Download Targeting the PD-1/PD-L1 axis in multiple myeloma

From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
Blood Spotlight
Targeting the PD-1/PD-L1 axis in multiple myeloma: a dream or
a reality?
Jacalyn Rosenblatt and David Avigan
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
The programmed cell death protein 1
(PD-1)/programmed cell death ligand 1
(PD-L1) pathway is a negative regulator
of immune activation that is upregulated
in multiple myeloma and is a critical
component of the immunosuppressive
tumor microenvironment. Expression is
increased in advanced disease and in
the presence of bone marrow stromal
cells. PD-1/PD-L1 blockade is associated with tumor regression in several
malignancies, but single-agent activity
is limited in myeloma patients. Combination therapy involving strategies to
expand myeloma-specific T cells and
T-cell activation via PD-1/PD-L1 blockade
are currently being explored. (Blood.
2017;129(3):275-279)
Introduction
Malignant cells evade host immunity through the activation of biologic
systems that suppress antigen presentation and effector cell function
and create an immunosuppressive milieu in the tumor microenvironment. Immunotherapeutic strategies seek to activate native innate and
adaptive anti-tumor immunity by reversing critical components of
tumor-mediated immune suppression.1 Antigen-presenting and
immune-effector cells interact via a complex series of inhibitory and
stimulatory signals that maintain the equilibrium between activation
and tolerance. This system helps mount responses that target foreign
pathogens while avoiding the expansion of autoreactive clones with
ensuing tissue damage. A series of positive and negative co-stimulation
signals have been identified that modulate the T-cell response between
activation and anergy, respectively.2 The presence of danger signals
induced by viral-mediated cytotoxic injury favors the increased
expression of positive co-stimulatory signals and the induction of
immunologic response.3 In contrast, a panel of negative co-stimulatory
factors, including the programmed cell death ligand 1 (PD-L1)/
programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte–
associated protein 4 (CTLA-4)/CD28, TIM-3/galectin-9, and LAG3,
mediate tolerance such that genetic deletion in animal models is associated with autoimmunity.4-9 Tumor cells exploit these biologic
mechanisms of tolerance to evade host immunity.10
PD-1/PD-L1 pathway in normal and
abnormal physiology
The PD-1/PD-L1 pathway is a critical inhibitor of immune activation
and plays an important role in mediating tolerance.7 The PD-1 receptor
is expressed on T cells, B cells, monocytes, and natural killer (NK)
T cells after activation.11 PD-L1 and PD-L2 are expressed on antigenpresenting cells, including dendritic cells (DCs) and macrophages.12 In
addition, PD-L1 is expressed on nonhematopoietic cells, including
pancreatic islet cells, endothelial cells, and epithelial cells, thus playing
a role in protecting tissue from immune-mediated injury.7,8,13 Binding
of PD-1 to PD-L1 or PD-L2 decreases secretion of Th1 cytokines,
inhibits T-cell proliferation, results in T-cell apoptosis, and inhibits
Submitted 8 August 2016; accepted 16 November 2016. Prepublished online
as Blood First Edition paper, 5 December 2016; DOI 10.1182/blood-2016-08731885.
BLOOD, 19 JANUARY 2017 x VOLUME 129, NUMBER 3
CTL-mediated killing. In the physiologic setting, this pathway plays a
critical role in maintaining immunologic equilibrium after initial T-cell
response, which prevents overactivation, collateral tissue damage, and
the inappropriate expansion of autoreactive T-cell populations.14,15
In pathologic settings such as chronic viral infection, signaling via
the PD-1/PD-L1 pathway results in the induction of an exhausted
T-cell phenotype characterized by the inability to mount protective
immunologic response.16-18 Similarly, in the context of malignancy,
upregulation of this pathway serves to prevent the activation and
function of tumor-reactive T-cell populations, which contributes to
immune escape and tumor growth.19-22 PD-L1 expression has also
been noted in immunoregulatory cells of the tumor microenvironment,
such as myeloid-derived suppressor cells that may work in concert
with malignant cells to promote tolerance.
