined as oxygen delivered at 6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen
delivered at >6 L/minute.
CPAP=continuous positive airway pressure; BiPAP=bilevel positive airway pressure

receiving axicabtagene ciloleucel (axi-cel), an
approved CD19 CAR-T therapy, 101 infectious events
were reported in 63.3% of patients. The infections
varied in severity and one was fatal. The most common
type was bacterial, but fungal and viral infections
were also prevalent. In multivariate analysis, poor
performance status and prior infections within 30
days were risk factors for severe bacterial infections,
whereas use of corticosteroids to mitigate CAR-T
toxicities was associated with overall infection risk.40
In this cohort no standardized infection prophylaxis
regimen was instated until approximately half of the
patients had already been treated.
In another single center study looking at a similar
population of 41 patients also receiving axi-cel, the
estimated cumulative incidence of any infection
by 12 months was 89.7% (confidence interval (CI)
83.9% to 93.4%). Again, in multivariate analysis,
the use of corticosteroids was associated with severe
infections. Patients in this cohort were also receiving
institutional infectious prophylaxis, which was three
months in duration, post treatment. Several patients
developed Pneumocystis jirovecii pneumonia and
varicella zoster infections once prophylaxis was
terminated at the scheduled three month time
point. Prolonged cytopenias and delayed immune
reconstitution were also reported in patients with
available data. Evidence of immune dysfunction
as reported by neutropenia with an absolute
neutrophil count <1000/µL, B cell aplasia, and low
immunoglobulin levels <400 mg/dL, and CD4+ counts
<200/µL persisted in a notable portion of patients up
to 18 months post treatment. The authors provided
guidelines for prolonged infectious prophylaxis for
opportunistic infections up to 18 months based on
immune reconstitution monitoring.41
Prolonged cytopenias
Prolonged cytopenias have also been observed after
treatment with CAR-Ts. In the pivotal ZUMA-1 study
of axi-cel, 78% of patients had grade 3 or higher
neutropenia and approximately 40% had anemia
and thrombocytopenia.42 The long term follow-up of
this study confirmed that some of these cytopenias
can persist up to several months.43 This has been
validated in real world data and other pivotal CAR-T
studies.44-46 Our understanding of this phenomenon
continues to evolve as we gather more data. Patients
treated in earlier studies were heavily pretreated,
with approximately 70% of patients having received
three or more lines of therapy. Prolonged marrow
recovery after recurrent toxic chemotherapeutic

Table 3 | American Society for Transplantation and Cellular Therapy consensus grading for immune effector cell associated neurotoxicity syndrome
Neurotoxicity domain Grade 1 Grade 2 Grade 3 Grade 4
ICE score* 7–9 3–6 0–2 0 (patient is unarousable and unable to perform ICE)
Depressed level of Awakens spontaneously Awakens to voice Awakens only to tactile stimulus Patient is unarousable or requires vigorous or
consciousness‡ repetitive tactile stimuli to arouse. Stupor or coma
Seizure N/A N/A Any clinical seizure focal or generalized that Life-threatening prolonged seizure (>5 min); or
resolves rapidly or nonconvulsive seizures on repetitive clinical or electrical seizures without
EEG that resolve with intervention return to baseline in between
Motor findings§ N/A N/A N/A Deep focal motor weakness such as hemiparesis or
paraparesis
Elevated ICP/ cerebral N/A N/A Focal/local edema on neuroimaging† Diffuse cerebral edema on neuroimaging;
edema decerebrate or decorticate posturing; or cranial
nerve VI palsy; or papilledema; or Cushing’s triad
Immune effector cell associated neurotoxicity syndrome (ICANS) grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral
edema) not attributable to any other cause; for example, a patient with an ICE score of 3 who has a generalized seizure is classified as grade 3 ICANS.
N/A indicates not applicable.
*A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may be classified as grade 4 ICANS if unarousable.
†Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It may be graded according to Common Terminology
Criteria for Adverse Events (CTCAE) v5.0.
‡Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication).
§Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, but they do not influence ICANS grading.
EEG=electroencephalogram; ICE=immune effector cell-associated encephalopathy; ICP=intracranial pressure; N/A=not applicable

