• IL-18-secreting CAR T cells promote clearance of antigen-low myeloma with reprogramming of cells in the myeloma microenvironment.

  • Multiantigen targeting enhances T-cell-target avidity, increasing engineered IL-18 output and potentiating antimyeloma activity.

Abstract

Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18–secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.

1.
Morgan
GJ
,
Walker
BA
,
Davies
FE
.
The genetic architecture of multiple myeloma
.
Nat Rev Cancer
.
2012
;
12
(
5
):
335
-
348
.
2.
Cancer Stat Facts: Myeloma. National Cancer Institute
. Accessed 14 February 2024. https://seer.cancer.gov/statfacts/html/mulmy.html.
3.
Moreau
P
,
Attal
M
,
Facon
T
.
Frontline therapy of multiple myeloma
.
Blood
.
2015
;
125
(
20
):
3076
-
3084
.
4.
Mikkilineni
L
,
Kochenderfer
JN
.
CAR T cell therapies for patients with multiple myeloma
.
Nat Rev Clin Oncol
.
2021
;
18
(
2
):
71
-
84
.
5.
Van De Donk
NWCJ
,
Richardson
PG
,
Malavasi
F
.
CD38 antibodies in multiple myeloma: back to the future
.
Blood
.
2018
;
131
(
1
):
13
-
29
.
6.
Mikkilineni
L
,
Kochenderfer
JN
.
Chimeric antigen receptor T-cell therapies for multiple myeloma
.
Blood
.
2017
;
130
(
24
):
2594
-
2602
.
7.
FDA approves idecabtagene vicleucel for multiple myeloma
. 2021. Accessed 14 February 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-idecabtagene-vicleucel-multiple-myeloma.
8.
FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma
. 2022. Accessed 14 February 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene-autoleucel-relapsed-or-refractory-multiple-myeloma.
9.
Rodriguez-Otero
P
,
Ailawadhi
S
,
Arnulf
B
, et al
.
Ide-cel or standard regimens in relapsed and refractory multiple myeloma
.
N Engl J Med
.
2023
;
388
(
11
):
1002
-
1014
.
10.
San-Miguel
J
,
Dhakal
B
,
Yong
K
, et al
.
Cilta-cel or standard care in lenalidomide-refractory multiple myeloma
.
N Engl J Med
.
2023
;
389
(
4
):
335
-
347
.
11.
Brudno
JN
,
Maric
I
,
Hartman
SD
, et al
.
T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor with a CD28 costimulatory moiety cause remissions of poor-prognosis relapsed multiple myeloma
.
J Clin Oncol
.
2018
;
36
(
22
):
2267
-
2280
.
12.
Cohen
AD
,
Garfall
AL
,
Stadtmauer
EA
, et al
.
B cell maturation antigen – specific CAR T cells are clinically active in multiple myeloma
.
J Clin Invest
.
2019
;
129
(
6
):
2210
-
2221
.
13.
Da Vià
MC
,
Dietrich
O
,
Truger
M
, et al
.
Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma
.
Nat Med
.
2021
;
27
(
4
):
616
-
619
.
14.
Truger
MS
,
Duell
J
,
Zhou
X
, et al
.
Single- and double-hit events in genes encoding immune targets before and after T cell–engaging antibody therapy in MM
.
Blood Adv
.
2021
;
5
(
19
):
3794
-
3798
.
15.
Lee
L
,
Lim
WC
,
Galas-Filipowicz
D
, et al
.
Limited efficacy of APRIL CAR in patients with multiple myeloma indicate challenges in the use of natural ligands for CAR T-cell therapy
.
J Immunother Cancer
.
2023
;
11
(
6
):
e006699
.
16.
Pegram
HJ
,
Lee
JC
,
Hayman
EG
, et al
.
Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning
.
Blood
.
2012
;
119
(
18
):
4133
-
4141
.
17.
Avanzi
MP
,
Yeku
O
,
Li
X
, et al
.
Engineered tumor-targeted T cells mediate enhanced anti-tumor efficacy both directly and through activation of the endogenous immune system
.
Cell Rep
.
2018
;
23
(
7
):
2130
-
2141
.
18.
Hu
B
,
Ren
J
,
Luo
Y
, et al
.
Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18
.
Cell Rep
.
2017
;
20
(
13
):
3025
-
3033
.
19.
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
.
20.
Katsarou
A
,
Sjöstrand
M
,
Naik
J
, et al
.
Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence
.