Antibody blockade of the PD-1/PD-L1 pathway has emerged as a
highly effective therapeutic strategy for a subset of patients with solid
tumors and hematologic malignancies.23-27 Durable responses have
been noted in melanoma, renal cancer, and non–small-cell lung cancer,
which has resulted in US Food and Drug Administration approval of
nivolumab for patients with advanced disease in these settings.28-32
In addition, combination therapy with CTLA-4 blockade in
melanoma demonstrates that concurrent blockade of several
negative costimulatory pathways may be associated with a
marked enhancement in efficacy.33,34 A major area of investigation is
defining biomarkers that predict sensitivity to these agents to identify
cancer settings and biologic categories of disease that are likely to
benefit from therapy with checkpoint blockade.23 The predictive value
of tumor expression of PD-L1 has been unclear and is complicated by
varying patterns of expression within the tumor bed, inconsistency
between in vitro and in vivo expression, and a lack of uniform
techniques for assessment. An association between mutational burden
and disease response has been noted in solid tumors, suggesting that
the presence of neo-antigens generated from mutational events and for
which high-affinity T cells remain in the repertoire may be predictive of efficacy of PD-1 blockade. The potency of this strategy in
hematologic malignancies has been most pronounced in Hodgkin
disease in which associated mutations in chromosome 9 drive PD-L1
expression and in which the tumor bed is characterized by a dense
© 2017 by The American Society of Hematology
275
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
276
ROSENBLATT and AVIGAN
infiltrate of T cells.24 These findings suggest that checkpoint blockade
is most likely to be effective in malignancies for which immune
regulation is important for disease progression, that increased
expression of negative co-stimulation by tumor or accessory cells in
the microenvironment is an important mediator of tolerance, and that
the presence of tumor-reactive effector cells subject to expansion are
present in the tumor bed and circulation.
PD-1/PD-L1 pathway in multiple myeloma
Multiple myeloma (MM) is associated with progressive immune
dysregulation characterized by decreased antigen-presenting and
effector cell function, loss of myeloma-reactive effector T-cell
populations, and a bone marrow microenvironment that promotes
immune escape.35-37 The role of the PD-1/PD-L1 pathway in mediating
immune escape in MM and the corresponding therapeutic efficacy
of PD-1/PD-L1 blockade has emerged as an area of great interest.38
PD-L1 is highly expressed on plasma cells isolated from patients with
MM but not on normal plasma cells. Notably, PD-L1 is not expressed
on plasma cells isolated from patients with monoclonal gammopathy of
undetermined significance.39-42 PD-1 is expressed on circulating T cells
isolated from patients with advanced MM, whereas expression of PD-1
on circulating T cells is reduced in patients who achieve a minimal
disease state following high-dose chemotherapy.41 Ligation of PD-1 on
potentially reactive T cells induces anergy and apoptosis. PD-L1
expression is associated with increased proliferation and increased
resistance to anti-myeloma therapy.43 PD-L1 expression on plasma
cells is upregulated in the setting of relapsed and refractory disease,
which suggests that it might have a role in the development of clonal
resistance.44 The mechanisms by which PD-L1 expression is regulated
are currently an area of investigation. Our laboratory has demonstrated
that microRNA plays a role in regulating the expression of PD-L1, and
in MM, MUC1 expression on plasma cells upregulates the expression
of PD-L1 via miR-200c. In a study of 81 patients with newly diagnosed
myeloma, higher serum PD-L1 levels were associated with poorer
responses and shorter progression-free survival.45 Accessory cells in
the bone marrow microenvironment, including plasmacytoid DCs and
myeloid-derived suppressor cells (MDSCs), express PD-L1, consistent
with their immunoregulatory phenotype.44,46,47 PD-1 blockade restores
the capacity of plasmacytoid DCs to evoke cytotoxic T-lymphocyte
killing of myeloma targets in vitro.44 Of note, PD-L1 expression on
malignant plasma cells is upregulated in the presence of interferon g or
Toll-like receptor ligands consistent with the presence of a counterregulatory mechanism that blunts killing of myeloma cells in the setting
of immune activation.39 PD-L1 is upregulated in the presence of
stromal cells in an interleukin-6–dependent manner,44 whereas PD-L1
blockade inhibits stromal cell–mediated plasma cell growth.48 Increased PD-1 expression is observed on NK cells derived from patients
with myeloma and is associated with loss of effector cell function49 that
is restored via PD-1 blockade. These findings support the role of the
PD-1/PD-L1 pathway in contributing to immune escape in MM and
suggest that blockade may be an effective therapeutic strategy.