6 doi: 10.1136/bmj-2021-068956 | BMJ 2022;378:e068956 | the bmj


insults was to be expected. However, some of these
cytopenias were biphasic, signaling that the bone
marrow’s regenerative ability was intact and that
other confounding factors might have been at play.
Moreover, patients were referred earlier in their
course, and clinical trials using CAR-T therapy for first
and second line therapies also reported prolonged
cytopenias, suggesting that this might be specific to
CAR-T therapy.47-49 At present, reports are limited,
retrospective, and variable in their definitions of
severity and time of onset of prolonged cytopenias.
No evidence based guidelines for management and
prevention exist, but the consensus between these
retrospective reports and expert opinion is that risk
factors include higher grade and prolonged CRS.48 50
A risk stratification tool for predicting hematological
toxicity after CAR-T (CAR-HEMATOTOX) has also
recently been developed, which incorporates
baseline blood counts and inflammatory markers
as risk factors.51 Management generally focuses on
ruling out myelodysplastic syndrome and supportive
care with growth factors and transfusions.52 These
cytopenias are largely reversible, although, very
rarely, more aggressive intervention is needed
to rescue patients from persistent cytopenias.53
Presence of cytopenias might also have prognostic
significance, as one retrospective study found that
longer duration of cytopenias following CAR-T
infusion was associated with improved progression
free survival (PFS).54
Clinical experience
The CAR-T field has grown in recent years, and
there are now six FDA approved commercial CAR-T
products with eight indications (tables 2, 3fig 2).
The antigen target varies by disease type, but in
general, CD19 has been the main target of interest in
ALL and non-Hodgkin’s B cell lymphoma, and B cell
maturation antigen (BCMA) has been the main target
of interest in multiple myeloma. Other targets that
are currently being explored include CD22, CD30,
CD33, CD70, and CD123 for various hematologic
malignancies, and B7H3 and EGFR for solid tumors.
Here, we review the clinical experience of all the FDA
approved CAR-T products, as well as some products
in development.
Acute lymphoblastic leukemia
ALL is the most common malignancy in childhood
and the second most common acute leukemia in
adults. Prognosis varies by disease characteristics,
but relapsed and refractory disease invariably carries
a poor prognosis.55 Tisagenlecleucel (tisa-cel) was
the first CAR-T therapy to be approved in August
2017 by the FDA for patients up to 25 years with B
cell acute lymphoblastic leukemia (B-ALL) that is
refractory or in second or later relapse. Approval was
based on the ELIANA trial, a phase 2 multicenter,
single-cohort study of tisa-cel in pediatric/young
adult patients with CD19+ relapsed and/or refractory
(R/R) B-ALL. In the updated analysis of 75 patients
who received tisa-cel infusion, the overall remission
the bmj | BMJ 2022;378:e068956 | doi: 10.1136/bmj-2021-068956
Clinical Review
rate—complete remission or complete remission
BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
with incomplete hematologic recovery (CRi)—within
three months was 81%. All patients who achieved a
response were negative for minimal residual disease
(MRD) by flow cytometry, and median duration of
response was also not reached at a median follow-up
of 13.1 months. CRS and neurotoxicity of any grade
occurred in 77% and 40% of patients, respectively,
with 47% of patients requiring ICU management.
The median persistence of tisa-cel in the blood was
168 days, with persistence up to 20 months in some
patients; this is thought to be mediated by the 4-1BB
costimulatory domain.
Until very recently, commercial CAR-T therapy
for ALL was only available for the pediatric/young
adult population. However, in October 2021,
brexucabtagene autoleucel (brexu-cel) received FDA
approval for adult patients (≥18 years) with R/R B-ALL
based on the ZUMA-3 trial.56 Brexu-cel had previously
been approved for R/R MCL and consists of a CD19
antigen binding domain with a CD28 costimulatory
domain. It is like axi-cel, but includes an extra step
during manufacturing that removes circulating
CD19-expressing malignant cells to prevent possible
activation and exhaustion of the CAR-Ts during the ex
vivo manufacturing process. ZUMA-3 was a phase 2,
multicenter, single-arm study evaluating brexu-cel in
adult patients with R/R B-ALL, 44% of whom had prior
allogeneic stem cell transplant (SCT). Here, 55/71
enrolled patients received infusion with an overall
complete remission/CRi rate of 71%; 97% of responders
achieved MRD negativity. The median duration of
remission in ZUMA-3 was 12.8 months. This compares
favorably with historical data such as 4.6 months in
the INO-VATE trial (inotuzumab ozogamicin)57 and 7.3
months in the TOWER study (blinatumomab).58 Grade
3 or higher CRS and neurotoxicity occurred in 24% and
25% of patients, respectively. Most patients no longer
had detectable CAR-Ts by polymerase chain reaction
assay at six months.
Despite these advances, approximately 30-50%
of B-ALL will eventually relapse after CD-19 CAR-T
therapy. Thus, some advocate for consolidative
allogeneic SCT for patients who achieve an MRD-
negative remission after CAR-T therapy, especially
after the shorter duration CD28-based CAR-T
therapy. At the discretion of their treating physician,
9% of patients in ELIANA and 18% of patients in
ZUMA-3 went on to receive allogeneic SCT following
CAR-T therapy. Other promising strategies include
the development of CD22-directed CAR-Ts after the
failure of CD19-directed59 60 or sequential CD19/
CD22 CAR-T therapy.61 Close monitoring of MRD
status by traditional multicolor flow cytometry or
even higher sensitivity next generation sequencing
(10−6 level) can help predict relapse risk and allow
for earlier intervention.62
Non-Hodgkin’s lymphoma
Large B cell lymphoma (LBCL)
DLBCL is the most common subtype of NHL,
comprising approximately 25% of all cases, and
7
Clinical Review
30–40% of patients are refractory to or relapse
after frontline chemoimmunotherapy.63 For those
who remain refractory to salvage chemotherapy or
relapse after autologous SCT, CD19-directed CAR-T
therapy has revolutionized the treatment landscape.
Before the advent of CAR-T therapy, patients with R/R
DLBCL had limited options and continued to receive
chemotherapy, preceding the eventual demise of the
vast majority.64 65
Three FDA approved CD19 CAR-T therapies are
available for adult patients with R/R LBCL after
two or more lines of systemic therapy: axi-cel,
approved in 2017 based on the ZUMA-1 trial43; tisa-
cel, approved in 2018 based on the JULIET trial46;
and lisocabtagene maruleucel (liso-cel), approved
in 2021, based on the TRANSCEND trial.45 All are
approved for DLBCL not otherwise specified, high
grade B cell lymphoma (HGBL), and DLBCL arising
from follicular lymphoma; axi-cel and liso-cel are
additionally approved for primary mediastinal B
cell lymphoma (PMBCL). Key differences in these
products include choice of costimulatory domain,
which impacts CAR-T expansion kinetics and
subsequent rates of CRS/ICANS, and manufacturing
time/time to infusion (table 2, 3). CD28-costimulated
CAR-Ts demonstrate earlier and more rapid expansion
(leading to more CRS/ICANS), while 4-1BB-
costimulated CAR-Ts show longer persistence.66
Axi-cel utilizes a CD28 costimulatory domain while
tisa-cel and liso-cel have 4-1BB costimulatory
domains; liso-cel is also manufactured such that it
has a constant 1:1 ratio of CD8:CD4 CAR-Ts, which
improved expansion and activity in animal models.67
Initial overall response rates (ORR) and complete
remission rates in the three pivotal trials ranged
from 52% to 82% and 40% to 54%.42 45 46 Notably,
responses were consistent among high risk subgroups
including those with HGBL with myc and bcl2 and/or
bcl6 rearrangements (double/triple hit lymphomas),
or those with primary refractory disease. Although
cross-trial comparisons are difficult owing to the
different grading criteria used, axi-cel had the
highest rate of grade ≥3 neurotoxicity (28%) and
tisa-cel had the highest rate of grade ≥3 CRS (22%).
Several real world CAR-T studies of axi-cel and tisa-
cel since then have shown similarly impressive
efficacy and safety, including in patients who were
older and had more comorbidities than those in the
initial trials. With longer follow-up, the 1 and 2 year
PFS rates for these products have plateaued at 35-
44%, suggesting that a single infusion of CD19 CAR-
Ts can result in durable responses for approximately
40% of patients. However, consolidative allogeneic
SCT is currently not recommended for patients who
respond because of the high risk of transplant related
mortality and older age/increased comorbidities
of patients with LBCL compared with patients with
B-ALL.
More recently, these three CD19 CAR-T products
were also studied in the earlier, second-line setting
against standard-of-care salvage chemotherapy
followed by autologous SCT–axi-cel in ZUMA-7, tisa-
8
cel in BELINDA, and liso-cel in TRANSFORM.68 69 All
BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
three trials were multicenter phase 3 trials specifically
evaluating “high risk” patients with LBCL, defined
as primary refractory or relapsed within 12 months
of first line chemoimmunotherapy. Key differences
in these trials include type of bridging therapy
permitted, whether crossover was allowed, event-
free survival (EFS) definitions, and manufacturing
times for the CAR-T arms. ZUMA-7 met its primary
endpoint—axi-cel demonstrated superior EFS over
standard care (median EFS, 8.3 v 2.0 months,
respectively; hazard ratio for event or death, 0.4).68
Thus, axi-cel became the first CD19 CAR-T product to
also receive FDA approval in the second line setting
for adults with high risk LBCL. TRANSFORM also
met its primary endpoint of EFS at interim analysis,
with a median EFS of 10.1 months in the liso-cel
group versus 2.3 months in the standard care group.
This was a registrational study for FDA approval in
this setting. Interestingly, BELINDA did not meet its
primary endpoint, with the tisa-cel and standard
care groups having similar EFS (3.0 months in both
groups), overall survival, and response rates.69
Indolent NHL
CD19 CAR-T therapy has also been studied in indolent
NHL, including follicular lymphoma, marginal zone
lymphoma (MZL), and chronic lymphocytic leukemia/
small lymphocytic lymphoma (CLL/SLL). Axi-cel was
approved by the FDA in March 2021 for adult patients
with relapsed or refractory follicular lymphoma (R/R
FL) after two or more lines of systemic therapy, based
on the ZUMA-5 trial.70 This phase 2 trial included
124 patients with follicular lymphoma (grades 1–3a)
and 22 patients with MZL (nodal or extranodal) who
had relapsed or refractory disease after two or more
lines of therapy, with a median of three prior lines
of therapy. The ORR was an impressive 92% among
all efficacy-evaluable patients: 94% (80% complete
response) in the follicular lymphoma group and 85%
(60% complete response) in the MZL group. Median
duration of response has not yet been reached and
the estimated one year PFS was 72%. Grade ≥3
CRS and neurotoxicity occurred in 7% and 19%,
respectively.70 71 Tisa-cel was also studied in 98 adult
patients with R/R FL in the phase 2 ELARA trial. At
interim analysis, tisa-cel demonstrated an ORR of
86% and a complete response rate of 69%, meeting
its primary endpoint of complete response rate. There
were no cases of grade >3 CRS and only 3% grade >3
ICANS.72 An FDA approval for this indication is also
anticipated.
Although CLL/SLL was one of the first B cell
malignancies to be successfully treated with CD19
CAR-Ts,73 response rates in subsequent studies
have been considerably lower than those seen with
LBCLs and they have not yet been approved in this
setting. A phase 2 dose optimization study of CD19
CD3ζ/4-1BB CAR-Ts in 32 adult patients with R/R
CLL showed an ORR of 44% and a complete response
rate of 28%.74 Median PFS for the entire cohort was
only one month, but was 40.2 months for those
doi: 10.1136/bmj-2021-068956 | BMJ 2022;378:e068956 | the bmj

