Inmunología y Oncología

1. REVIEW
Toll-like receptor 9 (TLR9) agonists in the treatment of cancer
AM Krieg
Coley Pharmaceutical Group Inc., Wellesley, MA, USA
Although still early in clinical development, agonists of Toll-
like receptor 9 (TLR9) have demonstrated potential for the
treatment of cancer. TLR9 agonists directly induce activa-
tion and maturation of plasmacytoid dendritic cells and
enhance differentiation of B cells into antibody-secreting
plasma cells. Preclinical and early clinical data support the
use of TLR9 agonists in patients with solid tumors and
hematologic malignancies. In preclinical studies, TLR9
agonists have shown activity not only as monotherapy, but
also in combination with multiple other therapies, including
vaccines, antibodies, cellular therapies, other immunothera-
pies, antiangiogenic agents, radiotherapy, cryotherapy and
some chemotherapies. Phase I and II clinical trials have
indicated that these agents have antitumor activity as single
agents and enhance the development of antitumor T-cell
responses when used as therapeutic vaccine adjuvants. The
activity and safety of these novel anticancer agents are being
explored in a wide range of tumor types as part of a variety
of therapeutic strategies with the goal of harnessing the
immune response to fight cancer.
Oncogene (2008) 27, 161–167; doi:10.1038/sj.onc.1210911
Keywords: PF-3512676; CpG ODN TLR9; Toll-like
receptor agonists; vaccine adjuvant
Toll-like receptor 9
The human immune system detects and responds to
infectious challenges using several families of receptors
that can recognize pathogen-expressed molecules, such as
lipopolysaccharide, viral RNA or bacterial DNA (Akira
et al., 2006). The most well understood of these receptors
are the Toll-like receptors (TLRs), of which a family of 10
related molecules has been identified in humans (Akira
et al., 2006). The immune role of TLR9 has been studied
most extensively in plasmacytoid dendritic cells (pDCs)
and B cells (Iwasaki and Medzhitov, 2004), which may be
the only human immune cells to constitutively express
TLR9. Cellular activation is reported to induce TLR9
expression in additional cell types, including human
neutrophils (Hayashi et al., 2003), monocytes and mono-
cyte-derived cells (Saikh et al., 2004; Siren et al., 2005) and
CD4 T cells (Gelman et al., 2006), but the biologic role for
this is less well understood. TLR9 expression has also been
reported in some nonimmune cells, including pulmonary
epithelial cells and lung cancers (Li et al., 2004; Platz et al.,
2004; Droemann et al., 2005), keratinocytes (Lebre et al.,
2007) and intestinal epithelium (Pedersen et al., 2005; Lee
et al., 2006).
TLR9 recognizes and is activated by unmethylated
cytosine-phosphate-guanine (CpG) dinucleotides, which
are relatively common in bacterial and viral DNA but are
suppressed and methylated in vertebrate DNA (Krieg,
2004). Binding of DNA containing unmethylated CpG
motifs to TLR9 causes a conformational shift in the
receptor, which is thought to result in recruitment of the
adapter protein MyD88, activation of signaling pathways
with the phosphorylation of mitogen-activated protein
kinases and activation of nuclear factor-kB (Latz et al.,
2007). At a cellular level, activation of TLR9 initiates a
cascade of innate and adaptive immune responses
(Figure 1). TLR9 agonists activate pDCs to secrete type
I interferon (IFN) and to express increased levels of co-
stimulatory molecules such as CD80 (B7.1) and CD86
(B7.2). This is believed to initiate a range of secondary
effects, including secretion of cytokines/chemokines (for
example, monocyte chemoattractant protein-1 (MCP-1),
IFN-g-inducible 10kDa protein (IP-10)), activation of
natural killer (NK) cells and expansion of T-cell popula-
tions, particularly type 1 helper T (TH1) cells and cytotoxic
T lymphocytes (CTLs) (Krieg, 2004, 2006). As a result a
potent, cell-mediated TH1 response is initiated. A humoral
immune response is also initiated as TLR9 agonists
enhance differentiation of B cells into antibody-secreting
plasma cells, potentially promoting antibody-dependent
cellular cytotoxicity (Appay et al., 2006). An under-
standing of the immune cascade initiated by TLR9
activation has prompted the clinical development of
several TLR9 agonists in the fields of infectious disease,
cancer and asthma/allergy. The rationale for investigating
TLR9 agonists as anticancer agents is based on the
hypothesis that the innate immune activation may have
direct antitumor effects and that the enhanced tumor
antigen presentation in a TH1-like cytokine and chemokine
milieu will promote an antitumor immune response.