Sci Transl Med
.
2021
;
13
(
623
):
eabh1962
.
21.
Hirabayashi
K
,
Du
H
,
Xu
Y
, et al
.
Dual-targeting CAR-T cells with optimal co-stimulation and metabolic fitness enhance antitumor activity and prevent escape in solid tumors
.
Nat Cancer
.
2021
;
2
(
9
):
904
-
918
.
22.
Majzner
RG
,
Rietberg
SP
,
Sotillo
E
, et al
.
Tuning the antigen density requirement for CAR T-cell activity
.
Cancer Discov
.
2020
;
10
(
5
):
702
-
723
.
23.
Hamieh
M
,
Dobrin
A
,
Cabriolu
A
, et al
.
CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape
.
Nature
.
2019
;
568
(
7750
):
112
-
116
.
24.
Mansilla-Soto
J
,
Eyquem
J
,
Haubner
S
, et al
.
HLA-independent T cell receptors for targeting tumors with low antigen density
.
Nat Med
.
2022
;
28
(
2
):
345
-
352
.
25.
Gogishvili
T
,
Danhof
S
,
Prommersberger
S
, et al
.
SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7+ normal lymphocytes
.
Blood
.
2017
;
130
(
26
):
2838
-
2847
.
26.
Smith
EL
,
Harrington
K
,
Staehr
M
, et al
.
Supplementary materials for: GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells
.
Sci Transl Med
.
2019
;
11
(
485
):
eaau7746
.
27.
Mailankody
S
,
Devlin
SM
,
Landa
J
, et al
.
GPRC5D-targeted CAR T cells for myeloma
.
N Engl J Med
.
2022
;
387
(
13
):
1196
-
1206
.
28.
Radhakrishnan
S V
,
Luetkens
T
,
Scherer
SD
, et al
.
CD229 CAR T cells eliminate multiple myeloma and tumor propagating cells without fratricide
.
Nat Commun
.
2020
;
11
(
1
):
798
.
29.
Sun
C
,
Mahendravada
A
,
Ballard
B
, et al
.
Safety and efficacy of targeting CD138 with a chimeric antigen receptor for the treatment of multiple myeloma
.
Oncotarget
.
2019
;
10
(
24
):
2369
-
2383
.
30.
Drent
E
,
Groen
RWJ
,
Noort
WA
, et al
.
Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma
.
Haematologica
.
2016
;
101
(
5
):
616
-
625
.
31.
Novak
AJ
,
Darce
JR
,
Arendt
BK
, et al
.
Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival
.
Blood
.
2004
;
103
(
2
):
689
-
694
.
32.
Moreaux
J
,
Legouffe
E
,
Jourdan
E
, et al
.
BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone
.
Blood
.
2004
;
103
(
8
):
3148
-
3157
.
33.
Garfall
AL
,
Maus
MV
,
Hwang
W-T
, et al
.
Chimeric antigen receptor T cells against CD19 for multiple myeloma
.
N Engl J Med
.
2015
;
373
(
11
):
1040
-
1047
.
34.
Shah
NN
,
Johnson
BD
,
Schneider
D
, et al
.
Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial
.
Nat Med
.
2020
;
26
(
10
):
1569
-
1575
.
35.
Larson
SM
,
Walthers
CM
,
Ji
B
, et al
.
CD19/CD20 bispecific chimeric antigen receptor (CAR) in naive/memory T cells for the treatment of relapsed or refractory non-Hodgkin lymphoma
.
Cancer Discov
.
2023
;
13
(
3
):
580
-
597
.
36.
Lee
L
,
Draper
B
,
Chaplin
N
, et al
.
An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma
.
Blood
.
2018
;
131
(
7
):
746
-
758
.
37.
Wong
DP
,
Roy
NK
,
Zhang
K
, et al
.
A BAFF ligand-based CAR-T cell targeting three receptors and multiple B cell cancers
.
Nat Commun
.
2022
;
13
(
1
):
217
.
38.
Fernández de Larrea
C
,
Staehr
M
,
Lopez
AV
, et al
.
Defining an optimal dual-targeted CAR T-cell therapy approach simultaneously targeting BCMA and GPRC5D to prevent BCMA escape–driven relapse in multiple myeloma
.
Blood Cancer Discov
.
2020
;
1
(
2
):
146
-
154
.
39.
Jaspers
JE
,
Khan
JF
,
Godfrey
WD
, et al
.
IL-18-secreting CAR T cells targeting DLL3 are highly effective in small cell lung cancer models
.
