Toll-like receptor 9 (TLR9) agonists show potential for cancer treatment. TLR9 agonists activate dendritic cells and enhance B cell antibody production. This can induce antitumor immune responses. Preclinical studies show TLR9 agonists have activity against cancer as monotherapy and in combination with other therapies. Early clinical trials indicate TLR9 agonists have antitumor activity as single agents and enhance antitumor T cell responses when used as vaccine adjuvants. Several TLR9 agonists are being studied in clinical trials for various cancer types.
T cell Immune Pathways Current and Future Implementation in Cancer Immunother...CrimsonpublishersCancer
T cells are central players in cancer immune response. The discovery of T cell immune pathways has revealed several inhibitory and stimulatory pathways that affect the differentiation and activation of T cell. Theses pathways represent ideal candidates that can be targeted to augment in-vivo. T cell immune response against tumors. In this mini review we will try to reveal some inhibitory and stimulatory T cell immune pathways to which efforts of those interested in cancer immunotherapy can be directed.
T cell Immune Pathways Current and Future Implementation in Cancer Immunother...CrimsonpublishersCancer
T cells are central players in cancer immune response. The discovery of T cell immune pathways has revealed several inhibitory and stimulatory pathways that affect the differentiation and activation of T cell. Theses pathways represent ideal candidates that can be targeted to augment in-vivo. T cell immune response against tumors. In this mini review we will try to reveal some inhibitory and stimulatory T cell immune pathways to which efforts of those interested in cancer immunotherapy can be directed.
Background : During the conference of ASCO 2015, there was no consensus about TIL role in beast cancer and no recommendations concerning the microscopic assessment of TIL. In fact, the patients could be put on anti-PD1 drugs without the necessity of highlighting PD1 positive cells by using immunohistochemistry. Nevertheless, many questions about the prognostic impact of TIL, the methods of assessment, the type of TIL to count remain unresolved. Material and Methods : We performed a review of the literature on the sites : Pubmed and Cochrane. We used the key-words : �TIL in cancer�; �TIL in breast cancer� and �prognostic impact of TIL in breast cancer�. Results : According to our inclusion and exclusion criteria, thirty eight articles were retained. Our review of the literature showed that assessing TIL in high grade tumors seem unnecessary. They seem available in intermediate graded tumors. In neo-adjuvant and adjuvant conditions, CD3+ lymphocytes seem to be correlated to a good response to chemotherapy. After a chemotherapy, quantification T reg lymphocytes CD4 + FOXP3+ seems helpful because the decrease of their number is correlated to a good prognosis. Conclusion : The role of TIL in breast cancer is clearly established. The mechanisms of immune escape induced to discovery of immune therapy. The role of the microscopic examination and the subtyping of TIL using immunohistochemistry hasn�t been clearly established. Through this review of the literature, we tried to establish a diagram highlighting the different subtypes of TIL to evaluate and their prognostic impact.
Development of immune checkpoint inhibitors for treating various cancer disea...SriramNagarajan16
Cancer is a state which involves an abnormal increase in the number of cells, with a potentiality to invade or spread to
other parts of the body and destroy their function. Every individual is born with an immune system that acts as a
security checkpoint. The immune system does possess B and T lymphocytes, B -cells acts as the military intelligence
and T-cells acts as soldiers it also possesses some receptors that scan normal cells and abnormal cells like a virus and
some other cells. Abnormal cells are detected and removed by the T-cells, but in some conditions, T-cells fail to detect
and eliminate cancer cells. This is because of higher mutations in cancer cells leads to a development of some of the
receptors like PD-L1 which acts as the signal jammer of the T-cell. This leads to failure in the work of T-cells against
the cancer cells not only this some other receptors like CTLA-4 of T-Cells acts as a type of “off switch” to keep the
immune system in off. Immune checkpoint inhibitors are used by targeting PD-1, PD-L1 and CTLA-4 targets and drugs
like pembrolizumab, nivolumab, ipilimumab and etc. are used to treat various types of cancer.
In recent years, therapeutic antibodies targeted to various immune checkpoint molecules have progressed from preclinical studies to clinical deployment with impressive results.
https://www.creativebiolabs.net/samalizumab-overview.htm
Hepatocellular carcinoma (HCC) has always been a difficult medical problem for the increasing mortality rate. According to the World Health Organization (WHO), hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer related deaths worldwide [1] and is considered as a highly refractory cancer. Surgery is the most effective treatment to HCC, but HCC is resistant to conventional chemotherapy. In recent years, immunotherapy has been attracting growing attention as a promising therapeutic method to HCC. Immunotherapies to HCC including chimeric antigen receptor T cells (CAR-T), immune checkpoint inhibitor and oncolytic virus have become research hotspots.
