Abstract

Chimeric antigen receptor T-cell therapy (CAR-T) targeting CD19 has transformed the management of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), with the US Food and Drug Administration approval of tisagenlecleucel for pediatric/young adult patients and brexucabtagene autoleucel for adults. Efficacy is contingent upon several factors including disease burden. Emerging data suggest that bridging therapy, lymphodepletion, and, for some patients, consolidation therapy have an important role in the success of treatment. Furthermore, strategies to define and manage immunotoxic side effects including hematotoxicity is critical to safe delivery. Advancements in CAR-T design beyond CD19 represent an ongoing therapeutic evolution. Overall, CAR-T signifies a paradigm shift in B-ALL management, with the potential for improved remission and survival in a historically challenging patient population.

1.
Key Statistics for Acute Lymphocytic Leukemia (ALL). 17 October 2018
. Accessed 17 March 2024. https://www.cancer.org/cancer/types/acute-lymphocytic-leukemia/about/key-statistics.html.
2.
Inaba
H
,
Greaves
M
,
Mullighan
CG
.
Acute lymphoblastic leukaemia
.
Lancet Lond Engl
.
2013
;
381
(
9881
):
1943
-
1955
.
3.
Kantarjian
H
,
Stein
A
,
Gökbuget
N
, et al
.
Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia
.
N Engl J Med
.
2017
;
376
(
9
):
836
-
847
.
4.
Kantarjian
HM
,
DeAngelo
DJ
,
Stelljes
M
, et al
.
Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia
.
N Engl J Med
.
2016
;
375
(
8
):
740
-
753
.
5.
Gökbuget
N
,
Dombret
H
,
Bonifacio
M
, et al
.
Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia
.
Blood
.
2018
;
131
(
14
):
1522
-
1531
.
6.
Jabbour
E
,
Haddad
FG
,
Short
NJ
,
Kantarjian
H
.
Treatment of adults with Philadelphia chromosome–positive acute lymphoblastic leukemia—from intensive chemotherapy combinations to chemotherapy-free regimens: a review
.
JAMA Oncol
.
2022
;
8
(
9
):
1340
-
1348
.
7.
Maude
SL
,
Frey
N
,
Shaw
PA
, et al
.
Chimeric antigen receptor T cells for sustained remissions in leukemia
.
N Engl J Med
.
2014
;
371
(
16
):
1507
-
1517
.
8.
Maude
SL
,
Laetsch
TW
,
Buechner
J
, et al
.
Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia
.
N Engl J Med
.
2018
;
378
(
5
):
439
-
448
.
9.
Shah
BD
,
Ghobadi
A
,
Oluwole
OO
, et al
.
KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study
.
Lancet Lond Engl
.
2021
;
398
(
10299
):
491
-
502
.
10.
Frey
NV
,
Gill
S
,
Hexner
EO
, et al
.
Long-term outcomes from a randomized dose optimization study of chimeric antigen receptor modified T cells in relapsed chronic lymphocytic leukemia
.
J Clin Oncol
.
2020
;
38
(
25
):
2862
-
2871
.
11.
Roddie
C
,
Dias
J
,
O’Reilly
MA
, et al
.
Durable responses and low toxicity after fast off-rate CD19 chimeric antigen receptor-T therapy in adults with relapsed or refractory B-cell acute lymphoblastic leukemia
.
J Clin Oncol
.
2021
;
39
(
30
):
3352
-
3363
.
12.
Hay
KA
,
Gauthier
J
,
Hirayama
AV
, et al
.
Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy
.
Blood
.
2019
;
133
(
15
):
1652
-
1663
.
13.
Lee
DW
,
Kochenderfer
JN
,
Stetler-Stevenson
M
, et al
.
T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial
.
Lancet Lond Engl
.
2015
;
385
(
9967
):
517
-
528
.
14.
Ortiz-Maldonado
V
,
Rives
S
,
Español-Rego
M
, et al
.