who achieved complete response. The suboptimal
response rates are thought to be in part due to T cell
dysfunction and immune suppression mediated by
the CLL cells. A small study of CD19 CAR-Ts with
concurrent ibrutinib demonstrated an ORR of 83%
(CR rate, 22%) and lower CRS severity compared
with patients who did not receive ibrutinib.75
Mantle cell lymphoma
MCL is a unique subtype of NHL which is usually
grouped with the indolent lymphomas, but can often
have a more aggressive disease course. ZUMA-2 was a
phase 2 multicenter trial of brexu-cel in patients with
R/R MCL who had previously received anthracycline
or bendamustine containing chemotherapy, an anti-
CD20 monoclonal antibody, and Bruton’s tyrosine
kinase (BTK) inhibitor therapy.76 In the 68 patients
who were infused, ORR was 93% with a CR rate of
67%. Estimated one year PFS was 61%. Almost
all patients developed CRS of any grade, but only
15% were grade ≥3, and 31% developed grade
≥3 neurotoxicity. Although the trial required all
patients to have previously been treated with BTK
inhibitor therapy, the FDA approved brexu-cel in July
2020 with the broader indication of just relapsed/
refractory MCL.
Multiple myeloma
Multiple myeloma is a neoplastic disorder of plasma
cells which accounts for approximately 10% of
all hematologic malignancies and predominantly
affects older adults (median age of diagnosis, 65-
74). Although multiple myeloma is still considered
incurable, the number of new therapies available
has increased over the past decade, which has
extended the median survival of affected patients.
However, a small subset of patients remains relapsed
or refractory despite these new classes of drugs, for
whom CAR-T therapy might be viable. BCMA is almost
universally expressed in both normal and malignant
plasma cells and thus has become the main antigen
target of interest in CAR-T therapy.77 78 Multiple
BCMA CAR-T constructs are under investigation, with
just one approved thus far.
Idecabtagene vicleucel (ide-cel) became the first
FDA approved CAR-T product for multiple myeloma
in March 2021, with the indication of relapsed or
refractory disease after four or more prior lines of
therapy, including an immunomodulatory agent,
proteasome inhibitor, and anti-CD38 monoclonal
antibody. Approval was based on the phase
2 multicenter KarMMA trial of adult patients
with relapsed or refractory multiple myeloma,
who had received a median of six prior lines of
therapy (including an immunomodulatory agent,
proteasome inhibitor, and anti-CD38 monoclonal
antibody).79 Among the 128 infused patients, 73%
achieved the primary endpoint of overall response
(partial response or better), with 33% achieving
complete response or better. Responses remained
high in subgroups with aggressive disease, including
high risk cytogenetic abnormalities, triple- or penta-
the bmj | BMJ 2022;378:e068956 | doi: 10.1136/bmj-2021-068956
Clinical Review
refractory disease, and extramedullary disease.
BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
Median estimated PFS was 8.8 months. Most patients
(84%) developed CRS, but only 5% were grade ≥3.
Neurotoxicity was uncommon.
Ciltacabtagene autoleucel (cilta-cel) is another
promising BCMA-directed CAR-T therapy which
expresses two BCMA-targeting single-domain
antibodies to increase avidity. Cilta-cel was studied
in the phase 1 LEGEND-2 trial in China80 and in the
phase 1/2 multicenter CARTITUDE-1 trial in the
US.81 Patients in CARTITUDE-1 were also heavily
pretreated, with 88% triple-class refractory. Among
the 97 infused patients, the ORR was 97% and 67%
achieved stringent complete response. Notably, at a
median follow-up of 12.4 months, median duration
of response and PFS had not yet been reached. CRS of
any grade occurred in 95% of patients, but only 5%
were grade ≥3. Cilta-cel was granted FDA approval in
February 2022, with a similar indication of relapsed/
refractory multiple myeloma after four or more prior
lines of therapy.
Other malignancies
Given the wide success of CAR-Ts in non-Hodgkin’s
lymphoma and B-ALL, CAR-T therapies are also being
explored with great interest in other hematologic
malignancies and solid tumors (table 4). Relapsed or
refractory acute myeloid leukemia (AML) represents
an area of unmet need, as many patients are either
not eligible for curative allogeneic SCT or still relapse
following SCT. However, finding an ideal target
antigen in AML has been challenging, as many of the
myeloid antigens expressed on malignant leukemia
cells are also expressed on normal hematopoietic
stem/progenitor cells (HSPCs), which could result
in profound myeloablation if targeted. Nonetheless,
clinical trials that target various markers are
ongoing, including CD33, CD123, and C-type lectin-
like molecule-1 (CLL-1). While CD33 and CD123 are
also expressed by healthy HSPCs, CLL-1 expression
is more restricted to AML blasts/leukemia stem cells
and monocytes.82 83 Additionally, CAR-T therapy
targeting CD30 is also under investigation for CD30-
expressing hematologic malignancies such as
Hodgkin’s lymphoma and various T cell lymphomas.
Two parallel phase 1/2 trials evaluated anti-CD30
CAR-T therapy in 41 patients with relapsed or
refractory Hodgkin’s lymphoma who had received
a median of seven prior lines of therapy including
brentuximab vedotin and immune checkpoint
inhibitors.84 The ORR was 62% with a CR rate of
51% for all patients, and even better at 79%/59%
for those who received fludarabine-based rather
than bendamustine-based lymphodepletion. CRS
(all grade 1) was observed in 24% and no patients
experienced neurotoxicity.
AML=acute myeloid lymphoma; CNS=central
nervous system; NHL=non-Hodgkin’s lymphoma.
CAR-T therapy has also been studied in solid tumor
malignancies during the past decade, although
these efforts have been met with considerably more
roadblocks and very few complete responses.85 86
9
Clinical Review

Table 4 | Summary of selected ongoing clinical trials investigating CAR-T therapy for other malignancies in the US

BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
ClinicalTrials.gov
Antigen Disease CAR type Study name Phase identifier
Hematologic
CLL-1 AML Autologous Study Evaluating the Safety of KITE-222 in Participants 1 NCT04789408
With Relapsed/Refractory Acute Myeloid Leukemia
AML Autologous Chimeric Antigen Receptor T-cells for The Treatment of AML 1 NCT04219163
Expressing CLL-1 Antigen
CD30 Hodgkin lymphoma Autologous Phase 2 Study Evaluating Autologous CD30.CAR-T Cells 2 NCT04268706
in Patients with Relapsed/Refractory Hodgkin Lymphoma
(CHARIOT)
NHL Autologous Phase 1 Study of Autologous CD30.CAR-T in Relapsed 1 NCT04526834
or Refractory CD30 Positive Non-Hodgkin Lymphoma
(CERTAIN)
CD33 AML Autologous Study of Anti-CD33 Chimeric Antigen Receptor-Expressing ½ NCT03971799
T Cells (CD33CART) in Children and Young Adults with
Relapsed/Refractory Acute Myeloid Leukemia
CD70 B/T-cell malignancies Allogeneic A Safety and Efficacy Study Evaluating CTX130 in Subjects 1 NCT04502446
with Relapsed or Refractory T or B Cell Malignancies
(COBALT-LYM)
CD123 AML Allogeneic Study Evaluating Safety and Efficacy of UCART123 1 NCT03190278
in Patients with Relapsed/ Refractory Acute Myeloid
Leukemia (AMELI-01)
Solid tumor
B7H3 Various non-CNS tumors Autologous B7H3 CAR-T Cell Immunotherapy for Recurrent/Refractory 1 NCT04483778
Solid Tumors in Children and Young Adults
CD171 Neuroblastoma Autologous Engineered Neuroblastoma Cellular Immunotherapy 1 NCT02311621
(ENCIT)-01
EGFR Various non-CNS tumors Autologous EGFR806 CAR-T Cell Immunotherapy for Recurrent/ 1 NCT03618381
Refractory Solid Tumors in Children and Young Adults
GD2 Various including neuroblastoma, Autologous C7R-GD2.CART Cells for Patients with Relapsed or 1 NCT03635632
osteosarcoma, uveal melanoma Refractory Neuroblastoma and Other GD2 Positive Cancers
(GAIL-N)
GPC3 Hepatocellular cancer Autologous Glypican 3-specific Chimeric Antigen Receptor Expressing T 1 NCT02905188
Cells for Hepatocellular Carcinoma (GLYCAR)
HER2 Various HER2+ cancers Autologous Safety and Activity Study of HER2-Targeted Dual Switch 1 NCT04650451
CAR-T Cells (BPX-603) in Subjects with HER2-Positive Solid
Tumors
IL-13Rα2 Melanoma Autologous Gene Modified Immune Cells (IL13Ralpha2 CAR-T Cells) 1 NCT04119024
After Conditioning Regimen for the Treatment of Stage IIIC
or IV Melanoma
Mesothelin Various including lung, ovarian, Autologous CAR-T Cells in Mesothelin Expressing Cancers 1 NCT03054298
mesothelioma
PSCA Prostate cancer Autologous PSCA-CAR-T Cells in Treating Patients With PSCA+ 1 NCT03873805
Metastatic Castration Resistant Prostate Cancer
PSMA Prostate cancer Autologous P-PSMA-101 CAR-T Cells in the Treatment of Subjects with 1 NCT04249947
Metastatic Castration-Resistant Prostate Cancer (mCRPC)

The main challenges include lack of a ubiquitous
target antigen within each tumor type, difficulty
with CAR-T trafficking to the main tumor sites,
and an immunosuppressive microenvironment
induced by the tumors. Earlier trials in glioblastoma
targeting epidermal growth factor receptor variant
III (EGFRvIII) failed to achieve any responses better
than stable disease, and although CAR-T trafficking
to the tumor site was demonstrated, there was also
increased expression of inhibitory molecules and
regulatory T cells in the tumor microenvironment
following CAR-T infusion.87 88 An earlier trial
targeting carcinoembryonic antigen (CEACAM5)
in gastrointestinal malignancies also highlighted
potential issues with “on-target/off-tissue” toxicity,
as several patients in dose cohort 4 experienced
acute respiratory distress thought to be due to
CAR-T trafficking to areas of CEACAM5 expression
on lung epithelial cells.89 Newer generations of
CAR-Ts are attempting to tackle some of these
issues by modulating antigen affinity, providing
additional signals for CAR-T activation/expansion,
or counteracting the immunosuppressive tumor
microenvironment with combination PD-1/PD-L1
blockade.86Table 4 lists select ongoing clinical trials
targeting various antigens, including B7H3, CD171,
EGFR, GD2, GPC3, HER2, IL-13Rα2, mesothelin,
PSCA, and PSMA.
Guidelines
Given that this treatment encompasses a new
family of “living drugs” with varying properties
and indications, formulating consensus guidelines
remains a challenge. Many decision points required
during therapy lack high quality evidence for
guidance. For assessment of candidacy, clinicians
initially relied on the inclusion and exclusion
criteria for each individual registrational study.
However, it is now clear that most patients do
not fit into those categories; a real world update
showed that approximately half of the patients
treated at several referral centers did not meet