In contrast, several findings suggest that PD-1 blockade alone will
be insufficient to induce clinically meaningful anti-myeloma immunity.
A recent report suggested that downregulation of effector cell function in myeloma may be attributed in part to senescence rather than
PD-1–mediated exhaustion.50,51 Clonal expansion within the T-cell
repertoire was observed in 75% of myeloma patients who were
characterized by low PD-1 expression, and it was thought to represent
a population of tumor-reactive cells with a senescent phenotype in
BLOOD, 19 JANUARY 2017 x VOLUME 129, NUMBER 3
contrast to the nonclonal T cells that expressed high levels of PD-1.
The presence of senescence as an alternative mechanism for T-cell
inactivation points to the potential importance of combining
checkpoint blockade with strategies that evoke the expansion of activated, myeloma-reactive T cells.
The clinical efficacy of PD-1 blockade is most pronounced in
malignancies such as melanoma and Hodgkin disease, which are
characterized by the presence of infiltrating effector cells in the tumor
bed. In addition, therapeutic efficacy has been correlated with
mutational burden and is thought to be associated with the presence of
neo-antigens derived from mutational events that produce non–selfepitopes targeted by high-affinity T cells.52 In contrast, myeloma is
characterized by low levels of infiltrating effector cells and a relatively
modest mutational burden compared with solid tumors, which suggests
a more restricted neo-antigen profile. Thus, it is likely that checkpoint
blockade will be more potent when coupled with therapies that stimulate myeloma-reactive T cells. Such approaches, including combining
checkpoint blockade with immunomodulatory drugs, transplantation,
and cellular therapies such as tumor vaccines, are currently being
studied in the context of clinical trials.
Single-agent therapy with PD-1 antibody
A phase 1b study of PD-1 blockade (nivolumab) was recently
completed in patients with relapsed or refractory hematologic
malignancies.53 Of the 81 patients treated on that study, 27 had MM.
The median age of the myeloma patients was 63 years, 96% had been
treated with 2 or more prior regimens, 56% had undergone prior
autologous transplantation, and 24 of 27 patients had experienced
disease progression after being treated with an immunomodulatory
drug and proteasome inhibitor. The median follow-up duration
for patients with MM was 65.6 weeks (range, 1.6 to 126 weeks).
Stabilization of disease was observed in 17 MM patients (63%), which
lasted a median of 11.4 weeks (range, 3.1 to 46.1 weeks). No
significant evidence of disease regression was observed.
Combination of PD1/PDL1 blockade with
immunomodulatory drugs
Lenalidomide reduces PD-1 expression on NK cells, helper cells, and
cytotoxic T cells and downregulates PD-L1 expression on tumor cells
and MDSCs in patients with MM.49,54 Importantly, in preclinical
studies, lenalidomide enhances the effect of PD-1/PD-L1 blockade on
T-cell– and NK-cell–mediated cytotoxicity.49,54 The combination of
lenalidomide and PD-1 or PDL-1 blockade increased interferon g
expression by bone marrow–derived effector cells in myeloma and
were associated with increased apoptosis of MM cells.48 These in vitro
effects strongly support the potential for synergy between lenalidomide
and PD-1 blockade. Several clinical trials are evaluating the therapeutic
efficacy of combining PD-1 or PD-L1 antibodies with lenalidomide or
pomalidomide.55-57 Preliminary results from a phase 1 study evaluating
pembrolizumab (anti-PD1 antibody) in combination with lenalidomide
and low-dose dexamethasone in patients with relapsed/refractory
MM (NCT02036502) demonstrated disease response in 13 (76%) of 17
patients.58 A phase 3 randomized trial evaluating pembrolizumab in
combination with pomalidomide and low-dose dexamethasone in patients
with relapsed/refractory MM is being initiated (NCT02576977).59
In newly diagnosed patients, a phase 3 clinical trial evaluating
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
BLOOD, 19 JANUARY 2017 x VOLUME 129, NUMBER 3
TARGETING THE PD-1/PD-L1 AXIS IN MULTIPLE MYELOMA
277
pembrolizumab in combination with lenalidomide and low-dose
dexamethasone compared with lenalidomide and low-dose
dexamethasone alone (KEYNOTE-185) is ongoing, with a target
enrollment of approximately 640 patients (NCT02579863).60 In
addition, clinical trials are ongoing to evaluate the combination
of antibodies targeting PD-L1. In patients with newly diagnosed MM, durvalumab is being evaluated in combination
with lenalidomide (NCT02685826). In patients with relapsed/
refractory disease, durvalumab is being studied alone and in
combination with pomalidomide (NCT02616640). Durvalumab in
combination with daratumumab is also being studied in patients
with refractory MM and in combination with pomalidomide,
dexamethasone, and daratumumab (NCT02807454). Atezolizumab
is being evaluated in combination with daratumumab in patients
with refractory MM (NCT02431208). In patients with asymptomatic MM, atezolizumab is being administered in a clinical trial with
the goal of assessing the biological and clinical effects of therapy
(NCT02784483).