Factors associated with the clinical outcome of patients with relapsed/refractory CD19+ acute lymphoblastic leukemia treated with ARI-0001 CART19-cell therapy
.
J Immunother Cancer
.
2021
;
9
(
12
):
e003644
.
15.
Ghorashian
S
,
Kramer
AM
,
Onuoha
S
, et al
.
Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR
.
Nat Med
.
2019
;
25
(
9
):
1408
-
1414
.
16.
Gardner
RA
,
Finney
O
,
Annesley
C
, et al
.
Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults
.
Blood
.
2017
;
129
(
25
):
3322
-
3331
.
17.
Laetsch
TW
,
Maude
SL
,
Rives
S
, et al
.
Three-year update of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia in the ELIANA Trial
.
J Clin Oncol
.
2023
;
41
(
9
):
1664
-
1669
.
18.
Mueller
KT
,
Maude
SL
,
Porter
DL
, et al
.
Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia
.
Blood
.
2017
;
130
(
21
):
2317
-
2325
.
19.
Schultz
LM
,
Baggott
C
,
Prabhu
S
, et al
.
Disease burden affects outcomes in pediatric and young adult B-cell lymphoblastic leukemia after commercial tisagenlecleucel: a Pediatric Real-World Chimeric Antigen Receptor Consortium Report
.
J Clin Oncol
.
2022
;
40
(
9
):
945
-
955
.
20.
Lee
DW
,
Santomasso
BD
,
Locke
FL
, et al
.
ASBMT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells
.
Biol Blood Marrow Transplant
.
2019;25(4):625-638
.
21.
Wayne
AS
,
Huynh
V
,
Hijiya
N
, et al
.
Three-year results from phase I of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia
.
Haematologica
.
2023
;
108
(
3
):
747
-
760
.
22.
Park
JH
,
Rivière
I
,
Gonen
M
, et al
.
Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia
.
N Engl J Med
.
2018
;
378
(
5
):
449
-
459
.
23.
Turtle
CJ
,
Hanafi
LA
,
Berger
C
, et al
.
CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients
.
J Clin Invest
.
2016
;
126
(
6
):
2123
-
2138
.
24.
Roloff
GW
,
Aldoss
I
,
Kopmar
NE
, et al
.
Brexucabtagene autoleucel in adults with relapsed/refractory B-cell ALL: outcomes and novel insights from the Real-World Outcomes Collaborative of CAR T in Adult ALL (ROCCA) [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
1030
.
25.
Roloff
G
,
Faramand
R
,
Aldoss
I
, et al
.
Outcomes following brexucabtagene autoleucel administered as an FDA-approved therapy for adults with relapsed/refractory B-ALL
.
J Clin Oncol
.
2023
;
41
(
16 suppl
):
7001
.
26.
Roddie
C
,
Pinto
JDA
,
O’Reilly
MA
.
Safety, efficiency and long-term follow-up of AUTO1, a fast-off rate CD19 CAR in relapsed/refractory B-cell acute lymphoblastic leukaemia and other B-cell malignancies [abstract]
.
Blood
.
2022
;
140
(
suppl 1
):
7452
-
7453
.
27.
Roddie
C
,
Sandhu
KS
,
Tholouli
E
, et al
.
Obecabtagene autoleucel (obe-cel, AUTO1) for relapsed/refractory adult B-cell acute lymphoblastic leukemia (R/R B-ALL): pooled analysis of the ongoing FELIX phase Ib/II study [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
222
.
28.
Jabbour
E
,
Tholouli
E
,
Sandhu
KS
, et al
.
Obecabtagene autoleucel (obe-cel, AUTO1) in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL): overall survival (OS), event-free survival (EFS) and the potential impact of chimeric antigen receptor (CAR)-T cell persistency and consolidative stem cell transplantation (SCT) in the open-label, single-arm FELIX phase Ib/II study [abstract]
.