Several synthetic oligodeoxynucleotide (ODN) agonists
for TLR9 are currently in development for the treatment of
cancer. Because the phosphodiester bond of native DNA is
rapidly degraded by endonucleases, these investigational
CpG ODNs use a nuclease-resistant phosphorothioate
backbone that improves the half-life in the body from just
Correspondence: Dr AM Krieg, Coley Pharmaceutical Group Inc.,
Suite 101, 93 Worcester Street, Wellesley, MA 02481, USA.
E-mail: akrieg@coleypharma.com
Oncogene (2008) 27, 161–167
& 2008 Nature Publishing Group All rights reserved 0950-9232/08 $30.00
www.nature.com/onc

2. a few minutes (for unmodified native DNA) to about 48h.
Coley Pharmaceutical Group (Wellesley, MA, USA) has
developed a CpG ODN known as CPG 7909 that is being
investigated as a vaccine adjuvant in several tumor types
(Table 1). CPG 7909 was licensed by Pfizer Pharmaceuticals
Inc. (New York, NY, USA) for clinical investigation as a
single agent or in combination with other therapeutic
approaches, and is now known as PF-3512676 when it is
not being used as a vaccine adjuvant. Other TLR9 agonists
in clinical development for cancer include ISS 1018
(Dynavax Technologies, Berkeley, CA, USA), IMO-2055
(Idera Pharmaceuticals Inc., Cambridge, MA, USA) and
CpG-28 (University of Paris, France).
Cancer therapy with TLR9 agonists
The initial impetus to develop TLR9 agonists as antic-
ancer drugs came from several preclinical studies demon-
strating antitumor activity in a wide variety of tumor
models. For example, in a murine cervical carcinoma
model, mice with established subcutaneous (s.c.) tumors
treated with CpG ODNs injected at a distant site
exhibited significant regression (Po0.05), and treated
mice had a significant improvement in survival (Po0.001)
compared with control mice (Baines and Celis, 2003). In
addition, >50% of mice (24 of 42) with established
tumors had a complete regression following treatment for
9 days (Baines and Celis, 2003). TLR9 agonists also have
been successfully combined with traditional anticancer
therapies (for example, radiation therapy, chemotherapy)
or other immunotherapies (for example, vaccines). For
example, in mice with established orthotopic rhabdomyo-
sarcoma tumors, treatment with a TLR9 agonist plus
topotecan resulted in an improvement in survival rate (41
versus 22% for topotecan alone, P ¼ 0.09) (Weigel et al.,
2003). The combination of a CpG ODN with radiation
therapy also enhanced tumor response in a murine
fibrosarcoma model (Milas et al., 2004). However, mice
and humans have a different TLR9 expression pattern,
and exposure to CpG motifs stimulates a more narrow
profile of cytokines/chemokines in humans (Krieg, 2007).
Thus, preclinical results cannot be considered predictive
of clinical findings. However, based on the strength of the
extensive preclinical data, several TLR9 agonists are now
being developed as anticancer agents.
Monotherapy with TLR9 agonists
Hematologic malignancies
In addition to enhancing maturation of B cells into
antibody-secreting plasma cells, TLR9 agonists have a
variety of other effects on B cells that may be relevant in
the treatment of hematologic malignancies. Activation of
TLR9 on primary malignant B cells upregulates expres-
sion of major histocompatibility complex molecules and
other surface receptors, thereby increasing their capacity
to stimulate T cells (Decker et al., 2000; Jahrsdorfer et al.,
2001; Wooldridge and Weiner, 2003). This may result in
an enhanced T-cell-mediated response to tumor antigens
on the malignant B cells. Furthermore, in patients with
advanced cutaneous T-cell lymphoma (CTCL), NK cells
and CD8þ
T cells were activated following culturing of
peripheral blood mononuclear cells with CpG ODNs,
and there was a marked increase in IFN-a production
(Wysocka et al., 2004). This could enhance the antitumor
immune response by activating NK cells, or may induce a
direct antiproliferative effect (Sabel and Sondak, 2003).
