Professional Documents
Culture Documents
Abstract | Around 15years ago, imatinib mesylate (Gleevec or Glivec, Novartis, Switzerland)
became the very first targeted anticancer drug to be clinically approved. This drug constitutes
thequintessential example of a successful precision medicine that has truly changed the fate of
patients with Philadelphia-chromosome-positive chronic myeloid leukaemia (CML) and
gastrointestinal stromal tumours by targeting the oncogenic drivers of these diseases, BCRABL1
and KIT and/or PDGFR, mutations in which lead to gain of function of tyrosine kinase activities.
Nonetheless, the aforementioned paradigm might not fully explain the clinical success of this agent
in these diseases. Growing evidence indicates that the immune system has a major role both in
determining the therapeutic efficacy of imatinib (and other targeted agents) and in restraining the
emergence of escape mutations. In this Review, we reevaluate the therapeutic utility of imatinib in
the context of the anticancer immunosurveillance system, and we discuss how this concept might
inform on novel combination regimens that include imatinib withimmunotherapies.
Correspondence to L.Z.
andG.K.
laurence.zitvogel@
gustaveroussy.fr;
kroemer@orange.fr
doi:10.1038/nrclinonc.2016.41
Published online 31 Mar 2016
REVIEWS
Key points
Imatinib does not affect Philadelphia-chromosome-positive haematopoietic stem
cells in patients achieving molecular response (MR); however, prolonged relapse-free
survival can be achieved before treatment discontinuation, implying that efficient
immunosurveillance has been established
In addition to targeting tumoural BCRABL1 and KIT oncogene products, imatinib
modulates protein tyrosine kinases involved in key signalling pathways in both
effector and regulatory immune cells implicated in cancer immunosurveillance
Low-dose imatinib has stimulatory effects on haematopoiesis and can contribute to
immune-mediated clearance of pathogens
In patients with chronic myeloid leukaemia, imatinib elicits antigen-specific Tcell
responses that can protect against relapses in patients with cytogenetically
controlled or minimal disease
Imatinib boosts natural killer-cell-induced IFN secretion and decreases regulatory
Tcell numbers in patients with gastrointestinal tumours; NKp30 isoform patterns
dictate the prognosis of the disease
We propose that novel treatment regimens combining imatinib with
immunotherapies will enable long-term relapse-free survival to be achieved in a
larger number of patients and will prevent the emergence of imatinib-resistant clones
www.nature.com/nrclinonc
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
a The history of the rst TKI in Ph1+ CML
CibaGeigy Lydon
biochemist lead
compound identied
in a screen for PKCi
19901992
First synthesis
of imatinib
First phase I
trials in CML
19961998
In vivo discovery
of tumoricidal
activity in
BCRABL
leukaemia
19982000
Discovery of
c-Kit mutations
in GIST
First phase I
trials in GIST
May 2001
June 2000:
phase III trial
20002001
2004
Lasker award
presented to Druker,
Lydon and Sawyers
20092011
IFN in combination
with TKI in clinical
trials
Discovery
of PDGFR
mutations
in GIST
2002
2004
Imatinib
eects on
NK cells
First immune
predictor of response:
NKp30 isoforms
20112014
On-target eect
of imatinib (IDO)
to suppress
TREG cells
Combination of
dasatinib and
ipilimumab in
refractory GIST
Figure 1 |Key time points in the discovery and development of imatinib for the treatment of chronic myeloid
Nature Reviews
Oncology
leukaemia (CML) and gastrointestinal stromal tumour (GIST). a | Development of imatinib
in CML. A| Clinical
new drug
application was submitted 2years and 9months after the first treatment of a patient with CML, triggering the FDA
approval of imatinib within 3months of the initial application. b | Development of imatinib in GIST. Hirota and
co-authors171 first discovered the somatic gain of function mutations of KIT in patients with GIST. A case report18 and the
outstanding results of the phaseI13 and II trials172 of imatinib led to the rapid launch of two phaseIII trials of this agent.
The first off-target effect of imatinib was demonstrated on NK cells in 2004 (REF.69). PKCi, protein kinase C inhibitor;
TKI,tyrosine kinase inhibitor.