J Clin Oncol
.
2024
;
42
(
16 suppl
):
6504
.
29.
Jacoby
E
,
Ghorashian
S
,
Vormoor
B
, et al
.
CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study
.
Leukemia
.
2022
;
36
(
6
):
1525
-
1532
.
30.
Qi
Y
,
Zhao
M
,
Hu
Y
, et al
.
Efficacy and safety of CD19-specific CAR T cell–based therapy in B-cell acute lymphoblastic leukemia patients with CNSL
.
Blood
.
2022
;
139
(
23
):
3376
-
3386
.
31.
Holland
EM
,
Yates
B
,
Ling
A
, et al
.
Characterization of extramedullary disease in B-ALL and response to CAR T-cell therapy
.
Blood Adv
.
2022
;
6
(
7
):
2167
-
2182
.
32.
Zhang
X
,
Zhang
G
,
Li
W
, et al
.
Factors associated with outcomes among refractory/relapsed TP53-mutated/chromosome 17p deletion acute B-cell lymphoblastic leukemia (B-ALL) patients treated with CD19-targeted chimeric antigen receptor (CAR)-T therapy [abstract]
.
Blood
.
2021
;
138
(
suppl 1
):
3828
.
33.
Pan
J
,
Tan
Y
,
Deng
B
, et al
.
Frequent occurrence of CD19-negative relapse after CD19 CAR T and consolidation therapy in 14 TP53-mutated r/r B-ALL children
.
Leukemia
.
2020
;
34
(
12
):
3382
-
3387
.
34.
Mishra
AK
,
Burridge
S
,
Espuelas
MO
, et al
.
Practice guideline: preparation for CAR T-cell therapy in children and young adults with B-acute lymphoblastic leukaemia
.
Br J Haematol
.
2024
;
204
(
5
):
1687
-
1696
.
35.
Feuchtinger
T
,
Bader
P
,
Subklewe
M
, et al
.
Approaches for bridging therapy prior to chimeric antigen receptor T cells for relapsed/refractory acute lymphoblastic B-lineage leukemia in children and young adults
.
Haematologica
.
2024
;
109
(
12
):
3892
-
3903
.
36.
Rubinstein
JD
,
Breese
EH
,
Krupski
MC
, et al
.
The choice of either conventional chemotherapy or inotuzumab ozogamicin as bridging regimen does not appear to impact clinical response to CD19-directed CAR-T therapy in pediatric B-ALL
.
Transplant Cell Ther
.
2023
;
29
(
5
):
311.e1
-
311.e7
.
37.
Ceolin
V
,
Brivio
E
,
van Tinteren
H
, et al
.
Outcome of chimeric antigen receptor T-cell therapy following treatment with inotuzumab ozogamicin in children with relapsed or refractory acute lymphoblastic leukemia
.
Leukemia
.
2023
;
37
(
1
):
53
-
60
.
38.
Myers
RM
,
Taraseviciute
A
,
Steinberg
SM
, et al
.
Blinatumomab nonresponse and high-disease burden are associated with inferior outcomes after CD19-CAR for B-ALL
.
J Clin Oncol
.
2022
;
40
(
9
):
932
-
944
.
39.
Fabrizio
VA
,
Boelens
JJ
,
Mauguen
A
, et al
.
Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy
.
Blood Adv
.
2022
;
6
(
7
):
1961
-
1968
.
40.
Turtle
CJ
,
Hanafi
LA
,
Berger
C
, et al
.
Addition of fludarabine to cyclophosphamide lymphodepletion improves in vivo expansion of CD19 chimeric antigen receptor-modified T cells and clinical outcome in adults with B cell acute lymphoblastic leukemia
.
Blood J
.
2015
;
126
(
23
):
3773
.
41.
Dekker
L
,
Calkoen
FG
,
Jiang
Y
, et al
.
Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia
.
Blood Adv
.
2022
;
6
(
7
):
1969
-
1976
.