Chronic lymphocytic leukemia (CLL) cells, which express
Figure 1 (1) Toll-like receptor 9 (TLR9) agonists stimulate innate and adaptive antitumor immune responses. TLR9 agonists induce
secretion of interferon-a(IFN-a) from immature plasmacytoid dendritic cells (pDCs), which may activate natural killer (NK) cell lysis
of tumor cells and release tumor antigens (Ags). (2) Dendritic cells activated directly or indirectly by the TLR9 agonist therapy can
capture and process tumor-associated antigens, increase surface expression of major histocompatibility complex (MHC) and co-
stimulatory receptors, and (3) migrate to the lymph nodes where antigens can be presented to lymphocytes, inducing (4) expansion of
lymphocytes that recognize the tumor antigen. Because the response occurs in a TH1-like cytokine milieu, the lymphocyte response
tends to be TH1-like, including cytotoxic T lymphocytes (CTLs).
Cancer therapy with TLR9 agonists
AM Krieg
162
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3. TLR9, are induced by CpG ODN to undergo apoptosis,
in contrast with normal primary B cells in which TLR9
activation protects against apoptosis (Jahrsdorfer et al.,
2005).
Several clinical studies of single-agent TLR9 agonists
have been completed in patients with hematologic
malignancies. In a phase I study of PF-3512676 in
patients (N ¼ 28) with CTCL, seven (25%) patients
achieved an objective response as determined by a
Physician Global Assessment (two complete responses
(CRs), five partial responses (PRs)) (Kim et al., 2004).
Common adverse events (AEs) included mild to
moderate injection-site reactions (erythema, induration,
edema, inflammation and pain) and flu-like symptoms
(fatigue, rigors, fever, arthralgia) (Kim et al., 2004). PF-
3512676 has also been studied in a phase I trial in
patients with refractory non-Hodgkin’s lymphoma
(NHL). In patients (N ¼ 23) receiving PF-3512676
(0.01–0.64 mg kg1
) intravenously (i.v.) up to three times
a week, NK cell numbers and activation were enhanced
in most subjects (Link et al., 2006). The majority of AEs
were mild to moderate and transient. Serious hemato-
logic AEs included anemia, thrombocytopenia and
neutropenia, but were mainly judged to be due to
disease progression (Link et al., 2006). In both trials,
PF-3512676 was determined to be well tolerated at levels
that can stimulate immune activation. These studies
indicated that TLR9 agonists may be useful in the
treatment of lymphoma. A phase I study is currently
being carried out with PF-3512676 as second-line
treatment for patients with CLL.
Skin cancers
Because melanoma is a highly immunogenic tumor that
has been shown to respond to immunotherapy, it is a
logical malignancy in which to explore the activity of
TLR9 agonists. Two general approaches have been
investigated using monotherapy with PF-3512676: local
therapy with intra- or perilesional injection and systemic
therapy with s.c. injection. PF-3512676 demonstrated
clinical activity in a phase I trial of intra- or perilesional
injection in patients with metastatic melanoma (n ¼ 5,
with one local regression) or basal cell carcinoma (n ¼ 5;
with one CR and three PRs) (Trefzer et al., 2002;
Hofmann et al., submitted). Treatment was associated
with increased levels of serum interleukin (IL)-6, IL-
12p40 and IP-10 in some patients, and cellular infiltrates
of CD8þ
lymphocytes were found after treatment in most
lesions. In a different trial involving patients with clinical
stage I/II melanoma, surgical resection of the primary
tumor was followed by randomization to receive either
saline or PF-3512676 (8 mg) intradermally at the excision
site, followed 1 week later by a sentinel lymph node
procedure (Molenkamp et al., 2007). In this setting, PF-
3512676 was shown to induce the release of inflammatory
cytokines and decrease the number of regulatory T cells
observed in sentinel lymph nodes of patients with stage I
to III melanoma (Molenkamp et al., 2007). Furthermore,
both myeloid and pDCs were activated (Molenkamp
et al., 2007), indicating that PF-3512676 clearly has
immunomodulatory activity. In a different phase II study
in patients (N ¼ 20) with metastatic melanoma treated
with s.c. PF-3512676, two (10%) patients had a PR and
three (15%) patients had stable disease (SD) (Pashenkov
et al., 2006). These patients with possible clinical benefit
from PF-3512676 therapy tended to have increased levels
of NK cell activity compared to the patients with
progressive disease. The majority of AEs were mild,
consisting of short-term local injection-site reactions and
transient flu-like symptoms (p2 days); grade 3/4
laboratory AEs typically resolved without intervention.
