Download A two-pronged attack against mantle cell lymphoma

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l l l LYMPHOID NEOPLASIA
Comment on Bhatt et al, page 1555
A two-pronged attack against
mantle
cell lymphoma
----------------------------------------------------------------------------------------------------Christian Steidl
BRITISH COLUMBIA CANCER AGENCY
In this issue of Blood, Bhatt et al describe direct cytotoxic and indirect immune
cell-mediated effects of interleukin-21 (IL-21) in mantle cell lymphoma (MCL),
providing a preclinical rationale for IL-21 therapy in this aggressive disease.1
M
CL is a virtually incurable aggressive
non-Hodgkin lymphoma with short
median overall survival. The addition of antiCD20 immunotherapy (rituximab), intensified
frontline therapy, and consolidative autologous
transplantation regimens has made some
impact on improved response rates, duration
of remissions, and overall survival, but,
despite these improvements, MCL continues
to have one of the worst outcomes of all
B-cell lymphomas.2 It can be anticipated that
improved biomarker and associated risk
stratification approaches, in conjunction with
these standard therapies, may somewhat
improve outcome, but the task at hand appears
abundantly clear: entirely novel treatment
approaches have to be explored. Over the last
decade, a number of targeted agents have already
been approved for MCL therapy, including
bortezomib (proteasome inhibitor),
lenalidomide (immunomodulatory drug),
ibrutinib (Bruton tyrosine kinase [BTK]
inhibitor), and temsirolimus (mechanistic
target of rapamycin [mTOR] inhibitor). Some of
these new drugs, BTK inhibitors in particular,3
might change the entire treatment landscape of
MCL in the near future and also the clinical
value of related predictive biomarkers.
However, there is another aspect of the
most recent additions to the armamentarium
of available drugs in MCL that fuels hope for
significantly improved survival, namely, drug
effects on the nonmalignant immune cells.
Although microenvironment biology, niche
formation, and host-specific factors are still
somewhat underappreciated, the pathogenic
importance of nonmalignant cell populations
in current disease models is increasingly
recognized.4 Most excitingly, strong clinical
activity is documented for a number of drugs
with molecular targets outside of the malignant
cell population, of which immune checkpoint
inhibitors are probably the most widely known
class of drugs. For example, programmed cell
death-1 blockade (nivolumab) has shown
convincing activity in Hodgkin lymphoma,
a disease that is characterized by immune
privilege and extensive cross talk between the
malignant and nonmalignant cells.5 Ibrutinib
and idelalisib (a phosphatidylinositol 3-kinase d
inhibitor) exert significant effects on natural
killer (NK) cells, T cells, macrophages, and
osteoclasts that appear to augment therapeutic
effects, although some mechanisms might also
lead to antagonistic effects with concurrent
rituximab therapy.6 Moreover, the activity of
lenalidomide has long been associated with
direct cytotoxic and indirect immunomodulatory
effects via T- and NK-cell activation and
a change in cytokine secretion profiles.7 Another
example is the treatment of Hodgkin lymphoma
with the bispecific tetravalent antibody AFM13
(anti-CD30/CD16a), which recruits and
engages NK cells in the direct vicinity of CD301
neoplastic cells.8 Although the paradigm of
simultaneous treatment of cancer cells and
host cells is established in principle, more insight
into the biological consequences of these dual
treatments is needed for drug development
and future clinical trial design.
Bhatt et al provide another example of
a two-pronged attack on both the malignant
cells and host immune cells in the form of
preclinical studies of IL-21 in in vitro and in
vivo models (see figure). Using established
MCL-derived cell lines, the authors
convincingly dissect the molecular pathway
of IL-21–induced cell death via IL-21
receptor–dependent signaling and STAT3dependent MYC upregulation (direct
cytotoxicity). Similar dependencies have been
demonstrated by the same group in diffuse
BLOOD, 24 SEPTEMBER 2015 x VOLUME 126, NUMBER 13
large B-cell lymphoma.9 Overall, the cytotoxic
effects of IL-21 and related MYC expression
are now well documented in two B-cell
lymphoma entities and are in agreement with
proapoptotic effects of IL-21 on activated and
naı̈ve B cells. However, a number of MCLderived cell lines are resistant to IL-21 in vitro,
and the exact resistance mechanisms need to
be determined in future studies. Interestingly,
the authors provide some evidence that the
level of MYC induction after IL-21 stimulation
might be linked to IL-21 sensitivity, suggesting
that (dynamic) MYC expression could be
evaluated as a biomarker. The indirect
effects of IL-21 treatment are related to NK
cell-dependent lysis of tumor cells, and the
presented in vivo data in a syngeneic mouse
transplantation model strongly suggest that
antitumor effects are dominated by enhanced
activity of CD41 T and NK cells. In this
proof-of-concept study, the authors chose to
treat the mice via intratumoral injections, and
it remains to be determined whether the
observed direct and indirect therapeutic effects
of IL-21, their relative contribution to tumor
reduction, and the composition of the tumor
microenvironment by histologic examination
will be dependent on the route of
administration (intravenous vs intratumoral).