42.
Ghilardi
G
,
Chong
EA
,
Svoboda
J
, et al
.
Bendamustine is safe and effective for lymphodepletion before tisagenlecleucel in patients with refractory or relapsed large B-cell lymphomas
.
Ann Oncol
.
2022
;
33
(
9
):
916
-
928
.
43.
Frey
NV
,
Shaw
PA
,
Hexner
EO
, et al
.
Optimizing chimeric antigen receptor T-cell therapy for adults with acute lymphoblastic leukemia
.
J Clin Oncol
.
2020
;
38
(
5
):
415
-
422
.
44.
Frey
NV
,
Porter
DL
.
CAR T-cells merge into the fast lane of cancer care
.
Am J Hematol
.
2016
;
91
(
1
):
146
-
150
.
45.
Myers
RM
,
Kadauke
S
,
Li
Y
, et al
.
Risk-adapted preemptive tocilizumab decreases severe cytokine release syndrome (CRS) after CTL019 CD19-targeted chimeric antigen receptor (CAR) T-cell therapy for pediatric B-cell acute lymphoblastic leukemia (B-ALL)
.
Biol Blood Marrow Transplant
.
2020
;
26
(
3
):
920
-
931
.
46.
Park
JH
,
Nath
K
,
Devlin
SM
, et al
.
CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results
.
Nat Med
.
2023
;
29
(
7
):
1710
-
1717
.
47.
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
(
499
):
eaau5907
.
48.
Weber
EW
,
Lynn
RC
,
Sotillo
E
,
Lattin
J
,
Xu
P
,
Mackall
CL
.
Pharmacologic control of CAR-T cell function using dasatinib
.
Blood Adv
.
2019
;
3
(
5
):
711
-
717
.
49.
Gu
C
,
Wu
Q
,
Zhang
J
, et al
.
Successful treatment of severe cytokine release syndrome after CAR-T therapy by ruxolitinib without compromising CAR-T efficacy
.
Leuk Lymphoma
.
2023
;
64
(
2
):
495
-
498
.
50.
Frigault
MJ
,
Maziarz
RT
,
Park
JH
, et al
.
Itacitinib for the prevention of immune effector cell therapy-associated cytokine release syndrome: results from the Phase 2 Incb 39110-211 placebo-controlled randomized cohort [abstract]
.
Blood
.
2023
;
142
(
suppl 1
):
356
.
51.
Sterner
RM
,
Sakemura
R
,
Cox
MJ
, et al
.
GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts
.
Blood
.
2019
;
133
(
7
):
697
-
709
.
52.
Manni
S
,
Del Bufalo
F
,
Merli
P
, et al
.
Neutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies
.
Nat Commun
.
2023
;
14
(
1
):
3423
.
53.
Zurko
JC
,
Johnson
BD
,
Aschenbrenner
E
, et al
.
Use of early intrathecal therapy to manage high-grade immune effector cell-associated neurotoxicity syndrome
.
JAMA Oncol
.
2022
;
8
(
5
):
773
-
775
.
54.
Shalabi
H
,
Harrison
C
,
Yates
B
,
Calvo
KR
,
Lee
DW
,
Shah
NN
.
Intrathecal hydrocortisone for treatment of children and young adults with CAR T-cell immune-effector cell-associated neurotoxicity syndrome
.
Pediatr Blood Cancer
.
2024
;
71
(
1
):
e30741
.
55.
Kim
DW
,
Bukhari
A
,
Lutfi
F
, et al
.
Low utility of the H-Score and HLH-2004 criteria to identify patients with secondary hemophagocytic lymphohistiocytosis after CAR-T cell therapy for relapsed/refractory diffuse large B-Cell lymphoma
.
Leuk Lymphoma
.
2022
;
63
(
6
):
1339
-
1347
.
56.
Lichtenstein
DA
,
Schischlik
F
,
Shao
L
, et al
.
Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T cells
.
Blood
.
2021
;
138
(
24
):
2469
-
2484
.
57.
Jain
T
,
Knezevic
A
,
Pennisi
M
, et al
.
Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic malignancies
.
Blood Adv
.
2020
;
4
(
15
):
3776
-
3787
.
58.
O’Reilly
MA
,
Neill
L
,
Collin
SM
, et al
.
High pretreatment disease burden as a risk factor for infectious complications following CD19 chimeric antigen receptor T-cell therapy for large B-cell lymphoma
.
HemaSphere
.
2024
;
8
(
1
):
e29
.
59.
Haidar
G
,
Garner
W
,
Hill
JA
.
Infections after anti-CD19 chimeric antigen receptor T-cell therapy for hematologic malignancies: timeline, prevention, and uncertainties
.
Curr Opin Infect Dis
.
2020
;
33
(
6
):
449
-
457
.
60.
Hayden
PJ
,
Roddie
C
,
Bader
P
, et al
.
Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA)
.
Ann Oncol
.
2022;33(3):259-275
.
61.
Verdun
N
,
Marks
P
.
Secondary cancers after chimeric antigen receptor T-cell therapy
.
N Engl J Med
.
2024
;
390
(
7
):
584
-
586
.
62.
Hamilton
MP
,
Sugio
T
,
Noordenbos
T
, et al
.
Risk of second tumors and T-cell lymphoma after CAR T-cell therapy
.
N Engl J Med
.
2024
;
390
(
22
):
2047
-
2060
.
63.
Lamble
AJ
,
Schultz
LM
,
Nguyen
K
, et al
.
Risk of T-cell malignancy after CAR T-cell therapy in children, adolescents, and young adults
.
Blood Adv
.
2024
;
8
(
13
):
3544
-
3548
.
64.
Ozdemirli
M
,
Loughney
TM
,
Deniz
E
, et al
.
Indolent CD4+ CAR T-cell lymphoma after cilta-cel CAR T-cell therapy
.
N Engl J Med
.
2024
;
390
(
22
):
2074
-
2082
.
65.
Ghilardi
G
,
Fraietta
JA
,
Gerson
JN
, et al
.
T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy
.
Nat Med
.
2024
;
30
(
4
):
984
-
989
.
66.
Shiqi
L
,
Jiasi
Z
,
Lvzhe
C
, et al
.
Durable remission related to CAR-T persistence in R/R B-ALL and long-term persistence potential of prime CAR-T
.
Mol Ther Oncolytics
.
2023
;
29
:
107
-
117
.
67.
Turicek
DP
,
Giordani
VM
,
Moraly
J
,
Taylor
N
,
Shah
NN
.
CAR T-cell detection scoping review: an essential biomarker in critical need of standardization
.
J Immunother Cancer
.
2023
;
11
(
5
):
e006596
.
68.
Gkazi
SA
,
Gravett
E
,
Bautista
C
,
Bartram
J
,
Ghorashian
S
,
Adams
SP
.
Clinically applicable assessment of tisagenlecleucel CAR T cell treatment by digital droplet PCR for copy number variant assessment
.
Int J Mol Sci
.
2022
;
23
(
14
):
7573
.
69.
Pulsipher
MA
,
Han
X
,
Maude
SL
, et al
.
Next-generation sequencing of minimal residual disease for predicting relapse after tisagenlecleucel in children and young adults with acute lymphoblastic leukemia
.
Blood Cancer Discov
.
2022
;
3
(
1
):
66
-
81
.
70.
Dourthe
ME
,
Rabian
F
,
Yakouben
K
, et al
.
Determinants of CD19-positive vs CD19-negative relapse after tisagenlecleucel for B-cell acute lymphoblastic leukemia
.
Leukemia
.
2021
;
35
(
12
):
3383
-
3393
.
71.
Lamble
AJ
,
Moskop
A
,
Pulsipher
MA
, et al
.