10 doi: 10.1136/bmj-2021-068956 | BMJ 2022;378:e068956 | the bmj


6SHFLƟFLW\IRUDQWLJHQ
$DQG%
KHWHURGLPHUL]LQJ
GRPDLQ
7FHOO
&'DFWLYDWLRQ
GRPDLQ
7UDQVPHPEUDQH
'XDOWDUJHWLQJ&$5V FRVWLPXODWRU\
UHFHSWRU
6HFUHWHG
F\WRNLQHV
7FHOO
ţ$UPRXUHGŤ&$5V
Fig 4 | Examples of novel strategies to improve CAR-T therapy efficacy and toxicity. CAR=chimeric antigen receptor
those criteria. The consensus is that most patients
require adequate organ function and reserve, mainly
cardiac, pulmonary, hepatic and renal, to be able to
safely withstand lymphodepleting chemotherapy
and survive an episode of sepsis with standard
supportive measures; however, exact cut offs are still
challenging and depend on the risk and benefit of
each individual situation.
Guidelines for grading and treating adverse events
of special interest of CAR-Ts, namely CRS and ICANS,
appeared with the first approved CAR-T to guide
investigators.90 However, with subsequent CAR-Ts,
it was apparent that no one size fits all, as certain
cell products have markedly different kinetics of
efficacy and toxicity and thus require interventions
at different time points. There was a time when it was
challenging for clinicians to adhere to several different
toxicity management guidelines. The ASTCT therefore
sponsored consensus guidelines that function across
products and disease states, address severity of
symptoms, and are easy to remember and follow.29
Emerging treatments and challenges
CAR-T therapy is still only in its infancy and many
opportunities lie ahead in improving efficacy and
reducing toxicities. Most current CAR-T models are
limited by sensitivity when target antigen density
is low (through mechanisms such as trogocytosis),
contributing to tumor antigen escape or primary
the bmj | BMJ 2022;378:e068956 | doi: 10.1136/bmj-2021-068956
Clinical Review
2)) 21
BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
6PDOO
PROHFXOH
7FHOO 7FHOO
ţ6ZLWFKDEOHŤ&$57SODWIRUPV
resistance.12 Methods being studied to improve
efficacy include better transduction systems such
as the Sleeping Beauty transposon/transposase
system and increasing CAR-T persistence via
additional costimulatory domains, “armored” CARs
with constitutive cytokine secretion,91 deepened
lymphodepletion regimens before CAR-T treatment,
and combination with checkpoint blockade to
reverse T cell exhaustion. Dual target CARs targeting
two antigens to overcome loss or down regulation
of one target antigen are also being developed,
primarily targeting CD19/CD2292-94 or CD19/CD20.
Methods being studied to mitigate toxicity (primary
CRS/ICANS) include switchable CAR-T platforms
incorporating a small molecule “on-off switch”
(CALIBR and UniCAR)95 96 and improved prophylaxis
strategies (fig 4).97
Additionally, given that a subset of patients has
such aggressive disease that they cannot wait the
three to four weeks it takes for their autologous
CAR-T product to be manufactured, multiple
allogeneic CAR-T products are also in development.
The T cells are largely derived from peripheral blood
mononuclear cells of healthy donors and engineered
using gene editing (such as the CRISPR-Cas9 system)
targeting the T cell receptor α constant (TRAC)
locus.98-100 The allogeneic CAR approach allows the
manufactured cells to be available immediately (ie,
“off the shelf”) and potentially used for multiple
11
Clinical Review
recipients, leading to decreased implementation
and manufacturing costs.101 However, preventing
graft-versus-host-disease or rapid clearance of the
allogeneic cells by the host immune system are two
ongoing challenges in this field.
Finally, cost of CAR-T infusion and equitable
access to these lifesaving therapies remain ongoing
issues. Many possible barriers to CAR-T referral and
utilization exist, including high costs and inadequate
reimbursement, geographic access, caregiver
availability, manufacturing issues, and patient/
disease-specific factors.102 The majority of patients
with DLBCL are treated at community oncology
centers, but CAR-T therapy can currently only be
performed at specialized transplant centers with FACT
accreditation owing to potential for serious toxicities.
At present fewer than 100 centers in the US are FACT
certified, so distance to a treatment center may limit
CAR-T access for some patients. Additionally, the high
cost of these products—$375 000-475 000 per dose—
and reimbursement challenges are likely prohibitive
for many who would otherwise be eligible.102 103
Recognizing these disparities and specific barriers
for each patient will be the first step in improving
access to CAR-T therapy.
Research questions
• What are the mechanisms of tumor escape in patients
who do not respond to CAR-T therapy?
• What is the pathophysiology behind the toxicities
seen with CAR-T therapy; how do we risk stratify
patients and pre-empt toxicities?
• What is the pathophysiology behind prolonged
cytopenias seen after CAR-T therapy?
• Who are the best candidates for CAR-T therapy?
• How can we design the “best” CAR-Ts to combine
affordable, quick, and reliable mass production with
excellent safety and efficacy?
Contributors: JEM, MH, and NEJ prepared and reviewed the
manuscript, and approved the final version.
Patient involvement: No patients were directly involved in the
creation of this article.
Competing interests: We have read and understood the BMJ policy
on declaration of interests and declare the following interests: none.
Provenance and peer review: Commissioned; externally peer
reviewed.
1  Burnet M. Cancer; a biological approach. I. The processes of control.
Br Med J 1957;1:779-86. doi:10.1136/bmj.1.5022.779  clinical outcomes in NHL. Blood 2018;132:804-14. doi:10.1182/
2  Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effect
of graft-versus-host disease in human recipients of allogeneic-
marrow grafts. N Engl J Med 1979;300:1068-73. doi:10.1056/
NEJM197905103001902  Nat Rev Immunol 2022;22:85-96. doi:10.1038/s41577-021-
3  Kolb HJ, Mittermüller J, Clemm C, et al. Donor leukocyte transfusions
for treatment of recurrent chronic myelogenous leukemia in marrow
transplant patients. Blood 1990;76:2462-5. doi:10.1182/blood.
V76.12.2462.2462  beha.2017.09.002
4  Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-
infiltrating lymphocytes and interleukin-2 in the immunotherapy of
patients with metastatic melanoma. A preliminary report. N Engl J
Med 1988;319:1676-80. doi:10.1056/NEJM198812223192527  for cytokine release syndrome and neurologic toxicity associated with
5  June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J
Med 2018;379:64-73. doi:10.1056/NEJMra1706169  38. doi:10.1016/j.bbmt.2018.12.758
6  Robbins PF, Kassim SH, Tran TL, et al. A pilot trial using lymphocytes
genetically engineered with an NY-ESO-1-reactive T-cell receptor:
long-term follow-up and correlates with response. Clin Cancer
Res 2015;21:1019-27. doi:10.1158/1078-0432.CCR-14-2708  aau5907
12
7  Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. Human
T-lymphocyte cytotoxicity and proliferation directed by a single
BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
chimeric TCRzeta /CD28 receptor. Nat Biotechnol 2002;20:70-5.
doi:10.1038/nbt0102-70 
8  Imai C, Mihara K, Andreansky M, et al. Chimeric receptors with
4-1BB signaling capacity provoke potent cytotoxicity against acute
lymphoblastic leukemia. Leukemia 2004;18:676-84. doi:10.1038/
sj.leu.2403302 
9  Jensen MC, Riddell SR. Designing chimeric antigen receptors to
effectively and safely target tumors. Curr Opin Immunol 2015;33:9-
15. doi:10.1016/j.coi.2015.01.002 
10  Finn OJ. Cancer immunology. N Engl J Med 2008;358:2704-15.
doi:10.1056/NEJMra072739 
11  Anderson KC, Bates MP, Slaughenhoupt BL, Pinkus GS, Schlossman
SF, Nadler LM. Expression of human B cell-associated antigens on
leukemias and lymphomas: a model of human B cell differentiation.
Blood 1984;63:1424-33. doi:10.1182/blood.V63.6.1424.1424 
12  LeBien TW, Tedder TF. B lymphocytes: how they develop and function.
Blood 2008;112:1570-80. doi:10.1182/blood-2008-02-078071 
13  Brentjens RJ, Latouche J-B, Santos E, et al. Eradication of systemic
B-cell tumors by genetically targeted human T lymphocytes co-
stimulated by CD80 and interleukin-15. Nat Med 2003;9:279-86.
doi:10.1038/nm827 
14  Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage
cells and regression of lymphoma in a patient treated with
autologous T cells genetically engineered to recognize CD19.
Blood 2010;116:4099-102. doi:10.1182/blood-2010-04-281931 
15  Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen
receptor-modified T cells in chronic lymphoid leukemia. N Engl J
Med 2011;365:725-33. doi:10.1056/NEJMoa1103849 
16  Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-
modified T cells for acute lymphoid leukemia. N Engl J
Med 2013;368:1509-18. doi:10.1056/NEJMoa1215134 
17  Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly
induce molecular remissions in adults with chemotherapy-refractory
acute lymphoblastic leukemia. Sci Transl Med 2013;5:177ra38.
doi:10.1126/scitranslmed.3005930 
18  Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion
and remissions of malignancy along with cytokine-associated
toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-
transduced T cells. Blood 2012;119:2709-20. doi:10.1182/
blood-2011-10-384388 
19  Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and
adolescent cancer statistics, 2014. CA Cancer J Clin 2014;64:83-
103. doi:10.3322/caac.21219 
20  Dores GM, Devesa SS, Curtis RE, Linet MS, Morton LM. Acute
leukemia incidence and patient survival among children and
adults in the United States, 2001-2007. Blood 2012;119:34-43.
doi:10.1182/blood-2011-04-347872 
21  SEER*Explorer Application.
22  Moskop, A, Hu ZH, Pasquini MC. Current uses of CAR T cell Therapies
in the US: CIDR summary slides, 2020.
23  Maus MV, Nikiforow S. The why, what, and how of the new
FACT standards for immune effector cells. J Immunother Cancer
2017;5:36, s40425-017-0239-0.
24  Locke FL, Ghobadi A, Lekakis LJ, et al. Outcomes by prior lines of
therapy (LoT) in ZUMA-1, the pivotal phase 2 study of axicabtagene
ciloleucel (Axi-Cel) in patients (Pts) with refractory large B cell
lymphoma. J Clin Oncol 2018;36(suppl 15):3039. doi:10.1200/
JCO.2018.36.15_suppl.3039.
25  Locke FL, Rossi JM, Neelapu SS, et al. Tumor burden, inflammation,
and product attributes determine outcomes of axicabtagene
ciloleucel in large B-cell lymphoma. Blood Adv 2020;4:4898-911.
doi:10.1182/bloodadvances.2020002394 
26  Rossi J, Paczkowski P, Shen Y-W, et al. Preinfusion polyfunctional
anti-CD19 chimeric antigen receptor T cells are associated with
blood-2018-01-828343 
27  Morris EC, Neelapu SS, Giavridis T, Sadelain M. Cytokine release
syndrome and associated neurotoxicity in cancer immunotherapy.
00547-6 
28  Frey N. Cytokine release syndrome: Who is at risk and how to treat.
Best Pract Res Clin Haematol 2017;30:336-40. doi:10.1016/j.
 