J Clin Invest
.
2023
;
133
(
9
):
e166028
.
40.
Svoboda
J
,
Landsburg
DL
,
Chong
EA
, et al
.
Fourth generation HUCART19-IL18 produces durable responses in lymphoma patients previously relapsed/refractory to anti-CD19 CAR T-cell theraphy
.
Hematol Oncol
.
2023
;
41
(
S2
):
35
-
37
.
41.
Hofgaard
PO
,
Jodal
HC
,
Bommert
K
, et al
.
A novel mouse model for multiple myeloma (MOPC315.BM) that allows noninvasive spatiotemporal detection of osteolytic disease
.
PLoS One
.
2012
;
7
(
12
):
e51892
.
42.
Schmidts
A
,
Ormhøj
M
,
Choi
BD
, et al
.
Rational design of a trimeric APRIL-based CAR-binding domain enables efficient targeting of multiple myeloma
.
Blood Adv
.
2019
;
3
(
21
):
3248
-
3260
.
43.
Carpenter
RO
,
Evbuomwan
MO
,
Pittaluga
S
, et al
.
B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma
.
Clin Cancer Res
.
2013
;
19
(
8
):
2048
-
2060
.
44.
Lam
N
,
Trinklein
ND
,
Buelow
B
,
Patterson
GH
,
Ojha
N
,
Kochenderfer
JN
.
Anti-BCMA chimeric antigen receptors with fully human heavy-chain-only antigen recognition domains
.
Nat Commun
.
2020
;
11
(
1
):
283
. 14.
45.
Qin
H
,
Dong
Z
,
Wang
X
, et al
.
CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies
.
Sci Transl Med
.
2019
;
11
(
511
):
eaaw9414
.
46.
Tirier
SM
,
Mallm
JP
,
Steiger
S
, et al
.
Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell transcriptomics
.
Nat Commun
.
2021
;
12
(
1
):
6960
.
47.
Feucht
J
,
Sun
J
,
Eyquem
J
, et al
.
Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency
.
Nat Med
.
2019
;
25
(
1
):
82
-
88
.
48.
Long
AH
,
Haso
WM
,
Shern
JF
, et al
.
4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors
.
Nat Med
.
2015
;
21
(
6
):
581
-
590
.
49.
Weber
EW
,
Parker
KR
,
Sotillo
E
, et al
.
Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling
.
Science
.
2021
;
372
(
6537
):
eaba1786
.
50.
Guedan
S
,
Posey
AD
,
Shaw
C
, et al
.
Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation
.
JCI Insight
.
2018
;
3
(
1
):
e96976
.
51.
Li
G
,
Boucher
JC
,
Kotani
H
, et al
.
4-1BB enhancement of CAR T function requires NF-κB and TRAFs
.
JCI Insight
.
2018
;
3
(
18
):
e121322
-
18
.
52.
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
.
53.
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
.
54.
James
SE
,
Chen
S
,
Ng
BD
, et al
.
Leucine zipper-based sorting system enables generation of multi-functional CAR T cells
.
bioRxiv
.
2023
.
55.
Morris
EC
,
Neelapu
SS
,
Giavridis
T
,
Sadelain
M
.
Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy
.
Nat Rev Immunol
.
2022
;
22
(
2
):
85
-
96
.
56.
Brudno
JN
,
Kochenderfer
JN
.
J.N. K. Toxicities of chimeric antigen receptor T cells: recognition and management
.
Blood
.
2016
;
127
(
26
):
3321
-
3330
.
57.
Shimabukuro-Vornhagen
A
,
Gödel
P
,
Subklewe
M
, et al
.
Cytokine release syndrome
.
J Immunother Cancer
.
2018
;
6
(
1
):
56
.
58.
Legut
M
,
Gajic
Z
,
Guarino
M
, et al
.
A genome-scale screen for synthetic drivers of T cell proliferation
.
Nature
.
2022
;
603
(
7902
):
728
-
735
.
59.
Croft
M
.
The role of TNF superfamily members in T-cell function and diseases
.
Nat Rev Immunol
.
2009
;
9
(
4
):
271
-
285
.
60.
Dinarello
CA
.
IL-18: AtH1-inducing, proinflammatory cytokine and new member of the IL-1 family
.
J Allergy Clin Immunol
.
1999
;
103
(
1 Pt 1
):
11
-
24
.
61.
Torigoe
K
,
Ushio
S
,
Okura
T
, et al
.