REVIEWS
Box 1 |Imatinib and protein tyrosine kinase signalling in immune cells
The differentiation, proliferation, and effector functions of innate and adaptive immune
cells are orchestrated by intricate signalling pathways involving numerous protein
tyrosine kinases158. The clinical development of imatinib has been guided by its
selectivity for oncogenic variants of ABL1 (BCRABL1) and KIT, although numerous
studies have demonstrated that imatinib can inhibit the unmutated ABL1 protein in
normal immune cells. Indeed, ABL1 and ABL2 are involved in the development of Tcells,
as well as in the function of mature Tcells159. At higher concentrations than those
required for the inhibition of ABL1, imatinib can also inhibit LCK, a kinase that is
essential for signalling via the Tcell receptor160,161, as well as other kinases, including
Bruton tyrosine kinase in Bcells56, macrophage colony-stimulating factor 1 receptor
(CSF1R) in monocytes and macrophages162, and KIT in dendritic cells69. The overall
outcome of imatinib on the antitumour immune response has proved complex, not only
because of the number of potential target signalling pathways in immune cells, but also
owing to their involvement in antagonist populations (effector and regulatory cells),
thedebulking effect causing a reduction in tumour-induced immune tolerance163,
andthe potential immunogenicity of cancer-cell death32
www.nature.com/nrclinonc
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
normalized following imatinib therapy80, probably as a
result of an ontarget effect. Moreover, the Nordic CML
study group81,82 reported that imatinib, as well as dasati
nib, reduced the suppressive functions of MDSC and
restored a TH1like tumour microenvironment.
Collectively, clinical data have shown that long-term
therapy with imatinib can stimulate anticancer responses
mediated by Tcells and NK cells in patients with CML
or GIST, and together with preclinical findings (TABLE1),
outline the likely contribution of innate or adaptive
immune responses to the antitumour effects mediated
by imatinib.
Model
Tumour subtype
orinfection
Immune bioactivity
Specific comments
Imatinib173
Leukaemia-derived
dendritic cells
CML
Imatinib174
A20 lymphoma
Upregulation of antigen
presentation and APCCD4
Tcell response
Overcome tolerance by
potent APC presentation
Imatinib79
Leukaemia and
lymphoma 12B1
andA20
Imatinib175
Bacterial infection
Imatinib176
Viral infection
Imatinib versus
nilotinib177
Plexiform neurofibroma
xenograft
ImatinibFlt3L69
C56BL/6 miceantiNK1.1
antibody or W/Wv mice
ImatinibIL2
B16F10
Mouse GIST
(REF.52)
Depletion of TAM is
associated with increased
tumour weight and decreased
TC1cell infiltrates
Human GIST
xenograft and murine
spontaneous GIST
Superiority of PLX3397to
inhibit the oncogene
Spontaneous GIST in
KitV558/+ tg mice
(REF.133)
ImatinibantiCSF1R
antibody or CSF1R
inhibitor PLX5622
(REF.178)
ImatinibCTLA4
blockade78
APC, antigen-presenting cell; BM, bone-marrow; CML, chronic myeloid leukaemia; DC, dendritic cell; GIST, gastrointestinal stromal tumours; IDO, indoleamine
2,3dioxygenase; IKDC, interferon-producing killer dendritic cell; LAT, linker for activated T cell; LCMV, lymphocytic choriomeningitis virus; OVA, ovalbumine; TAM,
tumour-associated macrophages; TC1, type 1 cytotoxic T; TCR, T-cell receptor; Tg, transgenic; TRAIL, TNF-related apoptosis-inducing ligand; TREG, regulatory T; VSV,
vesicular stomatitis virus.
REVIEWS
Antigen-specific Tcells
Before the TKI era, the main treatment modality for CML
was HSC transplantation (HSCT), and transplantation
remains the main treatment option for patientswho pres
ent with advanced-stage disease and for those whodo not
respond to TKI treatment84. HSCT is considered the only
curative treatment for CML, but is unfortunately associ
ated with greater morbidity and mortality than other
therapies. Remarkably, Tcell depletion before HLAidentical allogeneic bone-marrow transfera proce
dure that is performed to attenuate the graft-versus-host
disease (GVHD) results in an increased rate of relapse
in patients with CML, compared with those who receive
nonT-cell-depleted grafts85. Such relapses could be
avoided by donor lymphocyte infusion (DLI), support
ing the importance of Tcells in the control of CML: the
Tumour type
Immunomonitoring
Remarks
Imatinib70
56
Metastatic GIST
42
CML
CML
Circulating NK proportions
Imatinib101
80
Metastatic GIST
Imatinib
36
Primary GIST
Imatinib83
67 localized
24 metastatic
Imatinib179
6 at diagnosis
9 after imatinib
Chronic-phase
CML
Restoration of plasmacytoid DC
differentiation
Imatinib63
32 responders and
8nonresponders
CML
10
Ph+ ALL
Emergence of BCRABL1specific
CTLs in BM
28
CML
Imatinib versus
dasatinib153
54
CML
Imatinib versus
dasatinib81
(Nordic clinical trial)
Imatinib: n=18
Dasatinib: n=14
CML
Decrease in CD11b+CD14CD33+
MDSCs numbers and inhibitory
molecules, with increased CD40
expression
Imatinib
discontinuation75
Imatinib discontinuation
for >6months: n=16; or,
CMR while on treatment
for >2years: n=14
CML
Imatinib
discontinuation181
9 (discontinued imatinib
after an MMR >2years)
CML
Imatinib+rIL2 (REF.141)
Advanced solid
malignancies
Imatinib+rIFN-2b132
Imatinib
refractory GIST
10 and 16 (+p210/QS21/
GMCSF vaccine)
CML
78
ALL, acute lymphocytic leukaemia; BM, bone marrow; CML, chronic myeloid leukaemia; CMR, complete molecular remission; CNK, conventional natural killer;
DC,dendritic cell; DTH, delayed type hypersensitivity; GIST, gastrointestinal stromal tumours; IHC, immunohistochemistry; LPS, lipopolysaccharide; MDSC,
myeloid-derived suppressor cells; MHC, major histocompatibility complex; MMR, major molecular response; NK, natural killer; TC1, type 1 cytotoxic T; TEM, effector
memory Tcells; TH1, type 1 helper T; TIL,tumour-infiltrating lymphocyte; TKI, tyrosine kinase inhibitor; TREG, regulatory T; TTP, time to treatment progression.