These studies demonstrated that PF-3512676 is generally
well tolerated as a single agent in patients with melanoma
and is associated with antitumor activity.
Other solid tumors
Monotherapy with TLR9 agonists has also been eval-
uated in phase I trials in patients with advanced renal cell
carcinoma (RCC) or recurrent glioblastoma. A minor
response was observed in 2 of 24 patients with recurrent
Table 1 Toll-like receptor 9 agonists in clinical trials for cancer
Agent Company Tumor type Stage of development
PF-3512676 (formerly CPG 7909) Pfizer Breast cancer Phase I/II
CLL Phase I
CTCL Phase I
Melanoma Phase II
NHL Phase I/II
GlaxoSmithKline NSCLCa
Phase III
RCC Phase I
ISS 1018 Dynavax CRC Phase I
NHL Phase II
IMO-2055 Idera RCC Phase I
Refractory solid tumors Phase I/II
CpG-28 University of Paris Glioblastoma Phase II
Abbreviations: CLL, chronic lymphocytic leukemia; CRC, colorectal cancer; CTCL, cutaneous T-cell lymphoma; NHL, non-Hodgkin’s
lymphoma; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma. a
Clinical development in combination with chemotherapy has been
discontinued.
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163
Oncogene

4. glioblastoma receiving CpG-28 in a phase I trial.
Treatment-related AEs consisted mainly of fever (21%),
a worsening of neurologic conditions (17%) and reversible
grade 3 lymphopenia (29%) (Carpentier et al., 2006). In a
phase I dose-escalation trial in patients (N ¼ 31) with
advanced RCC receiving PF-3512676, one patient (3%)
had a PR and nine patients (29%) had SD (Thompson
et al., 2004). No treatment-related serious AEs were
observed, and injection-site reactions and flu-like symp-
toms were dose related and transient (Thompson et al.,
2004). A phase I trial is currently investigating the activity
of IMO-2055 as first- and second-line treatment of
patients with RCC.
Combination therapy with TLR9 agonists
Non-Hodgkin’s lymphoma
Preclinical studies have indicated that the combination
of a TLR9 agonist and rituximab (Rituxan), a mono-
clonal antibody (mAb) against CD20, may be more
effective than rituximab alone. In a murine lymphoma
model, the addition of a CpG ODN to antitumor mAb
therapy (with an anti-idiotype Ab) reduced the percen-
tage of mice developing a tumor by 70% (Wooldridge
et al., 1997). Two phase I clinical trials have investigated
the combination of a CpG ODN with rituximab in
patients with relapsed/refractory NHL. In a dose-
escalation study, 50 patients received PF-3512676
weekly for 4 weeks i.v. or s.c. in combination with
rituximab (375 mg m2
per week 4 weeks) i.v., while an
additional s.c. cohort received weekly monotherapy with
PF-3512676 for an additional 20 weeks following the
initial 4 weeks of treatment with rituximab (Leonard
et al., 2007, in press). Twelve patients (24%) had an
objective response (five CRs, seven PRs), including 50%
of the 12 patients receiving extended dosing with PF-
3512676 (two CRs, four PRs) (Leonard et al., 2007, in
press). The majority (76%) of patients experienced mild
to moderate treatment-related AEs (primarily injection-
site reactions and systemic flu-like symptoms). Few
grade 3/4 AEs occurred in more than one patient or at
more than one dose level, but four patients developed
grade 3/4 neutropenia (Leonard et al., 2007, in press). In
a phase I study, 20 patients with relapsed NHL received
ISS 1018 weekly for 4 weeks s.c. following the second of
four infusions with rituximab (375 mg m2
per week 4
weeks) (Friedberg et al., 2005). The overall response rate
was 32% (one unconfirmed CR, five PRs). Common
AEs included mild to moderate injection-site reactions
and systemic flu-like symptoms (Friedberg et al., 2005).
Combination therapy with TLR9 agonists is being
further evaluated for antitumor activity in a phase I/II
trial in combination with radiation therapy and in a
phase II trial in combination with rituximab.