29  Fajgenbaum DC, June CH. Cytokine Storm. N Engl J
Med 2020;383:2255-73. doi:10.1056/NEJMra2026131 
30  Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading
immune effector cells. Biol Blood Marrow Transplant 2019;25:625-
 
31  Mestermann K, Giavridis T, Weber J, et al. The tyrosine kinase inhibitor
dasatinib acts as a pharmacologic on/off switch for CAR T cells.
Sci Transl Med 2019;11:eaau5907. doi:10.1126/scitranslmed.
 
doi: 10.1136/bmj-2021-068956 | BMJ 2022;378:e068956 | the bmj
 Clinical Review

32  Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli 53  Wang L, Hong R, Zhou L, et al. New-onset severe cytopenia after
A, Sadelain M. CAR T cell-induced cytokine release syndrome CAR-T cell therapy: analysis of 76 patients with relapsed or refractory

BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
is mediated by macrophages and abated by IL-1 blockade. Nat acute lymphoblastic leukemia. Front Oncol 2021;11:702644.
Med 2018;24:731-8. doi:10.1038/s41591-018-0041-7  doi:10.3389/fonc.2021.702644 
33  Strati P, Ahmed S, Kebriaei P, et al. Clinical efficacy of anakinra 54  Gödel P, Sieg N, Heger J-M, et al. Hematologic rescue
to mitigate CAR T-cell therapy-associated toxicity in large of CAR T-cell–mediated prolonged pancytopenia using
B-cell lymphoma. Blood Adv 2020;4:3123-7. doi:10.1182/ autologous peripheral blood hematopoietic stem cells in a
bloodadvances.2020002328  lymphoma patient. Hemasphere 2021;5:e545. doi:10.1097/
34  Maakaron J, Penza S, El Boghdadly Z, et al. Procalcitonin as a HS9.0000000000000545 
potential biomarker for differentiating bacterial infectious fevers 55  Schaefer A, Huang Y, Kittai A, et al. Cytopenias after CD19 chimeric
from cytokine release syndrome. Blood 2018;132(suppl 1):4216. antigen receptor T-cells (CAR-T) therapy for diffuse large b-cell
doi:10.1182/blood-2018-99-120065. lymphomas or transformed follicular lymphoma: a single institution
35  Hines MR, Keenan C, Maron Alfaro G, et al. Hemophagocytic experience. Cancer Manag Res 2021;13:8901-6. doi:10.2147/
lymphohistiocytosis-like toxicity (carHLH) after CD19-specific CAR CMAR.S321202 
T-cell therapy. Br J Haematol 2021;194:701-7. doi:10.1111/ 56  Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children
bjh.17662  and young adults with B-cell lymphoblastic leukemia. N Engl J
36  Sandler RD, Tattersall RS, Schoemans H, et al. Diagnosis and Med 2018;378:439-48. doi:10.1056/NEJMoa1709866 
management of secondary HLH/MAS following HSCT and CAR-T cell 57  Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or
therapy in adults; a review of the literature and a survey of practice refractory adult B-cell acute lymphoblastic leukaemia: phase 2
within EBMT centres on behalf of the Autoimmune Diseases Working results of the single-arm, open-label, multicentre ZUMA-3 study.
Party (ADWP) and Transplant Complications Working Party (TCWP). Lancet 2021;398:491-502. doi:10.1016/S0140-6736(21)01222-
Front Immunol 2020;11:524. doi:10.3389/fimmu.2020.00524  8 
37  Gust J, Taraseviciute A, Turtle CJ. Neurotoxicity associated with 58  Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab
CD19-targeted CAR-T cell therapies. CNS Drugs 2018;32:1091-101. ozogamicin versus standard therapy for acute lymphoblastic
doi:10.1007/s40263-018-0582-9  leukemia. N Engl J Med 2016;375:740-53. doi:10.1056/
38  Mackall CL, Miklos DB. CNS Endothelial cell activation emerges NEJMoa1509277 
as a driver of CAR T Cell-associated neurotoxicity. Cancer 59  Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus
Discov 2017;7:1371-3. doi:10.1158/2159-8290.CD-17-1084  chemotherapy for advanced acute lymphoblastic leukemia. N Engl J
39  Sumransub N, El Jurdi N, Chiraphapphaiboon W, Maakaron JE. Med 2017;376:836-47. doi:10.1056/NEJMoa1609783 
Putting function back in dysfunction: Endothelial diseases and 60  Baird JH, Frank MJ, Craig J, et al. CD22-directed CAR T-cell
current therapies in hematopoietic stem cell transplantation and therapy mediates durable complete responses in adults with
cellular therapies. Blood Rev 2022;51:100883. doi:10.1016/j. relapsed or refractory large B-cell lymphoma after failure of
blre.2021.100883  CD19-directed CAR T-cell therapy and high response rates in
40  Ruark J, Mullane E, Cleary N, et al. Patient-reported neuropsychiatric adults with relapsed or refractory B-cell acute lymphoblastic
outcomes of long-term survivors after chimeric antigen receptor leukemia. Blood 2020;136(suppl 1):28-9. doi:10.1182/
T cell therapy. Biol Blood Marrow Transplant 2020;26:34-43. blood-2020-139087.
doi:10.1016/j.bbmt.2019.09.037  61  Adeel K, Fergusson NJ, Shorr R, Atkins H, Hay KA. Efficacy and safety
41  Wudhikarn K, Palomba ML, Pennisi M, et al. Infection during the first of CD22 chimeric antigen receptor (CAR) T cell therapy in patients
year in patients treated with CD19 CAR T cells for diffuse large B cell with B cell malignancies: a protocol for a systematic review and
lymphoma. Blood Cancer J 2020;10:79. doi:10.1038/s41408-020- meta-analysis. Syst Rev 2021;10:35. doi:10.1186/s13643-021-
00346-7  01588-7 
42  Baird JH, Epstein DJ, Tamaresis JS, et al. Immune reconstitution and 62  Liu S, Deng B, Yin Z, et al. Combination of CD19 and CD22 CAR-T