www.nature.com/nrclinonc
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
CTL tness: killing
TH1 cytokine release
Imatinib
CD28
CSF1R
TCR
IDO,
arginase,
CCL2
Mutated
c-Kit or
PDGFR
IDO
NKG2D
ligands
Pro-angiogenic
Pro-broblastic
NKp30
sB7-H6
KIR
B7-H6
Tumour
cell
M2 macrophage
MHC
class I
NK cell anergy
VEGF
Blockade of
T-cell priming
MDSC
Imatinib
TCR signalling
and TEM
responses
Memory B cells
BM CD20+CD5+
sIgM+ B cells
Imatinib
c-Kit
DC dierentiation
DC and NK cell
crosstalk
c-Abl1
and Abl2
LCK
BTK
B cell
Nature Reviews | Clinical Oncology
Figure 2 | Effects of imatinib on components of the anticancer immunosurveillance system. The ontarget effect
of imatinib on oncogenic protein tyrosine kinases (PTKs) is accompanied by decreased expression of indoleamine
2,3dioxygenase (IDO), reduced kynurenin secretion, and the subsequent apoptosis of regulatory T (TREG) cells and relative
expansion of cytotoxic Tcell lymphocytes (CTL), as well as by reduced secretion of VEGF and subsequent antiangiogenic
effects. This direct effect of imatinib also reduces NKG2D ligand expression on neoplastic cells, thereby compromising
their recognition by NKG2Dexpressing natural killer (NK) cells (upper left panel). Myeloid-derived suppressor cell (MDSC)
populations in patients with chronic myeloid leukaemia (CML) at diagnosis, which can be derived from the tumour clone
bearing the BCRABL1 fusion gene, are normalized following imatinib therapy or as a result of reduced VEGF serum
concentrations (upper panels). The imatinib-induced reprogramming of tumour-associated macrophages (TAMs) to an M2
phenotype is an on target process, which involves TAM interaction with apoptotic tumour cells (right upper panel). By
targeting KIT on dendritic cells (DCs), imatinib reduces spontaneous and FLT3Linduced DC differentiation, but permits
DCNK cell crosstalk in lymph nodes and the spleen (lower left panel). Imatinib targets ABL1 and ABL2, as well as LCK,
which are involved in Tcell development and the function of mature Tcells, contributing to decreased Tcell receptor
(TCR)-mediated Tcell proliferation and activation invitro and blunted delayed-type hypersensitivity invivo (lower right
panel). The off-target inhibition of Bruton tyrosine kinase (BTK) by imatinib induces reductions in IgM-expressing
memory-Bcell frequency, hypogammaglobulinaemia, and impaired humoural responses to vaccines. Imatinib can,
however, also promote expansion of a specific bone marrow subset of CD20+CD5+sIgM+ B lymphocytes, inducing higher
plasma levels of IgM specific for Olinked sugars expressed by leukaemic cells (lower right panel).
REVIEWS
Box 2 | Characteristics of imatinib-induced tumour-cell demise
Some conventional anticancer agents can induce tumour-cell stress and death, causing
cells to present or secrete danger-associated molecular patterns (DAMPs) that alert the
innate-immune system, thereby stimulating an anticancer immune response. This
applies to chemotherapeutic agents, such as anthracyclines and oxaliplatin164,
as well as to photodynamic stress165. The underlying mechanisms leading to such an
immunogenic cell death are heterogeneous, but the DAMPs linking immunogenic cell
death to the activation of dendritic cell precursors seem to be mostly chaperones (such
as calreticulin and heat-shock proteins), chemotactic factors (such as ATP), alarmins (for
example, HMGB1), and typeI interferons. Imatinib induces an autophagic response in
tumour cells expressing BCRABL1 or activated KIT45,46,166, and autophagy is a
prominent feature of immunogenic cell death because it facilitates the release of ATP
from dying tumour cells167,168. Imatinib can also induce caspase-independent cell death
with necrosis-like features in BCRABL1positive human leukaemic cells169; necrotic cell
death has prominent pro-inflammatory and perhaps immunogenic properties170,
although this has not been investigated in depth for imatinib-induced cell death.