antigens, including neo-antigens generated from mutational events,
are presented in the context of DC-mediated co-stimulation.63,64 A
multicenter trial has been initiated through the Clinical Trials Network
to assess the efficacy of vaccination in conjunction with lenalidomide.
Of note, PD-1 blockade amplifies response to a DC/myeloma fusion
vaccine in vitro.41 Similarly, in a murine model, PD-L1 blockade
was shown to augment response and prolongation of survival when
administered with a tumor vaccine after transplantation.65
Alternatively, engineered T cells are being explored as immunotherapy for hematologic malignancies, including MM.66,67 Chimeric
antigen receptor (CAR) T cells involve the incorporation of an antibody
variable chain and positive costimulatory molecule into the T-cell
z receptor such that engagement with the antigenic target provokes
T-cell–mediated killing. A potential concern is that ligation of PD-1 on
the CAR T cell will induce anergy.68 Preclinical models have demonstrated enhanced efficacy of a CAR T cell administered in conjunction
with PD-1 antibody.69 Concerns remain regarding potential toxicity as
a result of overexcitation of immune effectors.
Combination of PD-1/PD-L1 blockade with
strategies that stimulate myeloma-reactive
T-cell populations
Conclusion
In addition to the PD-1/PD-L1 pathway, other negative co-stimulatory
receptors are expressed on T cells isolated from patients with MM, and
they may play a role in mediating tolerance and provide a mechanism of
immune escape in patients treated with PD-1 blockade alone. In a recent
study, it was shown that CTLA-4, LAG3, and TIM-3 are expressed
on T cells isolated from patients with MM 3 and 12 months after
autologous transplant.61 Studies to assess the clinical effect of blocking
these pathways alone and in combination with PD-1 blockade will be
critical.
Disease evolution in myeloma is associated with loss of myelomareactive clones in the T-cell repertoire. The incorporation of strategies to
expand myeloma-specific T cells and repair the effector cell repertoire
will likely be critical to enhance the efficacy of checkpoint blockade.
One strategy has been the use of cytotoxic therapy to deplete suppressor
populations, which facilitates reconstitution of myeloma immunity. In a
murine myeloma model, PD-L1 blockade administered after low-dose
total body irradiation resulted in prolonged survival.62 Lymphopoietic
reconstitution after high-dose chemotherapy with stem cell rescue
is associated with the depletion of regulatory T cells and concurrent
expansion of myeloma-specific clones.61,63 An alternative strategy for
enhancing therapeutic efficacy of PD-1/PD-L1 blockade in myeloma is
through the use of tumor vaccines to expand myeloma-reactive T-cell
clones for potential further activation with checkpoint blockade. We
have developed a myeloma vaccine in which patient-derived tumor
cells are fused with autologous DCs such that a broad array of tumor
Preclinical studies support a critical but not exclusive role of the PD-1/
PD-L1 pathway in mediating effector cell dysfunction and immune
escape in patients with myeloma. The limited clinical results available
to date have not suggested significant single-agent clinical activity.53
This observation is likely a result of the complex nature of immune
dysfunction present in the tumor microenvironment in myeloma. In
contrast, checkpoint blockade is now being examined as a part of
combination therapies that reverse tumor-mediated immune suppression and expand myeloma-reactive T cells. Although it demonstrates
great potential, the therapeutic efficacy of PD-1/PD-L1 blockade
specifically and immune-based strategies in general will likely depend
on a sophisticated understanding of the immunologic milieu in a given
disease setting and a coordinated effort to repair what is broken.