The presented data provide a solid
preclinical rationale to consider recombinant
IL-21 in MCL therapy, in particular because
the indirect effects on immune effector cells in
the tumor microenvironment or in the
circulation might maintain activity in tumors
that harbor primary resistance to the
proapoptotic effects. But how exactly should
this approach move forward? Recombinant
IL-21 therapy has now been tested in renal cell
carcinoma, metastatic melanoma, and, most
recently, indolent B-cell lymphomas with
clearly demonstrated clinical activity.10 In the
last phase 1 trial, including patients with
relapsed small lymphocytic lymphoma/
chronic lymphocytic leukemia, follicular
lymphoma, and marginal zone lymphoma,
IL-21 was combined with rituximab via
intravenous bolus injections, with clinical
response in 42% of patients. It appears that
combination therapy with IL-21 will also be
a way forward in future trials including MCL;
however, with the emergence of other new
drugs in this indication, the ideal combination
partners of IL-21 have to be carefully
considered based on theoretical biological
synergies. Overall, Bhatt et al report
1521
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Antitumor activity of IL-21 in mantle cell lymphoma. The main (A) direct and (B) indirect effects are shown. Direct effect: IL-21 receptor engagement leads to activation of the intrinsic
apoptotic pathway in neoplastic cells in a STAT3- and MYC-dependent manner. Indirect effects: IL-21 increases NK and CD41 T-cell activity in the tumor microenvironment and leads
to enhanced lysis of tumor cells.
a promising therapeutic intervention in MCL
that reinforces the concept of concomitant
“tumor and host” treatment. This type of dual
treatment might represent a new standard for
clinical trial design that should incorporate
assessment of microenvironment biology and
related biomarker development. Leveraging
this concept, a brighter future might be ahead
for patients with MCL and other hard-to-treat
malignancies.
1522
Conflict-of-interest disclosure: The author
declares no competing financial interests. n
3. Wang ML, Rule S, Martin P, et al. Targeting BTK
with ibrutinib in relapsed or refractory mantle-cell
lymphoma. N Engl J Med. 2013;369(6):507-516.
REFERENCES
4. Scott DW, Gascoyne RD. The tumour
microenvironment in B cell lymphomas. Nat Rev
Cancer. 2014;14(8):517-534.
1. Bhatt S, Matthews J, Parvin S, et al. Direct and
immune-mediated cytotoxicity of interleukin-21
contributes to antitumor effects in mantle cell lymphoma.
Blood. 2015;126(13):1555-1564.
2. Campo E, Rule S. Mantle cell lymphoma:
evolving management strategies. Blood. 2015;125(1):
48-55.
5. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1
blockade with nivolumab in relapsed or refractory
Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):
311-319.
6. Maffei R, Fiorcari S, Martinelli S, Potenza L, Luppi
M, Marasca R. Targeting neoplastic B cells and harnessing
BLOOD, 24 SEPTEMBER 2015 x VOLUME 126, NUMBER 13
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
microenvironment: the “double face” of ibrutinib and
idelalisib. J Hematol Oncol. 2015;8:60.
up-regulates c-Myc and induces apoptosis of diffuse large
B-cell lymphomas. Blood. 2010;115(3):570-580.
7. Gribben JG, Fowler N, Morschhauser F. Mechanisms
of action of lenalidomide in B-cell non-Hodgkin lymphoma.
J Clin Oncol. 2015;33(25):2803-2811.
10. Timmerman JM, Byrd JC, Andorsky DJ, et al. A
phase I dose-finding trial of recombinant interleukin-21
and rituximab in relapsed and refractory low grade B-cell
lymphoproliferative disorders. Clin Cancer Res. 2012;
18(20):5752-5760.
8. Rothe A, Sasse S, Topp MS, et al. A phase 1 study of the
bispecific anti-CD30/CD16A antibody construct AFM13 in
patients with relapsed or refractory Hodgkin lymphoma. Blood.