NKp30 isoforms
Comprehensive phenotyping of peripheral-blood and
GIST-infiltrating NK cells revealed the selective reduc
tion of the expression of one particular NKcell cytotoxic
receptor: NKp30 (REFS70,101). Our group showed that
www.nature.com/nrclinonc
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
a
c-KIT
HLA-I
CD69+
TNF,
IFN
IDO
FOXP3+
IL-10 and
TGF
TReg cell
CD4+ T cell
TNF,
IL-6 and
IL-1
GIST
TNF,
IFN
CSF1R
CD69+
CD8+ T cell
M1 macrophage
Fibrous trabeulae
TNF,
IFN
CD56hi
NKp80hi
CD69+
NK bright
Imatinib
IDO
CD69+
FOXP3+
IL-10 and
TGF
TNF,
IFN
TNF,
IFN
TNF, IL-6
M2 macrophage
TNF,
IFN
and IL-1
Imatinib
CD56hi
NKp80hi
CD69+
TNF,
IFN
NK bright
Nature Reviews | Clinical Oncology
REVIEWS
Immunosuppression and VEGF
VEGF is not only an angiogenic factor and a growth
and survival factor for leukaemic blasts, but also medi
ates broad immunosuppressive activities108110. Imatinib
inhibits VEGF transcription by targeting the Sp1 and
Sp3 transcription factors111. Indeed, the amplification of
BCRABL1 in imatinib-resistant cells is associated with
elevated VEGF expression, which can be suppressed by
escalating the dose of imatinib. The potential prognos
tic value of plasma VEGF concentrations in patients
with CML treated with imatinib has been analysed in
a prospective clinical trial. In the SPIRIT study112, the
French CML group compared the antileukaemic effects
of several imatinib-based combinatorial regimens
in 403 patients with CML, and reported that plasma
VEGF level at diagnosis was an independent predictor
of BCRABL1 burden, with low levels associated with
longer PFS. Of note, the most pronounced drop in cir
culating VEGF concentrations was achieved in the arm
combining imatinib and recombinant IFN-112, which
is the only interferon that is approved for clinical use.
Future prospects
Considering the molecular basis of tumour resistance to
TKIs, various strategies targeting malignant cells have
been attempted to overcome drug resistance113,114. Despite
the putatively deleterious off-target effects ofimatinib on
different immune subsets, the absenceof opportunistic
infections in patients following long-term imatinib treat
ment and their ability to respond to immunotherapies
(such as IFN and DLI) suggest that such patients pos
sess an intact immune system that could be harnessed
to consolidate innate and adaptive immune responses
against the tumour, hence enabling long-term remis
sions or cures after TKI discontinuation. Nonetheless, to
date, immunotherapy with vaccines, NKcell-stimulatory
cytokines, immune-checkpoint blockade or NKp30
targets (FIG.4) have not been implemented in routine
clinical practice.
Vaccination strategies and imatinib
Despite the inability of imatinib to eliminate Ph+ HSC,
therapy discontinuation does not lead to relapse in
40% of patients, suggesting the establishment of adap
tive immune responses with long-term memory2731,115.
Furthermore, results of trials indicate that the deep
molecular response rates achieved in patients with CML
treated with imatinib could warrant therapy discontin
uation in most cases12. The assessment of CML-specific
Tcell responses directed at known or currently unidenti
fied CML antigens in these patients will help define the
role of imatinib-induced Tcells in the definitive cure of
CML. Implementation of immunotherapy approaches
aimed at the enhancement of Tcell responses to the
most-meaningful antigens could increase the proportion
of patients experiencing relapse-free survival following
imatinib discontinuation.
The identification of CML-specific tumour antigens
has provided the opportunity to perform vaccine trials,
most of which dealt with vaccines comprising peptide
epitopes spanning the BCRABL1 fusion region116,117.
www.nature.com/nrclinonc
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
a
APC
CTLA4
TCR
CTLA4
TCR
PD-L1
or PD-L2
APC
PD-1
PD-1
LAG3
KIR
CD28
TIM3
CD28
PD-L1
or PD-L2
TIM3
Bispecic antibodies
B7-H6 or KIT
CD3
LAG3
KIR
CD28
CD40
MHCpeptide
TCR
APC
APC
T cell
B7
NK-cell-stimulatory
cytokines (IFN type I, IL-15)
e Re-establishing immuno-
APC
Re-establishing
MHC class I
IDOi
KIT
IDO
Flt3L
Anti-CSF1R KIT
Restoring DC
Blocking M2
IFN/
IFN
Chloroquine
B7-H3 PD-L1?