INSPIRED Symposium Part 2: Prevention and Management of Relapse Following Chimeric Antigen Receptor T Cell Therapy for B Cell Acute Lymphoblastic Leukemia
.
Transplant Cell Ther
.
2023
;
29
(
11
):
674
-
684
.
72.
Ganzel
C
,
Wang
XV
,
Rowe
JM
, et al
.
At three years, patients with acute lymphoblastic leukaemia are still at risk for relapse. Results of the international MRC UKALLXII/ECOG E2993 trial
.
Br J Haematol
.
2020
;
191
(
1
):
37
-
43
.
73.
Biasco
L
,
Izotova
N
,
Rivat
C
, et al
.
Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients
.
Nat Can (Ott)
.
2021
;
2
(
6
):
629
-
642
.
74.
Finney
OC
,
Brakke
HM
,
Rawlings-Rhea
S
, et al
.
CD19 CAR T cell product and disease attributes predict leukemia remission durability
.
J Clin Invest
.
2019
;
129
(
5
):
2123
-
2132
.
75.
Leahy
AB
,
Devine
KJ
,
Li
Y
, et al
.
Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy
.
Blood
.
2022
;
139
(
14
):
2173
-
2185
.
76.
Myers
RM
,
Taraseviciute
A
,
Steinberg
SM
, et al
.
Blinatumomab nonresponse and high-disease burden are associated with inferior outcomes after CD19-CAR for B-ALL
.
J Clin Oncol
.
2021
;
40(9):932-945
.
77.
Gabelli
M
,
Oporto-Espuelas
M
,
Bonney
DK
, et al
.
Maintenance therapy for early loss of B-cell aplasia after CD19 CAR T-cell therapy
.
Blood Adv
.
2024;8(8):1959-1963
.
78.
Pan
J
,
Yang
JF
,
Deng
BP
, et al
.
High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients
.
Leukemia
.
2017
;
31
(
12
):
2587
-
2593
.
79.
Shadman
M
,
Gauthier
J
,
Hay
KA
, et al
.
Safety of allogeneic hematopoietic cell transplant in adults after CD19-targeted CAR T-cell therapy
.
Blood Adv
.
2019
;
3
(
20
):
3062
-
3069
.
80.
Nagler
A
,
Labopin
M
,
Dholaria
B
, et al
.
Second allogeneic stem cell transplantation in patients with acute lymphoblastic leukaemia: a study on behalf of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation
.
Br J Haematol
.
2019
;
186
(
5
):
767
-
776
.
81.
Chen
LY
,
Gong
WJ
,
Li
MH
, et al
.
Anti-CD19 CAR T-cell consolidation therapy combined with CD19+ feeding T cells and TKI for Ph+ acute lymphoblastic leukemia
.
Blood Adv
.
2023
;
7
(
17
):
4913
-
4925
.
82.
Cassaday
RD
,
Garcia
KLA
,
Fromm
JR
, et al
.
Phase 2 study of pembrolizumab for measurable residual disease in adults with acute lymphoblastic leukemia
.
Blood Adv
.
2020
;
4
(
14
):
3239
-
3245
.
83.
Li
AM
,
Hucks
GE
,
Dinofia
AM
, et al
.
Checkpoint inhibitors augment CD19-directed chimeric antigen receptor (CAR) T cell therapy in relapsed B-cell acute lymphoblastic leukemia [abstract]
.
Blood
.
2018
;
132
(
suppl 1
):
556
.
84.
Elsallab
M
,
Ellithi
M
,
Hempel
S
,
Abdel-Azim
H
,
Abou-el-Enein
M
.
Long-term response to autologous anti-CD19 chimeric antigen receptor T cells in relapsed or refractory B cell acute lymphoblastic leukemia: a systematic review and meta-analysis
.
Cancer Gene Ther
.
2023
;
30
(
6
):
845
-
854
.
85.
