Key Points

  • Sequential infusion of CAR19/22 T cell is highly active and well tolerated in patients with refractory/relapsed B-cell malignancies.

  • Dual-targeting of CD19 and CD22 may represent a feasible solution to reduce antigen-escape relapse after CD19/CD22-directed therapies.

Abstract

Antigen-escape relapse has emerged as a major challenge for long-term disease control after CD19-directed therapies, to which dual-targeting of CD19 and CD22 has been proposed as a potential solution. From March 2016 through January 2018, we conducted a pilot study in 89 patients who had refractory/relapsed B-cell malignancies, to evaluate the efficacy and safety of sequential infusion of anti-CD19 and anti-CD22, a cocktail of 2 single-specific, third-generation chimeric antigen receptor-engineered (CAR19/22) T cells. Among the 51 patients with acute lymphoblastic leukemia, the minimal residual disease-negative response rate was 96.0% (95% confidence interval [CI], 86.3-99.5). With a median follow-up of 16.7 months (range, 1.3-33.3), the median progression-free survival (PFS) was 13.6 months (95% CI, 6.5 to not reached [NR]), and the median overall survival (OS) was 31.0 months (95% CI, 10.6-NR). Among the 38 patients with non-Hodgkin lymphoma, the overall response rate was 72.2% (95% CI, 54.8-85.8), with a complete response rate of 50.0% (95% CI, 32.9-67.1). With a median follow-up of 14.4 months (range, 0.4-27.4), the median PFS was 9.9 months (95% CI, 3.3-NR), and the median OS was 18.0 months (95% CI, 6.1-NR). Antigen-loss relapse occurred in 1 patient during follow-up. High-grade cytokine release syndrome and neurotoxicity occurred in 22.4% and 1.12% patients, respectively. In all except 1, these effects were reversible. Our results indicated that sequential infusion of CAR19/22 T cell was safe and efficacious and may have reduced the rate of antigen-escape relapse in B-cell malignancies. This trial was registered at www.chictr.org.cn as #ChiCTR-OPN-16008526.