Purification and characterization of the human interleukin-18 receptor
.
J Biol Chem
.
1997
;
272
(
41
):
25737
-
25742
.
62.
Weinstock
JV
,
Blum
A
,
Metwali
A
,
Elliott
D
,
Arsenescu
R
.
IL-18 and IL-12 signal through the NF-kappa B pathway to induce NK-1R expression on T cells
.
J Immunol
.
2003
;
170
(
10
):
5003
-
5007
.
63.
Choi
BK
,
Lee
DY
,
Lee
DG
, et al
.
4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8 + T cell proliferation
.
Cell Mol Immunol
.
2017
;
14
(
9
):
748
-
757
.
64.
Boroughs
AC
,
Larson
RC
,
Marjanovic
ND
, et al
.
A distinct transcriptional program in human CAR T cells bearing the 4-1BB signaling domain revealed by scRNA-seq
.
Mol Ther
.
2020
;
28
(
12
):
2577
-
2592
.
65.
Pahl
HL
.
Activators and target genes of Rel/NF-κB transcription factors
.
Oncogene
.
1999
;
18
(
49
):
6853
-
6866
.
66.
Boston University NF-kB Transcription Factors
.
NF-kB Target Genes
. Accessed 14 February 2024. https://www.bu.edu/nf-kb/gene-resources/target-genes/.
67.
Hinz
M
,
Lemke
P
,
Anagnostopoulos
I
, et al
.
Nuclear factor κB–dependent gene expression profiling of hodgkin’s disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity
.
J Exp Med
.
2002
;
196
(
5
):
605
-
617
.
68.
Catz
SD
,
Johnson
JL
.
Transcriptional regulation of bcl-2 by nuclear factor κB and its significance in prostate cancer
.
Oncogene
.
2001
;
20
(
50
):
7342
-
7351
.
69.
Okamura
H
,
Tsutsui
H
,
Komatsu
T
, et al
.
Cloning of a new cytokine that induces IFN-y production by T cells
.
Nature
.
1995
;
378
(
6552
):
88
-
91
.
70.
Göbel
TW
,
Schneider
K
,
Schaerer
B
, et al
.
IL-18 stimulates the proliferation and IFN-γ release of CD4+ T cells in the chicken: conservation of a Th1-like system in a nonmammalian species
.
J Immunol
.
2003
;
171
(
4
):
1809
-
1815
.
71.
Castro
F
,
Cardoso
AP
,
Gonçalves
RM
,
Serre
K
,
Oliveira
MJ
.
Interferon-gamma at the crossroads of tumor immune surveillance or evasion
.
Front Immunol
.
2018
;
9
:
847
.
72.
Smeltz
RB
.
Profound enhancement of the IL-12/IL-18 pathway of IFN-gamma secretion in human CD8+ memory T cell subsets via IL-15
.
J Immunol
.
2007
;
178
(
8
):
4786
-
4792
.
73.
Okamoto
I
,
Kohno
K
,
Tanimoto
T
,
Ikegami
H
,
Kurimoto
M
.
Development of CD8+ effector T cells is differentially regulated by IL-18 and IL-12
.
J Immunol
.
1999
;
162
(
6
):
3202
-
3211
.
74.
Labanieh
L
,
Mackall
CL
.
CAR immune cells: design principles, resistance and the next generation
.
Nature
.
2023
;
614
(
7949
):
635
-
648
.
75.
Eyquem
J
,
Mansilla-Soto
J
,
Giavridis
T
, et al
.
Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection
.
Nature
.
2017
;
543
(
7643
):
113
-
117
.
76.
Gomes-Silva
D
,
Mukherjee
M
,
Srinivasan
M
, et al
.
Tonic 4-1BB costimulation in chimeric antigen receptors impedes T cell survival and is vector-dependent
.
Cell Rep
.
2017
;
21
(
1
):
17
-
26
.
77.
Haabeth
OAW
,
Hennig
K
,
Fauskanger
M
,
Løset
,
Bogen
B
,
Tveita
A
.
CD4+T-cell killing of multiple myeloma cells is mediated by resident bone marrow macrophages
.
Blood Adv
.
2020
;
4
(
12
):
2595
-
2605
.
78.
Fauskanger
M
,
Haabeth
OAW
,
Skjeldal
FM
,
Bogen
B
,
Tveita
AA
.
Tumor killing by CD4+ T cells is mediated via induction of inducible nitric oxide synthase-dependent macrophage cytotoxicity
.