infectious complications following axicabtagene ciloleucel therapy cell therapy in relapsed B-cell acute lymphoblastic leukemia
for large B-cell lymphoma. Blood Adv 2021;5:143-55. doi:10.1182/ after allogeneic transplantation. Am J Hematol 2021;96:671-9.
bloodadvances.2020002732  doi:10.1002/ajh.26160 
43  Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel 63  Pulsipher MA, Han X, Maude SL, et al. Next-generation sequencing of
CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J minimal residual disease for predicting relapse after tisagenlecleucel
Med 2017;377:2531-44. doi:10.1056/NEJMoa1707447  in children and young adults with acute lymphoblastic leukemia.
44  Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and Blood Cancer Discov 2022;3:66-81. doi:10.1158/2643-3230.BCD-
activity of axicabtagene ciloleucel in refractory large B-cell lymphoma 21-0095 
(ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet 64  Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing
Oncol 2019;20:31-42. doi:10.1016/S1470-2045(18)30864-7  outcome in the context of clinical and biologic heterogeneity.
45  Jacobson CA, Hunter BD, Redd R, et al. Axicabtagene ciloleucel in the Blood 2015;125:22-32. doi:10.1182/blood-2014-05-577189 
non-trial setting: outcomes and correlates of response, resistance, 65  Friedberg JW. Relapsed/refractory diffuse large B-cell lymphoma.
and toxicity. J Clin Oncol 2020;38:3095-106. doi:10.1200/ Hematology Am Soc Hematol Educ Program 2011;2011:498-505.
JCO.19.02103  doi:10.1182/asheducation-2011.1.498 
46  Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene 66  Seshadri T, Stakiw J, Pintilie M, Keating A, Crump M, Kuruvilla
maraleucel for patients with relapsed or refractory large B-cell J. Utility of subsequent conventional dose chemotherapy in
lymphomas (TRANSCEND NHL 001): a multicentre seamless relapsed/refractory transplant-eligible patients with diffuse large
design study. Lancet 2020;396:839-52. doi:10.1016/S0140- B-cell lymphoma failing platinum-based salvage chemotherapy.
6736(20)31366-0  Hematology 2008;13:261-6. doi:10.1179/102453308X343527 
47  Schuster SJ, Bishop MR, Tam CS, et al, JULIET Investigators. 67  Zhao Z, Condomines M, van der Stegen SJC, et al. Structural design
Tisagenlecleucel in adult relapsed or refractory diffuse large of engineered costimulation determines tumor rejection kinetics
B-cell lymphoma. N Engl J Med 2019;380:45-56. doi:10.1056/ and persistence of CAR T cells. Cancer Cell 2015;28:415-28.
NEJMoa1804980  doi:10.1016/j.ccell.2015.09.004 
48  Schaefer A, Saygin C, Maakaron J, et al. Cytopenias after chimeric 68  Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-care axicabtagene
antigen receptor T-cells (CAR-T) infusion; patterns and outcomes. ciloleucel for relapsed or refractory large B-cell lymphoma:
Biol Blood Marrow Transplant 2019;25:S171. doi:10.1016/j. results from the US lymphoma CAR T consortium. J Clin
bbmt.2018.12.311. Oncol 2020;38:3119-28. doi:10.1200/JCO.19.02104 
49  Fried S, Avigdor A, Bielorai B, et al. Early and late hematologic toxicity 69  Locke FL, Miklos DB, Jacobson CA, et al, All ZUMA-7 Investigators and
following CD19 CAR-T cells. Bone Marrow Transplant 2019;54:1643- Contributing Kite Members. Axicabtagene ciloleucel as second-line
50. doi:10.1038/s41409-019-0487-3  therapy for large B-cell lymphoma. N Engl J Med 2022;386:640-54.
50  Strati P, Adkins S, Nastoupil LJ, et al. Hematopoietic recovery doi:10.1056/NEJMoa2116133 
and immune reconstitution after axi-cel CAR T-cell therapy in 70  Bishop MR, Dickinson M, Purtill D, et al. Second-line tisagenlecleucel
patients with relapsed/refractory large B-cell lymphoma. J Clin or standard care in aggressive B-cell lymphoma. N Engl J
Oncol 2019;37(suppl 15):7545. doi:10.1200/JCO.2019.37.15_ Med 2022;386:629-39. doi:10.1056/NEJMoa2116596 
suppl.7545. 71  Jacobson C, Chavez JC, Sehgal AR, et al. Primary analysis of
51  Nahas GR, Komanduri KV, Pereira D, et al. Incidence and risk factors zuma-5: a phase 2 study of axicabtagene ciloleucel (Axi-Cel) in
associated with a syndrome of persistent cytopenias after CAR-T cell patients with relapsed/refractory (R/R) indolent non-hodgkin
therapy (PCTT). Leuk Lymphoma 2020;61:940-3. doi:10.1080/104 lymphoma (iNHL). Blood 2020;136(suppl 1):40-1. doi:10.1182/
28194.2019.1697814  blood-2020-136834.
52  Rejeski K, Perez A, Sesques P, et al. CAR-HEMATOTOX: a model for 72  Jacobson CA, Chavez JC, Sehgal AR, et al. Axicabtagene ciloleucel in
CAR T-cell-related hematologic toxicity in relapsed/refractory large relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a
B-cell lymphoma. Blood 2021;138:2499-513. doi:10.1182/ single-arm, multicentre, phase 2 trial. Lancet Oncol 2022;23:91-103.
blood.2020010543  doi:10.1016/S1470-2045(21)00591-X 

the bmj | BMJ 2022;378:e068956 | doi: 10.1136/bmj-2021-068956 13

Clinical Review

73  Fowler NH, Dickinson M, Dreyling M, et al. Tisagenlecleucel in adult 90  Thistlethwaite FC, Gilham DE, Guest RD, et al. The clinical efficacy
relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. of first-generation carcinoembryonic antigen (CEACAM5)-specific