Non-small cell lung cancer
Several preclinical models have also suggested that a
TLR9 agonist can synergize with cytotoxic chemotherapy
(reviewed in Krieg, 2007). In a Lewis lung cancer model,
the combination of PF-3512676 and paclitaxel significantly
enhanced median survival compared with control mice
(Po0.0001), and no additive toxicity was observed
(Weeratna et al., 2004). Based on both preclinical and
clinical proof-of-concept studies, a randomized controlled
phase II trial was conducted in chemotherapy-naive
patients with stage IIIb/IV non-small cell lung cancer
(NSCLC) (Manegold et al., 2007, in press). Patients
received 4–6 cycles of taxane/platinum chemotherapy with
0.20mgkg1
PF-3512676 s.c. on weeks 2 and 3 of each
cycle (n¼ 75) or chemotherapy alone (n¼ 37). The
objective response rate was 38% in the PF-3512676 plus
chemotherapy arm (n¼ 74) versus 19% in the chemother-
apy-alone arm (n¼ 37) by investigator evaluation, and the
median overall survival was 12.3 months in the PF-
3512676 plus chemotherapy arm versus 6.8 months in the
chemotherapy-alone arm (hazard ratio¼ 0.747, P ¼ 0.188)
(Manegold et al., 2007, in press). The most common PF-
3512676-related AEs were mild to moderate injection-site
reactions and flu-like symptoms, although PF-3512676
was associated with an increase in the rate of neutropenia,
anemia and thrombocytopenia.
Following completion of the phase II trials, two phase
III studies were conducted exploring the combination of
PF-3512676 (0.2 mg kg1
s.c. days 8 and 15) with
paclitaxel/carboplatin (200mg m2
per area under the
curve six i.v. day 1) or gemcitabine/cisplatin (1250 mg m2
i.v. day 1 and 8/75mg m2
i.v. day 1) versus chemother-
apy alone as first-line treatment of patients with advanced
NSCLC (Readett et al., 2007). No improvement in
overall survival or progression-free survival was observed
when PF-3512676 was added to standard platinum-based
doublet chemotherapy in either trial. However, there was
a higher frequency of grade 3/4 neutropenia and
thrombocytopenia and a higher frequency of ‘sepsis-like
events’ and ‘septic deaths’ reported as serious AEs in the
PF-3512676 plus chemotherapy arms (Readett et al.,
2007). Based on the recommendation of an independent
data monitoring safety committee, these phase III studies
were terminated, along with two phase II trials in which
PF-3512676 was also combined with cytotoxic che-
motherapy in patients with advanced NSCLC.
TLR9 agonists as vaccine adjuvants
A distinguishing characteristic of CpG ODNs is their
ability to induce strong CD4þ
and CD8þ
T-cell
responses and rapid production of antigen-specific
antibodies when used as a vaccine adjuvant with many
types of antigen (Krieg, 2007). These CpG ODN
adjuvants have been heavily studied for the treatment
of infectious diseases, and several clinical trials are also
investigating their activity as tumor vaccines. The
addition of CPG 7909 to a peptide MART-1 vaccine in
patients with human leukocyte antigen-A2þ
melanoma
caused an approximate 10-fold increase in the number
of antigen-specific CD8þ
T cells (Speiser et al., 2005;
Appay et al., 2006). Anti-MAGE-3 antibody titers were
enhanced with the addition of CPG 7909 to a MAGE-3
Cancer therapy with TLR9 agonists
AM Krieg
164
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5. recombinant protein vaccine in a phase I/II trial, and one
patient had a durable objective response (PR for 9 þ
months) (van Ojik et al., 2002). CPG 7909 is also being
studied as a vaccine adjuvant in patients with metastatic
RCC. Preliminary results suggest that vaccination with
autologous tumor cells, CPG 7909 and granulocyte
macrophage colony-stimulating factor followed by main-
tenance therapy with IFN-a and PF-3512676 has
antitumor activity in this population (3 of 12 patients
had a PR) (Van Den Eertwegh et al., 2006). Phase I and
II trials have been further investigating CPG 7909 as a
vaccine adjuvant in patients with melanoma and breast
cancer. The most advanced cancer vaccine program is a
phase III, randomized, controlled, clinical trial of the
tumor antigen MAGE-A3 combined with CPG 7909
(and other adjuvants) for the treatment of patients with
early-stage (stage IB, II or IIIA), completely resected
NSCLC whose tumors express the antigen (Table 1).