Sun
W
,
Malvar
J
,
Sposto
R
, et al
.
Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia & Lymphoma study
.
Leukemia
.
2018
;
32
(
11
):
2316
-
2325
.
86.
Wudhikarn
K
,
King
AC
,
Geyer
MB
, et al
.
Outcomes of relapsed B-cell acute lymphoblastic leukemia after sequential treatment with blinatumomab and inotuzumab
.
Blood Adv
.
2022
;
6
(
5
):
1432
-
1443
.
87.
Sotillo
E
,
Barrett
DM
,
Black
KL
, et al
.
Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy
.
Cancer Discov
.
2015
;
5
(
12
):
1282
-
1295
.
88.
Fry
TJ
,
Shah
NN
,
Orentas
RJ
, et al
.
CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy
.
Nat Med
.
2018
;
24
(
1
):
20
-
28
.
89.
Shah
NN
,
Highfill
SL
,
Shalabi
H
, et al
.
CD4/CD8 T-cell selection affects chimeric antigen receptor (CAR) T-cell potency and toxicity: updated results from a phase I Anti-CD22 CAR T-Cell Trial
.
J Clin Oncol
.
2020
;
38
(
17
):
1938
-
1950
.
90.
Pan
J
,
Niu
Q
,
Deng
B
, et al
.
CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia
.
Leukemia
.
2019
;
33
(
12
):
2854
-
2866
.
91.
Schultz
LM
,
Jeyakumar
N
,
Kramer
AM
, et al
.
CD22 CAR T cells demonstrate high response rates and safety in pediatric and adult B-ALL: phase 1b results
.
Leukemia
.
2024
;
38
(
5
):
963
-
968
.
92.
Cordoba
S
,
Onuoha
S
,
Thomas
S
, et al
.
CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial
.
Nat Med
.
2021
;
27
(
10
):
1797
-
1805
.
93.
Shalabi
H
,
Qin
H
,
Su
A
, et al
.
CD19/22 CAR T-cells in children and young adults with B-ALL: phase I results and development of a novel bicistronic CAR
.
Blood
.
2022;140(5):451-463
.
94.
Spiegel
JY
,
Patel
S
,
Muffly
L
, et al
.
T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial
.
Nat Med
.
2021
;
27
(
8
):
1416
-
1431
.
95.
Gardner
R
,
Annesley
C
,
Finney
O
, et al
.
Early clinical experience of CD19 x CD22 dual specific CAR T cells for enhanced anti-leukemic targeting of acute lymphoblastic leukemia [abstract]
.
Blood
.
2018
;
132
(
suppl 1
):
278
.
96.
Annesley
C
,
Summers
C
,
Pulsipher
MA
, et al
.
SCRI-CAR19x22v2 T cell product demonstrates bispecific activity in B-ALL [abstract]
.
Blood
.
2021
;
138
(
suppl 1
):
470
.
97.
Ghorashian
S
,
Lucchini
G
,
Richardson
R
, et al
.
CD19/CD22 targeting with cotransduced CAR T cells to prevent antigen-negative relapse after CAR T-cell therapy for B-cell ALL
.
Blood
.
2024
;
143
(
2
):
118
-
123
.
98.
Wang
T
,
Tang
Y
,
Cai
J
, et al
.
Coadministration of CD19- and CD22-directed chimeric antigen receptor T-cell therapy in childhood B-cell acute lymphoblastic leukemia: a single-arm, multicenter, phase II trial
.
J Clin Oncol
.
2023
;
41
(
9
):
1670
-
1683
.
99.
Pan
J
,
Tang
K
,
Luo
Y
, et al
.
Sequential CD19 and CD22 chimeric antigen receptor T-cell therapy for childhood refractory or relapsed B-cell acute lymphocytic leukaemia: a single-arm, phase 2 study
.
Lancet Oncol
.
2023
;
24
(
11
):
1229
-
1241
.
100.