BMJ: first published as 10.1136/bmj-2021-068956 on 31 August 2022. Downloaded from http://www.bmj.com/ on 28 May 2023 by guest. Protected by copyright.
Nat Med 2022;28:325-32. doi:10.1038/s41591-021-01622-0  CAR T cells is limited by poor persistence and transient pre-
74  Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen conditioning-dependent respiratory toxicity. Cancer Immunol
receptor-modified T cells in chronic lymphoid leukemia. N Engl J Immunother 2017;66:1425-36. doi:10.1007/s00262-017-2034-7 
Med 2011;365:725-33. doi:10.1056/NEJMoa1103849  91  Kebriaei P, Singh H, Huls MH, et al. Phase I trials using
75  Frey NV, Gill S, Hexner EO, et al. Long-term outcomes from a Sleeping Beauty to generate CD19-specific CAR T cells. J Clin
randomized dose optimization study of chimeric antigen receptor Invest 2016;126:3363-76. doi:10.1172/JCI86721 
modified T cells in relapsed chronic lymphocytic leukemia. J Clin 92  Cao Y, Xiao Y, Wang N, et al. CD19/CD22 chimeric antigen receptor T
Oncol 2020;38:2862-71. doi:10.1200/JCO.19.03237  cell cocktail therapy following autologous transplantation in patients
76  Gauthier J, Hirayama AV, Purushe J, et al. Feasibility and efficacy with relapsed/refractory aggressive B cell lymphomas. Transplant Cell
of CD19-targeted CAR T cells with concurrent ibrutinib for CLL Ther 2021;27:910-11. doi:10.1016/j.jtct.2021.08.012 
after ibrutinib failure. Blood 2020;135:1650-60. doi:10.1182/ 93  Spiegel JY, Patel S, Muffly L, et al. CAR T cells with dual targeting
blood.2019002936  of CD19 and CD22 in adult patients with recurrent or refractory
77  Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed B cell malignancies: a phase 1 trial. Nat Med 2021;27:1419-31.
or refractory mantle-cell lymphoma. N Engl J Med 2020;382:1331- doi:10.1038/s41591-021-01436-0 
42. doi:10.1056/NEJMoa1914347  94  Zhou X, Ge T, Li T, et al. CAR19/22 T cell therapy in adult refractory
78  O’Connor BP, Raman VS, Erickson LD, et al. BCMA is essential Burkitt’s lymphoma. Cancer Immunol Immunother 2021;70:2379-
for the survival of long-lived bone marrow plasma cells. J Exp 84. doi:10.1007/s00262-021-02850-6 
Med 2004;199:91-8. doi:10.1084/jem.20031330  95  Viaud S, Ma JSY, Hardy IR, et al. Switchable control over in vivo CAR T
79  Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation expansion, B cell depletion, and induction of memory. Proc Natl Acad
antigen is a promising target for adoptive T-cell therapy of multiple Sci U S A 2018;115:E10898-906. doi:10.1073/pnas.1810060115 
myeloma. Clin Cancer Res 2013;19:2048-60. doi:10.1158/1078- 96  Wermke M, Kraus S, Ehninger A, et al. Proof of concept for a rapidly
0432.CCR-12-2422  switchable universal CAR-T platform with UniCAR-T-CD123 in
80  Munshi NC, Anderson LDJr, Shah N, et al. Idecabtagene relapsed/refractory AML. Blood 2021;137:3145-8. doi:10.1182/
vicleucel in relapsed and refractory multiple myeloma. N Engl J blood.2020009759 
Med 2021;384:705-16. doi:10.1056/NEJMoa2024850  97  Ahmed N, Caimi P, Reese JS, et al. Prophylactic tocilizumab in
81  Zhao W-H, Liu J, Wang B-Y, et al. A phase 1, open-label study of LCAR- patients with relapsed refractory lymphoma treated with anti
B38M, a chimeric antigen receptor T cell therapy directed against CD19 chimeric antigen receptor T-cell therapy. Biol Blood Marrow
B cell maturation antigen, in patients with relapsed or refractory Transplant 2020;26:S275-6. doi:10.1016/j.bbmt.2019.12.447.
multiple myeloma. J Hematol Oncol 2018;11:141. doi:10.1186/ 98  Ren J, Zhang X, Liu X, et al. A versatile system for rapid multiplex
s13045-018-0681-6  genome-edited CAR T cell generation. Oncotarget 2017;8:17002-11.
82  Mardiana S, Gill S. CAR T cells for acute myeloid leukemia: state of the doi:10.18632/oncotarget.15218 
art and future directions. Front Oncol 2020;10:697. doi:10.3389/ 99  Razeghian E, Nasution MKM, Rahman HS, et al. A deep insight
fonc.2020.00697  into CRISPR/Cas9 application in CAR-T cell-based tumor
83  Gill S, Tasian SK, Ruella M, et al. Preclinical targeting of human immunotherapies. Stem Cell Res Ther 2021;12:428. doi:10.1186/
acute myeloid leukemia and myeloablation using chimeric antigen s13287-021-02510-7 
receptor-modified T cells. Blood 2014;123:2343-54. doi:10.1182/ 100  Eyquem J, Mansilla-Soto J, Giavridis T, et al. Targeting a CAR to
blood-2013-09-529537  the TRAC locus with CRISPR/Cas9 enhances tumour rejection.
84  Wang J, Chen S, Xiao W, et al. CAR-T cells targeting CLL-1 Nature 2017;543:113-7. doi:10.1038/nature21405 
as an approach to treat acute myeloid leukemia. J Hematol 101  Depil S, Duchateau P, Grupp SA, Mufti G, Poirot L. ‘Off-the-shelf’
Oncol 2018;11:7. doi:10.1186/s13045-017-0553-5  allogeneic CAR T cells: development and challenges. Nat Rev Drug
85  Ramos CA, Grover NS, Beaven AW, et al. Anti-CD30 CAR-T cell Discov 2020;19:185-99. doi:10.1038/s41573-019-0051-2 
therapy in relapsed and refractory hodgkin lymphoma. J Clin 102  Kansagra A, Farnia S, Majhail N. Expanding access to chimeric
Oncol 2020;38:3794-804. doi:10.1200/JCO.20.01342  antigen receptor T-cell therapies: challenges and opportunities.
86  Yeku O, Li X, Brentjens RJ. Adoptive T-cell therapy for solid tumors. Am Soc Clin Oncol Educ Book 2020;40:1-8. doi:10.1200/
Am Soc Clin Oncol Educ Book 2017;37:193-204. doi:10.1200/ EDBK_279151 
EDBK_180328  103  Leech AA, Neumann PJ, Cohen JT, Jagasia M, Dusetzina SB.
87  Wagner J, Wickman E, DeRenzo C, Gottschalk S. CAR T cell therapy for Balancing value with affordability: cell immunotherapy for cancer
solid tumors: bright future or dark reality?Mol Ther 2020;28:2320- treatment in the U.S. Oncologist 2020;25:e1117-9. doi:10.1634/
39. doi:10.1016/j.ymthe.2020.09.015  theoncologist.2020-0025 
88  Goff SL, Morgan RA, Yang JC, et al. Pilot trial of adoptive transfer 104  Hirayama AV, Gauthier J, Hay KA, et al. The response to
of chimeric antigen receptor-transduced T cells targeting EGFRvIII lymphodepletion impacts PFS in patients with aggressive
in patients with glioblastoma. J Immunother 2019;42:126-35. non-Hodgkin lymphoma treated with CD19 CAR T cells.
doi:10.1097/CJI.0000000000000260  Blood 2019;133:1876-87. doi:10.1182/blood-2018-11-887067 
89  O’Rourke DM, Nasrallah MP, Desai A, et al. A single dose of peripherally 105  Myers GD, Verneris MR, Goy A, Maziarz RT. Perspectives on
infused EGFRvIII-directed CAR T cells mediates antigen loss and outpatient administration of CAR-T cell therapy in aggressive
induces adaptive resistance in patients with recurrent glioblastoma. Sci B-cell lymphoma and acute lymphoblastic leukemia. J Immunother
Transl Med 2017;9:eaaa0984. doi:10.1126/scitranslmed.aaa0984  Cancer 2021;9:e002056. doi:10.1136/jitc-2020-002056 

14 doi: 10.1136/bmj-2021-068956 | BMJ 2022;378:e068956 | the bmj