Autophagy
inhibition
CD28
f
TKI
NK-cell
stimulation
Blocking TREG
Reversing
NKp30
phenotype
Novel ICB
Bispecic ICB
Reprogramming
the inltrate
anti-CSFR1, CSF1,
anti-IL-10, anti-FAP etc.
Antagonistic
antibodies
Figure 4 | Combination immunotherapeutic approaches with imatinib. Several complementary treatment approaches
Nature Reviews | Clinical Oncology
could be envisioned in combination with first-generation or second-generation tyrosine kinase inhibitors (TKIs). The Tcell
arm of immune responses could be ameliorated with peptidebased or protein-based vaccines, with immune-checkpoint
inhibitors (such as the anti-cytotoxic-Tlymphocyte-associated-antigen4 antibody ipilimumab, which depletes TREG cells
in the tumour), with dendritic cell (DC) growth factors (such as FLT3L) and DC adjuvants (such as Toll-like receptor (TLR)
agonists, antiCD40 agonistic antibodies, or others). The natural killer (NK)-cell arm of immunity could be boosted with
NKcell-stimulatory cytokines (such as IL15 or typeI interferon), with anti-KIR antibody or antiIL10 antibody, mostly in
patients with an unfavourable NKp30 isoform profile. Chimeric antigen receptor (CAR) Tcells can be engineered to
express the extracellular domain of NKp30 or antibodies recognizing B7H6 to promote killing of cells expressing NKp30
ligands and B7H6, respectively. Blocking indoleamine 2,3dioxygenase (IDO) enzymatic activity or reprogramming
M2type tumour-associated macrophages (TAM) using antiCSF1R (macrophage colony-stimulating factor 1 receptor)
orsmall-molecule inhibitors of CSF1R signalling could be instrumental in preventing the proangiogenic and/or
profibroblastic effects of TAM after TKI therapy. ICB, immune checkpoint blockade; KIR, killer IgG-like receptor.
REVIEWS
median followup of 3.6years, one patient died of an
unrelated illness while in remission, and six of seven
evaluable patients had ongoing partial or complete
responses (five patients), or had a PFS duration (one
patient) exceeding the expected genotype-specific-PFS,
based on the phaseIII imatinib monotherapy trial data
(CALGB150105/SWOGS0033)132. This highly promising
pilot study underscores that the combination of imati
nib and IFN warrants further development in patients
withGIST132.
Given the capacity of imatinib to boost NKcell func
tions, our group analysed the combination of imatinib
with IL2, an NKcell-stimulatory cytokine. When com
bined with IL2, imatinib induced the intratumoural
accumulation of a subset of premature NK cells, a CD3
CD19B220+CD49b+CD11cdimMHC classII+ subpopula
tion, which is endowed with antigen presenting as well as
TRAIL-dependent lytic functions133136the latter upon
trans-presentation of IL15 by IL15R137,138. On the basis
of synergistic anticancer activity of the combination of
imatinib with IL2 in metastatic tumour models139, we
launched a phaseI clinical trial in 17 patients with refrac
tory solid malignancies to determine the maximum toler
ated dose (MTD) of recombinant IL2 (rIL2) combined
with metronomic cyclophosphamide and imatinib140,141.
rIL2 markedly changed the pharmacokinetics of imati
nib, increasing the blood concentrations of its main
metabolite. Conversely, when combined with imatinib,
the MTD of rIL2 was reduced to 6 MIU daily for 5 con
secutive days. The combination therapy markedly dimin
ished the absolute counts of circulating Bcells, CD4+
Tcells and CD8+ Tcells in a dose-dependent manner;
NK cells upregulated HLADR, TRAIL, and CD56 sur
face expression. Importantly, the abundance of HLADR+
NK cells after one course of combination therapy was
positively correlated with the PFS and overall survival of
patients141. This combinatorial regimen warrants further
investigation in phaseII clinical trials, possibly in patients
with GIST, a setting in which Tcells and NK cells seem
to have an important therapeutic role.
www.nature.com/nrclinonc
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
other TKIs only mediate long-term anticancer effects in
a context in which NK cells and T lymphocytes are fully
functional. Second, in patients with GIST, the compo
sition and function of the NKcell and Tcell infiltrates
of the tumour predicts clinical outcome after imatinib
treatment83,101. Third, the functional competence of NK
cells (and relative expression of NKp30 isoforms) dic
tates the long-term fate of patients with GIST treated with
imatinib. Fourth, imatinib affects the composition of the
immune infiltrate of GISTs, and this dynamic parameter
affects clinical outcome83. Fifth, imatinib can cause atypi
cal stress and death of CML orGIST cells, and this might
contribute to priming and/or recruitment of innate-im
mune effectors. Sixth, imatinib directly and indirectly
inhibits TREG cells and MDSCs, hence removing a major
break on anticancer immunity. Some evidence exists
that TKIs targeting the same receptor kinases as imati
nib can stimulate tumour-specific NKcell and Tcell
responses81,153 (TABLE2); however, it remains to be seen
whether other TKIs can stimulate anticancer immune
responses. BRAF inhibitors might stimulate anti-
melanoma immune responses, which might prolong the
clinical efficacy of these agents154.