Authorship
Contribution: J.R. and D.A. contributed equally to writing this
review.
Conflict-of-interest disclosure: J.R. receives research funding
from Bristol-Myers Squibb. D.A. serves on an immuno-oncology
advisory board for Celgene.
Correspondence: Jacalyn Rosenblatt, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, KS 134,
Boston, MA 02215: e-mail: [email protected].
References
2. Krogsgaard M, Davis MM. How T cells ‘see’
antigen. Nat Immunol. 2005;6(3):239-245.
immunotherapy. Mol Oncol. 2015;9(10):
1936-1965.
5. Oca~
na-Guzman R, Torre-Bouscoulet L, SadaOvalle I. TIM-3 Regulates Distinct Functions in
Macrophages. Front Immunol. 2016;7:229.
3. Dowling JK, Mansell A. Toll-like receptors: the swiss
army knife of immunity and vaccine development.
Clin Transl Immunology. 2016;5(5):e85.
6. Krummel MF, Allison JP. CD28 and CTLA-4 have
opposing effects on the response of T cells to
stimulation. J Exp Med. 1995;182(2):459-465.
4. Śledzińska A, Menger L, Bergerhoff K, Peggs KS,
Quezada SA. Negative immune checkpoints on
T lymphocytes and their relevance to cancer
7. Keir ME, Butte MJ, Freeman GJ, Sharpe AH.
PD-1 and its ligands in tolerance and immunity.
Annu Rev Immunol. 2008;26:677-704.
1. Zarour HM. Reversing T-cell Dysfunction and
Exhaustion in Cancer. Clin Cancer Res. 2016;
22(8):1856-1864.
8. Keir ME, Liang SC, Guleria I, et al. Tissue
expression of PD-L1 mediates peripheral T cell
tolerance. J Exp Med. 2006;203(4):883-895.
9. Nishimura H, Nose M, Hiai H, Minato N, Honjo T.
Development of lupus-like autoimmune diseases
by disruption of the PD-1 gene encoding an ITIM
motif-carrying immunoreceptor. Immunity. 1999;
11(2):141-151.
10. Gajewski TF, Schreiber H, Fu YX. Innate
and adaptive immune cells in the tumor
microenvironment. Nat Immunol. 2013;14(10):
1014-1022.
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
278
BLOOD, 19 JANUARY 2017 x VOLUME 129, NUMBER 3
ROSENBLATT and AVIGAN
11. Nurieva R, Thomas S, Nguyen T, et al.
T-cell tolerance or function is determined by
combinatorial costimulatory signals. EMBO J.
2006;25(11):2623-2633.
12. Latchman Y, Wood CR, Chernova T, et al. PD-L2
is a second ligand for PD-1 and inhibits T cell
activation. Nat Immunol. 2001;2(3):261-268.
13. Menke J, Lucas JA, Zeller GC, et al. Programmed
death 1 ligand (PD-L) 1 and PD-L2 limit
autoimmune kidney disease: distinct roles.
J Immunol. 2007;179(11):7466-7477.
14. Ansari MJ, Salama AD, Chitnis T, et al. The
programmed death-1 (PD-1) pathway regulates
autoimmune diabetes in nonobese diabetic (NOD)
mice. J Exp Med. 2003;198(1):63-69.
15. Freeman GJ, Long AJ, Iwai Y, et al. Engagement
of the PD-1 immunoinhibitory receptor by a novel
B7 family member leads to negative regulation
of lymphocyte activation. J Exp Med. 2000;192(7):
1027-1034.
16. Barber DL, Wherry EJ, Masopust D, et al.
Restoring function in exhausted CD8 T cells
during chronic viral infection. Nature. 2006;
439(7077):682-687.
17. Blackburn SD, Shin H, Haining WN, et al.
Coregulation of CD81 T cell exhaustion by
multiple inhibitory receptors during chronic viral
infection. Nat Immunol. 2009;10(1):29-37.
18. Day CL, Kaufmann DE, Kiepiela P, et al. PD-1
expression on HIV-specific T cells is associated
with T-cell exhaustion and disease progression.
Nature. 2006;443(7109):350-354.
19. Dong H, Strome SE, Salomao DR, et al. Tumorassociated B7-H1 promotes T-cell apoptosis:
a potential mechanism of immune evasion. Nat
Med. 2002;8(8):793-800.