Gauthier
J
,
Bezerra
ED
,
Hirayama
AV
, et al
.
Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies
.
Blood
.
2021
;
137
(
3
):
323
-
335
.
101.
Holland
EM
,
Molina
JC
,
Dede
K
, et al
.
Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation
.
J Immunother Cancer
.
2022
;
10
(
5
):
e004483
.
102.
Xu
Q
,
Shi
Y
,
Xue
L
, et al
.
Outcomes of second anti-CD19 CAR T-cell therapy (CART2) in acute B lymphoblastic leukemia and the impact of Allo-HSCT on efficacy
.
Cell Transplant
.
2023
;
32
:
09636897231204724
.
103.
Myers
RM
,
Li
Y
,
Barz Leahy
A
, et al
.
Humanized CD19-targeted chimeric antigen receptor (CAR) T cells in CAR-naive and CAR-exposed children and young adults with relapsed or refractory acute lymphoblastic leukemia
.
J Clin Oncol
.
2021
;
39
(
27
):
3044
-
3055
.
104.
Zarebski
LM
,
Urrutia
M
,
Goldbaum
FA
.
Llama single domain antibodies as a tool for molecular mimicry
.
J Mol Biol
.
2005
;
349
(
4
):
814
-
824
.
105.
Sun
Y
,
Yang
XN
,
Yang
SS
, et al
.
Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity
.
Signal Transduct Targeted Ther
.
2023
;
8
(
1
):
445
. 12.
106.
Benjamin
R
,
Jain
N
,
Maus
MV
, et al;
CALM Study Group
.
UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial
.
Lancet Haematol
.
2022
;
9
(
11
):
e833
-
e843
.
107.
Depil
S
,
Duchateau
P
,
Grupp
SA
,
Mufti
G
,
Poirot
L
.
‘Off-the-shelf’ allogeneic CAR T cells: development and challenges
.
Nat Rev Drug Discov
.
2020
;
19
(
3
):
185
-
199
.
108.
Chattaraj
A
,
Rehman
MEU
,
Khan
I
, et al
.
Safety and efficacy of allogeneic CAR-T cells in B-cell malignancies: a systematic review and meta-analysis
.
J Clin Oncol
.
2022
;
40
(
16 suppl
):
e19530
.
109.
Yang
J
,
He
J
,
Zhang
X
, et al
.
Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study
.
Blood Cancer J
.
2022
;
12
(
7
):
104
.
110.
Klebanoff
CA
,
Crompton
JG
,
Leonardi
AJ
, et al
.
Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy
.
JCI Insight
.
2017
;
2
(
23
):
e95103
.
111.
Mehra
V
,
Agliardi
G
,
Dias Alves Pinto
J
, et al
.
AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival
.
J Immunother Cancer
.
2023
;
11
(
9
):
e007002
.
112.
Di
M
,
Long
JB
,
Isufi
I
, et al
.
Total costs of care during chimeric antigen receptor T-cell therapy in patients with relapsed/refractory B cell non-Hodgkin lymphoma: a large private insurance claim-based analysis [abstract]
.
Blood
.
2022
;
140
(
suppl 1
):
10818
-
10819
.
113.
Castella
M
,
Boronat
A
,
Martín-Ibáñez
R
, et al
.
Development of a novel anti-CD19 chimeric antigen receptor: a paradigm for an affordable CAR T cell production at academic institutions
.
Mol Ther Methods Clin Dev
.
2019
;
12
:
134
-
144
.
114.
Mallapaty
S
.
Cutting-edge CAR-T cancer therapy is now made in India — at one-tenth the cost
.
Nature
.
2024
;
627
(
8005
):
709
-
710
.
115.
Neelapu
SS
,
Dickinson
M
,
Munoz
J
, et al
.
Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial
.
Nat Med
.
2022
;
28
(
4
):
735
-
742
.
You do not currently have access to this content.
Sign in via your Institution