Imatinib and next-generation agents have mediated
long-term therapeutic effects that, in many patients with
CML, persist well beyond cessation of the treatment2830.
It is tempting to speculate that the characteristics of the
de Klein,A. etal. A cellular oncogene is translocated
to the Philadelphia chromosome in chronic myelocytic
leukaemia. Nature 300, 765767 (1982).
2. Deininger,M.W., Goldman,J.M. & Melo,J.V.
Themolecular biology of chronic myeloid leukemia.
Blood 96, 33433356 (2000).
3. Sawyers,C.L. Chronic myeloid leukemia.
N.Engl.J.Med. 340, 13301340 (1999).
4. Buchdunger,E. etal. Selective inhibition of the
platelet-derived growth factor signal transduction
pathway by a protein-tyrosine kinase inhibitor of the
2phenylaminopyrimidine class. Proc. Natl Acad. Sci.
USA 92, 25582562 (1995).
5. Druker,B.J. etal. Effects of a selective inhibitor of the
Abl tyrosine kinase on the growth of BcrAbl positive
cells. Nat. Med. 2, 561566 (1996).
6. Druker,B.J. & Lydon,N.B. Lessons learned from the
development of an Abl tyrosine kinase inhibitor for
chronic myelogenous leukemia. J.Clin. Invest. 105,
37 (2000).
7. Deininger,M.W., Goldman,J.M., Lydon,N.
& Melo,J.V. The tyrosine kinase inhibitor
CGP57148B selectively inhibits the growth of
BCRABL-positive cells. Blood 90, 36913698
(1997).
8. Druker,B.J. etal. Efficacy and safety of a specific
inhibitor of the BCRABL tyrosine kinase in chronic
myeloid leukemia. N.Engl. J.Med. 344, 10311037
(2001).
9. Abt,M.C. etal. Commensal bacteria calibrate the
activation threshold of innate antiviral immunity.
Immunity 37, 158170 (2012).
10. Druker,B.J. etal. Five-year followup of patients
receiving imatinib for chronic myeloid leukemia.
N.Engl. J.Med. 355, 24082417 (2006).
11. Hughes,T.P. etal. Long-term prognostic significance
of early molecular response to imatinib in newly
diagnosed chronic myeloid leukemia: an analysis from
the International Randomized Study of Interferon and
STI571 (IRIS). Blood 116, 37583765 (2010).
12. Kalmanti,L. etal. Safety and efficacy of imatinib in
CML over a period of 10years: data from the
randomized CML-study IV. Leukemia 29, 11231132
(2015).
13. van Oosterom,A.T. etal. Safety and efficacy of
imatinib (STI571) in metastatic gastrointestinal
stromal tumours: a phaseI study. Lancet 358,
14211423 (2001).
1.
REVIEWS
37. Shin,J.Y., Hu,W., Naramura,M. & Park,C.Y. High
cKit expression identifies hematopoietic stem cells
with impaired self-renewal and megakaryocytic bias.
J.Exp. Med. 211, 217231 (2014).
38. Bodine,D.M., Seidel,N.E., Zsebo,K.M. & Orlic,D.
Invivo administration of stem cell factor to mice
increases the absolute number of pluripotent
hematopoietic stem cells. Blood 82, 445455
(1993).
39. Thoren,L.A. etal. Kit regulates maintenance of
quiescent hematopoietic stem cells. J.Immunol. 180,
20452053 (2008).
40. Napier,R.J. etal. Low doses of imatinib induce
myelopoiesis and enhance host anti-microbial
immunity. PLoS Pathog. 11, e1004770 (2015).
41. Garcia,M. etal. Productive replication of Ebola virus
is regulated by the c-Abl1 tyrosine kinase. Sci. Transl.
Med. 4, 123ra24 (2012).
42. Swimm,A.I. etal. Abl family tyrosine kinases
regulate sialylated ganglioside receptors for
polyomavirus. J.Virol. 84, 42434251 (2010).
43. Wetzel,D.M., McMahon-Pratt,D. & Koleske,A.J.
The Abl and Arg kinases mediate distinct modes of
phagocytosis and are required for maximal
Leishmania infection. Mol. Cell. Biol. 32, 31763186
(2012).
44. Reeves,P.M. etal. Disabling poxvirus pathogenesis
by inhibition of Abl-family tyrosine kinases. Nat. Med.