Safety of TLR9 agonists
Overall, TLR9 agonists are generally well tolerated in
patients with cancer. The most common AEs observed
with administration of TLR9 agonists are local injec-
tion-site reactions (for example, erythema, edema,
inflammation and pain) or systemic flu-like symptoms
(for example, headache, rigors, pyrexia, nausea and
vomiting). These symptoms typically develop with 24 h
of dosing and are transient, generally lasting for less
than 2 days (Krieg, 2006). Grade 3/4 hematologic AEs
(that is, anemia, neutropenia and thrombocytopenia)
have been observed with TLR9 agonists (Link et al.,
2006; Leonard et al., 2007, in press; Manegold et al.,
2007, in press), and may require monitoring in future
clinical trials. However, unlike other therapeutic im-
munotherapies for cancer such as IFN-a, TLR9 agonist
therapy has not been associated with clinically signifi-
cant autoimmune diseases.
Conclusions
Although it is still early in their clinical development,
TLR9 agonists are generally well tolerated and have
demonstrated potential as a novel immunotherapeutic
approach to the treatment of cancer. Objective tumor
responses to TLR9 agonist monotherapy have been
observed in multiple tumor types, including both solid
tumors and hematologic malignancies. Although these
results are encouraging evidence of the potential clinical
benefits of TLR9 activation, the greatest improvement in
patient outcomes is likely to result from the use of this
approach in combination with other therapies that work in
a synergistic manner. Preclinical work and early clinical
trials suggested that combination with cytotoxic che-
motherapy may be one such approach, but two phase III
trials of PF-3512676 administered concurrently with
chemotherapy for patients with NSCLC have recently
reported a lack of incremental efficacy with the addition of
PF-3512676. The reason for the failure of these trials is
unclear, but possible factors include the advanced stage of
the disease, the use of concomitant steroid therapy as
premedication for the chemotherapy, and possible im-
mune-suppressive effects of the repeated chemotherapy
cycles. Therapies based on activating an immune response
against cancer may be expected to have a higher chance for
success in clinical settings of earlier disease, such as the
ongoing NSCLC vaccine trial in the adjuvant setting.
Combination therapy with antiangiogenic agents
should avoid the immune-suppressive effects of che-
motherapy and also has shown benefit in preclinical
models when combined with TLR9 agonists (Damiano
et al., 2006, 2007). An ongoing clinical trial in NSCLC is
addressing the safety and potential clinical benefit of
PF-3512676 combined with the antiepidermal growth
factor receptor agent erlotinib.
Tumors can develop a variety of mechanisms to evade
or suppress the immune system, and combination
immunotherapeutic approaches may allow for multiple
opportunities to slow or halt tumor progression. T-cell
expression of CTL-associated antigen 4 (CTLA4) is
induced during immune responses as a brake on the
immune system, reducing the magnitude and functional
capacity of the effector T-cell response. Blockade of
CTLA4 with mAbs sustains T-cell proliferation and
activation. By stimulating the DC side of the immune
response and enhancing antigen presentation to T cells,
TLR9 agonists may synergize with the effect of anti-
CTLA4 mAbs ability to remove the brake on the T cells.
Indeed, in preclinical tumor vaccine models, the combi-
nation of a TLR9 agonist and CTLA4 blockade led to
improved rejection of established tumors through com-
plementary mechanisms: the effect of anti-CTLA4 mAbs
is largely dependent on CD4þ
T cells, whereas the effect
of the combination appears to be mediated by CD8þ
T
cells (Davila et al., 2003; Daftarian et al., 2004). The
combination of anti-CTLA4 mAb and PF-3512676 is
currently being evaluated in a phase I, open-label,
nonrandomized, dose-escalation study in patients with
metastatic melanoma and may provide a foundation for
future therapeutic approaches. At the present time, the
use of TLR9 agonists for enhancing tumor vaccination is
the most advanced application of this technology in
oncology, and the early results from this approach appear
promising. Clinical trials are ongoing in other settings
and in combination with other therapeutic approaches,
and the true therapeutic potential of TLR9 agonists for
the treatment of cancer remains to be determined.
Acknowledgements
Financial support for medical editorial assistance was pro-
vided by Pfizer Pharmaceuticals. I thank Todd Parker, PhD,
ProEd Communications Inc., for expert editorial assistance
with manuscript preparation.
Conflict of Interest
Arthur M Krieg is a founder, employee and shareholder in
Coley Pharmaceutical Group and has a financial interest in
the development of TLR9 agonists for cancer therapy.
Cancer therapy with TLR9 agonists
AM Krieg
165
Oncogene

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