2015;125(26):4024-4031.
9. Sarosiek KA, Malumbres R, Nechushtan H, Gentles
AJ, Avisar E, Lossos IS. Novel IL-21 signaling pathway
DOI 10.1182/blood-2015-08-662106
© 2015 by The American Society of Hematology
l l l MYELOID NEOPLASIA
Comment on Cheng et al, page 1585
Nuclear, not cytoplasmic,
PKR
maneuvers in AML
----------------------------------------------------------------------------------------------------Motohiko Oshima and Atsushi Iwama
CHIBA UNIVERSITY
In this issue of Blood, Cheng et al have identified a novel and previously
unrecognized nuclear function of double-stranded RNA-activated protein kinase
(PKR) in the pathogenesis of acute myeloid leukemia (AML). Increased PKR
promotes genomic instability and is associated with inferior outcomes in both
AML and a mouse model of myelodysplastic syndrome (MDS) and leukemia.
Thus, nuclear PKR has an oncogenic function and can be a novel therapeutic
target to prevent leukemia progression or relapse and improve clinical outcomes.1
P
KR is a ubiquitously expressed serine and
threonine protein kinase that was initially
characterized as an antiviral protein induced
by interferon (IFN).2 PKR is now known to
have multifaceted roles in the regulation of
inflammatory immune responses (see figure).3
PKR in the cytoplasm is activated by multiple stimuli, such as cytokines (IFNs, etc), bacterial and viral infection, and DNA
damage. Active PKR triggers production of IFNs and proinflammatory cytokines, apoptosis, and autophagy. In this study,
Cheng et al showed that nuclear PKR activates PP2A by promoting nuclear localization of the regulatory B subunit (B55a).
Activated PP2A in turn antagonizes autophosphorylation and activation of ATM, thereby inhibiting DNA damage response.
P indicates phosphorylation. See Figure 4I in the article by Cheng et al beginning on page 1585.
BLOOD, 24 SEPTEMBER 2015 x VOLUME 126, NUMBER 13
PKR in the cytoplasm is activated by multiple
stimuli, such as cytokines (IFNs, etc), bacterial
and viral infection, and DNA damage through
a mechanism involving its dimerization and
autophosphorylation. Active PKR triggers
signaling of several pathways and regulates
transcription to produce IFNs and
proinflammatory cytokines. In addition,
PKR triggers apoptosis through Fas-associated
protein with death domain (FADD)–mediated
activation of caspase-8, and autophagy through
eukaryotic initiation factor 2a (eIF2a)–mediated
activation of the microtubule-associated protein
LC3. PKR is also required for inflammasome
activation and promotes the release of
inflammasome-dependent cytokines, such
as IL-1b, IL-18, and HMGB1.4
Because of its proapoptotic functions, PKR
has been considered to have tumor-suppressor
activities. Indeed, the loss of PKR catalytic
activity and an inactivating mutation in PKR
have been detected in B-cell chronic
lymphocytic leukemia and T-cell acute
lymphoblastic leukemia, respectively.5,6
However, the authors have previously
demonstrated that mice expressing a PKR
transgene specifically in hematopoietic cells
develop an MDS-like phenotype with
pancytopenia and bone marrow dysplasia.
Furthermore, increased PKR has been
reported in patients with acute leukemias.7
This evidence suggested that PKR has
a previously unrecognized role in
tumorigenesis. Although PKR’s role in the
cytoplasm has been well characterized as
described above, PKR also resides in the nucleus
but the function of nuclear PKR remained
unclear. Of interest, active PKR appeared to
be mainly nuclear in high-risk MDS patient
samples and acute leukemia cell lines deficient
in phosphatase and tensin homologue (PTEN),
whereas it was mostly cytoplasmic in low-risk
MDS patient samples and PTEN-positive
acute leukemia cell lines, supporting that nuclear
PKR may play a role in tumorigenesis.8
In this study, the authors first demonstrated
that high PKR expression in CD341 AML
cells from 414 newly diagnosed AML patients
correlated with worse survival and shortened
remission duration. This trend was also true in
large cohort studies of breast, lung, and ovarian
cancer patients available from published
reports and databases. These findings
contradict the previously believed tumorsuppressive role of PKR based on its
proapoptotic function in the cytoplasm.
1523
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2015 126: 1521-1523
doi:10.1182/blood-2015-08-662106
A two-pronged attack against mantle cell lymphoma
Christian Steidl
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