11, 731739 (2005).
45. Sheng,Z., Ma,L., Sun,J.E., Zhu,L.J. & Green,M.R.
BCRABL suppresses autophagy through
ATF5mediated regulation of mTOR transcription.
Blood 118, 28402848 (2011).
46. Helgason,G.V., Karvela,M. & Holyoake,T.L. Kill one
bird with two stones: potential efficacy of BCRABL
and autophagy inhibition in CML. Blood 118,
20352043 (2011).
47. Appel,S. etal. Imatinib mesylate affects the
development and function of dendritic cells generated
from CD34+ peripheral blood progenitor cells. Blood
103, 538544 (2004).
48. Appel,S. etal. Effects of imatinib on monocytederived dendritic cells are mediated by inhibition
ofnuclear factor-B and Akt signaling pathways.
Clin.Cancer Res. 11, 19281940 (2005).
49. Taieb,J., Maruyama,K., Borg,C., Terme,M.
& Zitvogel,L. Imatinib mesylate impairs
Flt3Lmediated dendritic cell expansion and
antitumor effects invivo. Blood 103, 19661967;
author reply 1967 (2004).
50. Boissel,N. etal. Defective blood dendritic cells in
chronic myeloid leukemia correlate with high
plasmatic VEGF and are not normalized by imatinib
mesylate. Leukemia 18, 16561661 (2004).
51. van Dongen,M. etal. Anti-inflammatory M2 type
macrophages characterize metastasized and tyrosine
kinase inhibitor-treated gastrointestinal stromal
tumors. Int. J.Cancer 127, 899909 (2010).
52. Cavnar,M.J. etal. KIT oncogene inhibition drives
intratumoral macrophage M2 polarization.
J.Exp.Med. 210, 28732886 (2013).
53. Dietz,A.B. etal. Imatinib mesylate inhibits Tcell
proliferation invitro and delayed-type hypersensitivity
invivo. Blood 104, 10941099 (2004).
54. Seggewiss,R. etal. Imatinib inhibits Tcell receptormediated Tcell proliferation and activation in a dosedependent manner. Blood 105, 24732479 (2005).
55. Gao,H. etal. Imatinib mesylate suppresses cytokine
synthesis by activated CD4 Tcells of patients with
chronic myelogenous leukemia. Leukemia 19,
19051911 (2005).
56. de Lavallade,H. etal. Tyrosine kinase inhibitors
impair Bcell immune responses in CML through
off-target inhibition of kinases important for cell
signaling. Blood 122, 227238 (2013).
57. Steegmann,J.L. etal. Chronic myeloid leukemia
patients resistant to or intolerant of interferon alpha
and subsequently treated with imatinib show reduced
immunoglobulin levels and hypogammaglobulinemia.
Haematologica 88, 762768 (2003).
58. Cervetti,G. etal. Reduction of immunoglobulin levels
during imatinib therapy of chronic myeloid leukemia.
Leuk. Res. 32, 191192 (2008).
59. Carulli,G. etal. Reduced circulating Blymphocytes
and altered Bcell compartments in patients suffering
from chronic myeloid leukaemia undergoing therapy
with Imatinib. Hematol. Oncol. 33, 250252 (2014).
60. Carulli,G. etal. Abnormal phenotype of bone marrow
plasma cells in patients with chronic myeloid leukemia
undergoing therapy with Imatinib. Leuk. Res. 34,
13361339 (2010).
www.nature.com/nrclinonc
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2
REVIEWS
104. Binici,J. etal. A soluble fragment of the tumor
antigen BCL2associated athanogene 6 (BAG6) is
essential and sufficient for inhibition of NKp30
receptor-dependent cytotoxicity of natural killer cells.
J.Biol. Chem. 288, 3429534303 (2013).
105. Reiners,K.S. etal. Soluble ligands for NK cell
receptors promote evasion of chronic lymphocytic
leukemia cells from NK cell anti-tumor activity. Blood
121, 36583665 (2013).
106. Brandt,C.S. etal. The B7 family member B7H6 is a
tumor cell ligand for the activating natural killer cell
receptor NKp30 in humans. J.Exp. Med. 206,
14951503 (2009).
107. Semeraro,M. etal. Clinical impact of the NKp30/
B7H6 axis in high-risk neuroblastoma patients.
Sci.Transl. Med. 7, 283ra55 (2015).
108. Voron,T. etal. VEGFA modulates expression of
inhibitory checkpoints on CD8+ Tcells in tumors.
J.Exp. Med. 212, 139148 (2015).
109. Terme,M., Tartour,E. & Taieb,J. VEGFA/VEGFR2targeted therapies prevent the VEGFA-induced
proliferation of regulatory Tcells in cancer.
Oncoimmunology 2, e25156 (2013).