20. Ahmadzadeh M, Johnson LA, Heemskerk B, et al.
Tumor antigen-specific CD8 T cells infiltrating the
tumor express high levels of PD-1 and are
functionally impaired. Blood. 2009;114(8):1537-1544.
21. Taube JM, Anders RA, Young GD, et al.
Colocalization of inflammatory response with B7-h1
expression in human melanocytic lesions supports
an adaptive resistance mechanism of immune
escape. Sci Transl Med. 2012;4(127):127ra37.
22. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T,
Minato N. Involvement of PD-L1 on tumor cells in
the escape from host immune system and tumor
immunotherapy by PD-L1 blockade. Proc Natl
Acad Sci USA. 2002;99(19):12293-12297.
23. Mahoney KM, Rennert PD, Freeman GJ.
Combination cancer immunotherapy and new
immunomodulatory targets. Nat Rev Drug Discov.
2015;14(8):561-584.
24. 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.
25. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety
and activity of anti-PD-L1 antibody in patients with
advanced cancer. N Engl J Med. 2012;366(26):
2455-2465.
26. Topalian SL, Hodi FS, Brahmer JR, et al. Safety,
activity, and immune correlates of anti-PD-1
antibody in cancer. N Engl J Med. 2012;366(26):
2443-2454.
27. Armand P. Immune checkpoint blockade in
hematologic malignancies. Blood. 2015;125(22):
3393-3400.
28. Robert C, Long GV, Brady B, et al. Nivolumab in
previously untreated melanoma without BRAF
mutation. N Engl J Med. 2015;372(4):320-330.
29. Weber JS, D’Angelo SP, Minor D, et al.
Nivolumab versus chemotherapy in patients
with advanced melanoma who progressed after
anti-CTLA-4 treatment (CheckMate 037): a
randomised, controlled, open-label, phase 3 trial.
Lancet Oncol. 2015;16(4):375-384.
30. Gettinger SN, Horn L, Gandhi L, et al. Overall
Survival and Long-Term Safety of Nivolumab
(Anti-Programmed Death 1 Antibody, BMS936558, ONO-4538) in Patients With Previously
Treated Advanced Non-Small-Cell Lung Cancer.
J Clin Oncol. 2015;33(18):2004-2012.
31. Motzer RJ, Escudier B, McDermott DF, et al;
CheckMate 025 Investigators. Nivolumab versus
Everolimus in Advanced Renal-Cell Carcinoma.
N Engl J Med. 2015;373(19):1803-1813.
32. Rizvi NA, Mazières J, Planchard D, et al. Activity
and safety of nivolumab, an anti-PD-1 immune
checkpoint inhibitor, for patients with advanced,
refractory squamous non-small-cell lung cancer
(CheckMate 063): a phase 2, single-arm trial.
Lancet Oncol. 2015;16(3):257-265.
33. Larkin J, Chiarion-Sileni V, Gonzalez R, et al.
Combined Nivolumab and Ipilimumab or
Monotherapy in Untreated Melanoma. N Engl J
Med. 2015;373(1):23-34.
34. Postow MA, Chesney J, Pavlick AC, et al.
Nivolumab and ipilimumab versus ipilimumab
in untreated melanoma. N Engl J Med. 2015;
372(21):2006-2017.
35. Nielsen H, Nielsen HJ, Tvede N, et al. Immune
dysfunction in multiple myeloma. Reduced natural
killer cell activity and increased levels of soluble
interleukin-2 receptors. APMIS. 1991;99(4):340-346.
36. Rosenblatt J, Bar-Natan M, Munshi NC, Avigan
DE. Immunotherapy for multiple myeloma. Expert
Rev Hematol. 2014;7(1):91-96.
37. Dosani T, Carlsten M, Maric I, Landgren O. The
cellular immune system in myelomagenesis: NK
cells and T cells in the development of MM and
their uses in immunotherapies. Blood Cancer J.
2015;5:e321.
38. Guillerey C, Nakamura K, Vuckovic S, Hill GR,
Smyth MJ. Immune responses in multiple
myeloma: role of the natural immune surveillance
and potential of immunotherapies. Cell Mol Life
Sci. 2016;73(8):1569-1589.