Front Immunol
.
2018
;
9
:
1684
.
79.
Balasubramani
A
,
Shibata
Y
,
Crawford
GE
,
Baldwin
AS
,
Hatton
RD
,
Weaver
CT
.
Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli
.
Immunity
.
2010
;
33
(
1
):
35
-
47
.
80.
Sica
A
,
Dorman
L
,
Viggiano
V
, et al
.
Interaction of NF-κB and NFAT with the interferon-γ promoter
.
J Biol Chem
.
1997
;
272
(
48
):
30412
-
30420
.
81.
Murray
PJ
.
Macrophage polarization
.
Annu Rev Physiol
.
2017
;
79
:
541
-
566
.
82.
Tugal
D
,
Liao
X
,
Jain
MK
.
Transcriptional control of macrophage polarization
.
Arterioscler Thromb Vasc Biol
.
2013
;
33
(
6
):
1135
-
1144
.
83.
Orecchioni
M
,
Ghosheh
Y
,
Pramod
AB
,
Ley
K
.
Macrophage polarization: different gene signatures in M1(Lps+) vs. classically and M2(LPS-) vs. alternatively activated macrophages
.
Front Immunol
.
2019
;
10
:
1084
.
84.
Kuznetsova
T
,
Prange
KHM
,
Glass
CK
,
de Winther
MPJ
.
Transcriptional and epigenetic regulation of macrophages in atherosclerosis
.
Nat Rev Cardiol
.
2020
;
17
(
4
):
216
-
228
.
85.
Ming-Chin Lee
K
,
Achuthan
AA
,
De Souza
DP
, et al
.
Type I interferon antagonism of the JMJD3-IRF4 pathway modulates macrophage activation and polarization
.
Cell Rep
.
2022
;
39
(
3
):
110719
.
86.
Den Haan
JMM
,
Lehar
SM
,
Bevan
MJ
.
CD8+ but not CD8- dendritic cells cross-prime cytotoxic T cells in vivo
.
J Exp Med
.
2000
;
192
(
12
):
1685
-
1696
.
87.
Møller
SH
,
Wang
L
,
Ho
PC
.
Metabolic programming in dendritic cells tailors immune responses and homeostasis
.
Cell Mol Immunol
.
2022
;
19
(
3
):
370
-
383
.
88.
Helft
J
,
Böttcher
J
,
Chakravarty
P
, et al
.
GM-CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c+MHCII+ macrophages and dendritic cells
.
Immunity
.
2015
;
42
(
6
):
1197
-
1211
.
89.
Na
YR
,
Jung
D
,
Gu
GJ
,
Seok
SH
.
GM-CSF grown bone marrow derived cells are composed of phenotypically different dendritic cells and macrophages
.
Mol Cells
.
2016
;
39
(
10
):
734
-
741
.
90.
Leick
MB
,
Silva
H
,
Scarfò
I
, et al
.
Non-cleavable hinge enhances avidity and expansion of CAR-T cells for acute myeloid leukemia
.
Cancer Cell
.
2022
;
40
(
5
):
494
-
508.e5
.
91.
Cohen
AD
,
Garfall
AL
,
Stadtmauer
EA
, et al
.
B cell maturation antigen–specific CAR T cells are clinically active in multiple myeloma
.
J Clin Invest
.
2019
;
129
(
6
):
2210
-
2221
.
92.
Sun
Y
,
Yang
X-N
,
Yang
S-S
, et al
.
Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity
.
Signal Transduct Target Ther
.
2023
;
8
(
1
):
445
.
93.
Alizadeh
D
,
Wong
RA
,
Gholamin
S
, et al
.
IFNγ is critical for CAR T cell–mediated myeloid activation and induction of endogenous immunity
.
Cancer Discov
.
2021
;
11
(
9
):
2248
-
2265
.
94.
Hu
X
,
Ivashkiv
LB
.
Cross-regulation of signaling pathways by interferon-γ: implications for immune responses and autoimmune diseases
.
Immunity
.
2009
;
31
(
4
):
539
-
550
.
95.
Lee
H
,
Ahn
S
,
Maity
R
, et al
.
Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma
.
Nat Med
.
2023
;
29
(
9
):
2295
-
2306
.
96.
Mantovani
A
,
Allavena
P
,
Marchesi
F
,
Garlanda
C
.
Macrophages as tools and targets in cancer therapy
.
Nat Rev Drug Discov
.
2022
;
21
(
11
):
799
-
820
.
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