REFERENCES

REFERENCES
1.
Lim
WA
,
June
CH
.
The Principles of Engineering Immune Cells to Treat Cancer
.
Cell
.
2017
;
168
(
4
):
724
-
740
.
2.
Wang
RF
,
Wang
HY
.
Immune targets and neoantigens for cancer immunotherapy and precision medicine
.
Cell Res
.
2017
;
27
(
1
):
11
-
37
.
3.
June
CH
,
Sadelain
M
.
Chimeric Antigen Receptor Therapy
.
N Engl J Med
.
2018
;
379
(
1
):
64
-
73
.
4.
Sadelain
M
,
Rivière
I
,
Riddell
S
.
Therapeutic T cell engineering
.
Nature
.
2017
;
545
(
7655
):
423
-
431
.
5.
June
CH
,
O’Connor
RS
,
Kawalekar
OU
,
Ghassemi
S
,
Milone
MC
.
CAR T cell immunotherapy for human cancer
.
Science
.
2018
;
359
(
6382
):
1361
-
1365
.
6.
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
.
2015
;
385
(
9967
):
517
-
528
.
7.
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
.
8.
Neelapu
SS
,
Locke
FL
,
Bartlett
NL
, et al
.
Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma
.
N Engl J Med
.
2017
;
377
(
26
):
2531
-
2544
.
9.
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
.
10.
Schuster
SJ
,
Bishop
MR
,
Tam
CS
, et al
.
Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma
.
N Engl J Med
.
2019
;
380
(
1
):
45
-
56
.
11.
Schuster
SJ
,
Svoboda
J
,
Chong
EA
, et al
.
Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas
.
N Engl J Med
.
2017
;
377
(
26
):
2545
-
2554
.
12.
Wang
Z
,
Wu
Z
,
Liu
Y
,
Han
W
.
New development in CAR-T cell therapy
.
J Hematol Oncol
.
2017
;
10
(
1
):
53
.
13.
Majzner
RG
,
Mackall
CL
.
Tumor Antigen Escape from CAR T-cell Therapy
.
Cancer Discov
.
2018
;
8
(
10
):
1219
-
1226
.
14.
Jackson
HJ
,
Brentjens
RJ
.
Overcoming Antigen Escape with CAR T-cell Therapy
.
Cancer Discov
.
2015
;
5
(
12
):
1238
-
1240
.
15.
Grupp
SA
,
Maude
SL
,
Rives
S
, et al
.
Updated Analysis of the Efficacy and Safety of Tisagenlecleucel in Pediatric and Young Adult Patients with Relapsed/Refractory (r/r) Acute Lymphoblastic Leukemia
.
Blood
.
2018
;
132
(
suppl 1
).
Abstract 895
.
16.
Braig
F
,
Brandt
A
,
Goebeler
M
, et al
.
Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking
.
Blood
.
2017
;
129
(
1
):
100
-
104
.
17.
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
.
18.
Fischer
J
,
Paret
C
,
El Malki
K
, et al
.
CD19 Isoforms Enabling Resistance to CART-19 Immunotherapy Are Expressed in B-ALL Patients at Initial Diagnosis
.
J Immunother
.
2017
;
40
(
5
):
187
-
195
.
19.
Bagashev
A
,
Sotillo
E
,
Tang
CH
, et al
.
CD19 alterations emerging after CD19-directed immunotherapy cause retention of the misfolded protein in the endoplasmic reticulum
.
Mol Cell Biol
.
2018
;
38
(
21
):
e00383
-
18
.
20.
Gardner
R
,
Wu
D
,
Cherian
S
, et al
.
Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy
.
Blood
.
2016
;
127
(
20
):
2406
-
2410
.
21.
Jacoby
E
,
Nguyen
SM
,
Fountaine
TJ
, et al
.
CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity
.
Nat Commun
.
2016
;
7
(
1
):
12320
.
22.
Ruella
M
,
Barrett
DM
,
Kenderian
SS
, et al
.
Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies
.
J Clin Invest
.
2016
;
126
(
10
):
3814
-
3826
.
23.
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
.
24.
Rosenthal
J
,
Naqvi
AS
,
Luo
M
, et al
.
Heterogeneity of surface CD19 and CD22 expression in B lymphoblastic leukemia
.
Am J Hematol
.
2018
;
93
(
11
):
E352
-
E355
.
25.
Lee
DW
,
Gardner
R
,
Porter
DL
, et al
.
Current concepts in the diagnosis and management of cytokine release syndrome [published correction appears in Blood. 2015;126(8):1048]
.
Blood
.
2014
;
124
(
2
):
188
-
195
.
26.
Brudno
JN
,
Kochenderfer
JN
.
Toxicities of chimeric antigen receptor T cells: recognition and management
.
Blood
.
2016
;
127
(
26
):
3321
-
3330
.
27.
Neelapu
SS
,
Tummala
S
,
Kebriaei
P
, et al
.
Chimeric antigen receptor T-cell therapy-assessment and management of toxicities
.
Nat Rev Clin Oncol
.
2018
;
15
(
1
):
47
-
62
.
28.
Cheson
BD
,
Fisher
RI
,
Barrington
SF
, et al;
United Kingdom National Cancer Research Institute
.
Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification
.
J Clin Oncol
.
2014
;
32
(
27
):
3059
-
3068
.
29.
Xu
H
,
Wang
N
,
Cao
W
,
Huang
L
,
Zhou
J
,
Sheng
L
.
Influence of various medium environment to in vitro human T cell culture
.
In Vitro Cell Dev Biol Anim
.
2018
;
54
(
8
):
559
-
566
.
30.
Xu
H
,
Cao
W
,
Huang
L
, et al
.
Effects of cryopreservation on chimeric antigen receptor T cell functions
.
Cryobiology
.
2018
;
83
:
40
-
47
.
31.
Tang
YT
,
Wang
D
,
Luo
H
, et al
.
Aggressive NK-cell leukemia: clinical subtypes, molecular features, and treatment outcomes
.
Blood Cancer J
.
2017
;
7
(
12
):
660
.
32.
Huang
L
,
Liu
D
,
Wang
N
, et al
.
Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia
.
Cell Res
.
2018
;
28
(
2
):
172
-
186
.
33.
Fine
JP
,
Gray
RJ
.
A Proportional Hazards Model for the Subdistribution of a Competing Risk
.
J Am Stat Assoc
.
1999
;
94
(
446
):
496
-
509
.
34.
LeBien
TW
,
Tedder
TF
.
B lymphocytes: how they develop and function
.
Blood
.
2008
;
112
(
5
):
1570
-
1580
.
35.
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
.
36.
Zah
E
,
Lin
MY
,
Silva-Benedict
A
,
Jensen
MC
,
Chen
YY
.
T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells
.
Cancer Immunol Res
.
2016
;
4
(
6
):
498
-
508
.
37.
Hegde
M
,
Mukherjee
M
,
Grada
Z
, et al
.
Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape
.
J Clin Invest
.
2016
;
126
(
8
):
3036
-
3052
.
38.
Feng
KC
,
Guo
YL
,
Liu
Y
, et al
.
Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma
.
J Hematol Oncol
.
2017
;
10
(
1
):
4
.
39.
Hill
JA
,
Li
D
,
Hay
KA
, et al
.
Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy
.
Blood
.
2018
;
131
(
1
):
121
-
130
.
40.
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
.
41.
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
.
42.
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
(
12
):
2709
-
2720
.
43.
Fraietta
JA
,
Lacey
SF
,
Orlando
EJ
, et al
.
Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia
.
Nat Med
.
2018
;
24
(
5
):
563
-
571
.
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