39. Liu J, Hamrouni A, Wolowiec D, et al. Plasma
cells from multiple myeloma patients express
B7-H1 (PD-L1) and increase expression after
stimulation with IFN-gamma and TLR ligands
via a MyD88-, TRAF6-, and MEK-dependent
pathway. Blood. 2007;110(1):296-304.
40. Yousef S, Marvin J, Steinbach M, et al.
Immunomodulatory molecule PD-L1 is expressed
on malignant plasma cells and myelomapropagating pre-plasma cells in the bone marrow
of multiple myeloma patients. Blood Cancer J.
2015;5:e285.
41. Rosenblatt J, Glotzbecker B, Mills H, et al. PD-1
blockade by CT-011, anti-PD-1 antibody,
enhances ex vivo T-cell responses to autologous
dendritic cell/myeloma fusion vaccine.
J Immunother. 2011;34(5):409-418.
42. Kawano Y, Moschetta M, Manier S, et al.
Targeting the bone marrow microenvironment in
multiple myeloma. Immunol Rev. 2015;263(1):
160-172.
43. Ishibashi M, Tamura H, Sunakawa M, et al.
Myeloma drug resistance induced by binding
of myeloma B7-H1 (PD-L1) to PD-1. Cancer
Immunol Res. 2016;4(9):779-788.
44. Tamura H, Ishibashi M, Yamashita T, et al.
Marrow stromal cells induce B7-H1 expression
on myeloma cells, generating aggressive
characteristics in multiple myeloma. Leukemia.
2013;27(2):464-472.
45. Wang L, Wang H, Chen H, et al. Serum levels
of soluble programmed death ligand 1 predict
treatment response and progression free survival
in multiple myeloma. Oncotarget. 2015;6(38):
41228-41236.
46. Ray A, Das DS, Song Y, et al. Targeting
PD1-PDL1 immune checkpoint in plasmacytoid
dendritic cell interactions with T cells, natural killer
cells and multiple myeloma cells. Leukemia. 2015;
29(6):1441-1444.
47. Favaloro J, Liyadipitiya T, Brown R, et al. Myeloid
derived suppressor cells are numerically,
functionally and phenotypically different in
patients with multiple myeloma. Leuk Lymphoma.
2014;55(12):2893-2900.
48. Görgün G, Samur MK, Cowens KB, et al.
Lenalidomide Enhances Immune Checkpoint
Blockade-Induced Immune Response in Multiple
Myeloma. Clin Cancer Res. 2015;21(20):
4607-4618.
49. Benson DM Jr, Bakan CE, Mishra A, et al. The
PD-1/PD-L1 axis modulates the natural killer
cell versus multiple myeloma effect: a
therapeutic target for CT-011, a novel
monoclonal anti-PD-1 antibody. Blood. 2010;
116(13):2286-2294.
50. Suen H, Brown R, Yang S, et al. Multiple myeloma
causes clonal T-cell immunosenescence:
identification of potential novel targets for
promoting tumour immunity and implications for
checkpoint blockade. Leukemia. 2016;30(8):
1716-1724.
51. Suen H, Brown R, Yang S, Ho PJ, Gibson J,
Joshua D. The failure of immune checkpoint
blockade in multiple myeloma with PD-1 inhibitors
in a phase 1 study. Leukemia. 2015;29(7):
1621-1622.
52. Schumacher TN, Schreiber RD. Neoantigens
in cancer immunotherapy. Science. 2015;
348(6230):69-74.
53. Lesokhin AM, Ansell SM, Armand P, et al.
Nivolumab in Patients With Relapsed or
Refractory Hematologic Malignancy: Preliminary
Results of a Phase Ib Study. J Clin Oncol. 2016;
34(23):2698-2704.
54. Luptakova K, Rosenblatt J, Glotzbecker B, et al.
Lenalidomide enhances anti-myeloma cellular
immunity. Cancer Immunol Immunother. 2013;
62(1):39-49.
55. Ashraf Z, Badros MH, Ning Ma, et al. A Phase II
Study of Anti PD-1 Antibody Pembrolizumab,
Pomalidomide and Dexamethasone in Patients with
Relapsed/Refractory Multiple Myeloma (RRMM)
[abstract]. Blood. 2015;126(23). Abstract 506.