110. Motz,G.T. etal. Tumor endothelium FasL establishes
a selective immune barrier promoting tolerance in
tumors. Nat. Med. 20, 607615 (2014).
111. Legros,L. etal. Imatinib mesylate (STI571) decreases
the vascular endothelial growth factor plasma
concentration in patients with chronic myeloid
leukemia. Blood 104, 495501 (2004).
112. Legros,L. etal. Interferon decreases VEGF levels in
patients with chronic myeloid leukemia treated with
imatinib. Leuk. Res. 38, 662665 (2014).
113. Gramza,A.W., Corless,C.L. & Heinrich,M.C.
Resistance to tyrosine kinase inhibitors in
gastrointestinal stromal tumors. Clin. Cancer Res. 15,
75107518 (2009).
114. Cioffi,A. & Maki,R.G.G.I. Stromal tumors: 15 years
of lessons from a rare cancer. J.Clin. Oncol. 33,
18491854 (2015).
115. Yhim,H.Y. etal. Imatinib mesylate discontinuation
inpatients with chronic myeloid leukemia who have
received front-line imatinib mesylate therapy and
achieved complete molecular response. Leuk. Res. 36,
689693 (2012).
116. Greiner,J. & Schmitt,M. Leukemia-associated
antigens as target structures for a specific
immunotherapy in chronic myeloid leukemia.
Eur.J.Haematol. 80, 461468 (2008).
117. Li,Y., Lin,C. & Schmidt,C.A. New insights into
antigen specific immunotherapy for chronic myeloid
leukemia. Cancer Cell. Int. 12, 52 (2012).
118. Cathcart,K. etal. A multivalent bcrabl fusion
peptidevaccination trial in patients with chronic
myeloid leukemia. Blood 103, 10371042 (2004).
119. Bocchia,M. etal. Effect of a p210 multipeptide
vaccine associated with imatinib or interferon in
patients with chronic myeloid leukaemia and
persistent residual disease: a multicentre
observational trial. Lancet 365, 657662 (2005).
120. Maisonneuve,C., Bertholet,S., Philpott,D.J. &
DeGregorio,E. Unleashing the potential of NODandToll-like agonists as vaccine adjuvants. Proc. Natl
Acad. Sci. USA 111, 1229412299 (2014).
121. Valmori,D. etal. Vaccination with NYESO1 protein
and CpG in Montanide induces integrated antibody/
Th1 responses and CD8 Tcells through crosspriming.Proc. Natl Acad. Sci. USA 104, 89478952
(2007).
122. Sabbatini,P. etal. Phase I trial of overlapping long
peptides from a tumor self-antigen and poly-ICLC
shows rapid induction of integrated immune response
in ovarian cancer patients. Clin. Cancer Res. 18,
64976508 (2012).
123. De Carvalho,D.D. etal. BCRABL-mediated
upregulation of PRAME is responsible for knocking
down TRAIL in CML patients. Oncogene 30,
223233 (2011).
124. Perez,D. etal. Cancer testis antigen expression in
gastrointestinal stromal tumors: new markers for
early recurrence. Int. J.Cancer 123, 15511555
(2008).
125. Perez,D. etal. Protein expression of cancer
testisantigens predicts tumor recurrence and
treatment response to imatinib in gastrointestinal
stromal tumors. Int. J.Cancer 128, 29472952
(2011).
126. Talpaz,M., Hehlmann,R., Quintas-Cardama,A.,
Mercer,J. & Cortes,J. Reemergence of interferon-
in the treatment of chronic myeloid leukemia.
Leukemia 27, 803812 (2013).
REVIEWS
175. Sinai,P. etal. Imatinib mesylate inhibits antigenspecific memory CD8 Tcell responses invivo.
J.Immunol. 178, 20282037 (2007).
176. Mumprecht,S., Matter,M., Pavelic,V.
& Ochsenbein,A.F. Imatinib mesylate selectively
impairs expansion of memory cytotoxic Tcells
withoutaffecting the control of primary viral
infections.Blood 108, 34063413 (2006).
177. Wei,J. etal. Nilotinib is more potent than imatinib
fortreating plexiform neurofibroma invitro and
invivo. PLoS ONE 9, e107760 (2014).
178. Kim,T.S. etal. Increased KIT inhibition enhances
therapeutic efficacy in gastrointestinal stromal
tumor.Clin. Cancer Res. 20, 23502362 (2014).
179. Mohty,M. etal. Imatinib and plasmacytoid
dendriticcell function in patients with chronic
myeloidleukemia. Blood 103, 46664668
(2004).
Acknowledgements
Author contributions
www.nature.com/nrclinonc
.
d
e
v
r
e
s
e
r
s
t
h
g
i
r
l
l
A
.
d
e
t
i
m
i
L
s
r
e
h
s
i
l
b
u
P
n
a
l
l
i
m
c
a
M
6
1
0
2