56. San Miguel J, Mateos MV, Shah JJ, et al.
Pembrolizumab in Combination with Lenalidomide
and Low-Dose Dexamethasone for Relapsed/
Refractory Multiple Myeloma (RRMM): Keynote023 [abstract]. Blood. 2015;126(23). Abstract 505.
57. Kocoglu M, Badros A. The Role of
Immunotherapy in Multiple Myeloma.
Pharmaceuticals (Basel). 2016;9(1).
58. Mateos MV, Orlowski RZ, Siegel DS, et al.
Pembrolizumab in combination with lenalidomide
and low-dose dexamethasone for relapsed/
refractory multiple myeloma (RRMM): Final
efficacy and safety analysis [abstract]. J Clin
Oncol. 2016;34. Abstract 8010.
59. Shah JJ, Jagannath S, Mateos MV, et al.
Keynote-183: A randomized, open-label phase 3
study of pembrolizumab in combination with
pomalidomide and low-dose dexamethasone in
refractory or relapsed and refractory mutliple
myeloma [abstract]. J Clin Oncol. 2016;34.
Abstract TPS8070.
60. Palumbo A, Mateos MV, San Miguel J, et al.
Keynote-185: A randomized, open label phase 3
study of pembrolizumab in combination with
lenalidomide and low dose dexamethasone in
newly diagnosed and treatment-naive multiple
myeloma (MM) [abstract]. J Clin Oncol. 2016;34.
Abstract TPS8069.
61. Chung DJ, Pronschinske KB, Shyer JA, et al. T-cell
Exhaustion in Multiple Myeloma Relapse after
Autotransplant: Optimal Timing of Immunotherapy.
Cancer Immunol Res. 2016;4(1):61-71.
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
BLOOD, 19 JANUARY 2017 x VOLUME 129, NUMBER 3
62. Jing W, Gershan JA, Weber J, et al. Combined
immune checkpoint protein blockade and low
dose whole body irradiation as immunotherapy for
myeloma. J Immunother Cancer. 2015;3(1):2.
63. Rosenblatt J, Avivi I, Vasir B, et al. Vaccination with
dendritic cell/tumor fusions following autologous
stem cell transplant induces immunologic and
clinical responses in multiple myeloma patients.
Clin Cancer Res. 2013;19(13):3640-3648.
64. Rosenblatt J, Vasir B, Uhl L, et al. Vaccination
with dendritic cell/tumor fusion cells results in
cellular and humoral antitumor immune responses
TARGETING THE PD-1/PD-L1 AXIS IN MULTIPLE MYELOMA
in patients with multiple myeloma. Blood. 2011;
117(2):393-402.
65. Hallett WH, Jing W, Drobyski WR, Johnson BD.
Immunosuppressive effects of multiple myeloma
are overcome by PD-L1 blockade. Biol Blood
Marrow Transplant. 2011;17(8):1133-1145.
66. Rotolo A, Caputo V, Karadimitris A. The prospects
and promise of chimeric antigen receptor
immunotherapy in multiple myeloma. Br J
Haematol. 2016;173(3):350-364.
67. Atanackovic D, Radhakrishnan SV, Bhardwaj N,
Luetkens T. Chimeric Antigen Receptor (CAR)
279
therapy for multiple myeloma. Br J Haematol.
2016;172(5):685-698.
68. Moon EK, Wang LC, Dolfi DV, et al. Multifactorial
T-cell hypofunction that is reversible can limit the
efficacy of chimeric antigen receptor-transduced
human T cells in solid tumors. Clin Cancer Res.
2014;20(16):4262-4273.
69. Cherkassky L, Morello A, Villena-Vargas J,
et al. Human CAR T cells with cell-intrinsic
PD-1 checkpoint blockade resist tumormediated inhibition. J Clin Invest. 2016;126(8):
3130-3144.
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
2017 129: 275-279
doi:10.1182/blood-2016-08-731885 originally published
online December 5, 2016
Targeting the PD-1/PD-L1 axis in multiple myeloma: a dream or a
reality?
Jacalyn Rosenblatt and David Avigan
Updated information and services can be found at:
http://www.bloodjournal.org/content/129/3/275.full.html
Articles on similar topics can be found in the following Blood collections
Blood Spotlight (64 articles)
Free Research Articles (4527 articles)
Immunobiology (5489 articles)
Lymphoid Neoplasia (2557 articles)
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society
of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.