This presentation is part of MIU CE Pharmacy Program and is designed primarily for pharmacists with the following learning objectives:
1- Explain the mechanisms of action behind immune response to cancer and the application of immunotherapy in cancer treatment
2- Distinguish new and emerging immunotherapy classes and individual agents efficacy, safety to therapy in cancer treatment
3-Strategies to counsel and assist patients to overcome barriers to therapy, including Treatment side effects to improve adherence to therapy
This intro is geared towards interested novices who wish to find a resource that can serve as a starting point for further self-study. This is not meant to replace a doctor's advice. Please approach a medical professional for any health condition.
Background : During the conference of ASCO 2015, there was no consensus about TIL role in beast cancer and no recommendations concerning the microscopic assessment of TIL. In fact, the patients could be put on anti-PD1 drugs without the necessity of highlighting PD1 positive cells by using immunohistochemistry. Nevertheless, many questions about the prognostic impact of TIL, the methods of assessment, the type of TIL to count remain unresolved. Material and Methods : We performed a review of the literature on the sites : Pubmed and Cochrane. We used the key-words : �TIL in cancer�; �TIL in breast cancer� and �prognostic impact of TIL in breast cancer�. Results : According to our inclusion and exclusion criteria, thirty eight articles were retained. Our review of the literature showed that assessing TIL in high grade tumors seem unnecessary. They seem available in intermediate graded tumors. In neo-adjuvant and adjuvant conditions, CD3+ lymphocytes seem to be correlated to a good response to chemotherapy. After a chemotherapy, quantification T reg lymphocytes CD4 + FOXP3+ seems helpful because the decrease of their number is correlated to a good prognosis. Conclusion : The role of TIL in breast cancer is clearly established. The mechanisms of immune escape induced to discovery of immune therapy. The role of the microscopic examination and the subtyping of TIL using immunohistochemistry hasn�t been clearly established. Through this review of the literature, we tried to establish a diagram highlighting the different subtypes of TIL to evaluate and their prognostic impact.
Development of immune checkpoint inhibitors for treating various cancer disea...SriramNagarajan16
Cancer is a state which involves an abnormal increase in the number of cells, with a potentiality to invade or spread to
other parts of the body and destroy their function. Every individual is born with an immune system that acts as a
security checkpoint. The immune system does possess B and T lymphocytes, B -cells acts as the military intelligence
and T-cells acts as soldiers it also possesses some receptors that scan normal cells and abnormal cells like a virus and
some other cells. Abnormal cells are detected and removed by the T-cells, but in some conditions, T-cells fail to detect
and eliminate cancer cells. This is because of higher mutations in cancer cells leads to a development of some of the
receptors like PD-L1 which acts as the signal jammer of the T-cell. This leads to failure in the work of T-cells against
the cancer cells not only this some other receptors like CTLA-4 of T-Cells acts as a type of “off switch” to keep the
immune system in off. Immune checkpoint inhibitors are used by targeting PD-1, PD-L1 and CTLA-4 targets and drugs
like pembrolizumab, nivolumab, ipilimumab and etc. are used to treat various types of cancer.
In recent years, therapeutic antibodies targeted to various immune checkpoint molecules have progressed from preclinical studies to clinical deployment with impressive results.
https://www.creativebiolabs.net/samalizumab-overview.htm
Hepatocellular carcinoma (HCC) has always been a difficult medical problem for the increasing mortality rate. According to the World Health Organization (WHO), hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer related deaths worldwide [1] and is considered as a highly refractory cancer. Surgery is the most effective treatment to HCC, but HCC is resistant to conventional chemotherapy. In recent years, immunotherapy has been attracting growing attention as a promising therapeutic method to HCC. Immunotherapies to HCC including chimeric antigen receptor T cells (CAR-T), immune checkpoint inhibitor and oncolytic virus have become research hotspots.
This presentation is part of MIU CE Pharmacy Program and is designed primarily for pharmacists with the following learning objectives:
1- Explain the mechanisms of action behind immune response to cancer and the application of immunotherapy in cancer treatment
2- Distinguish new and emerging immunotherapy classes and individual agents efficacy, safety to therapy in cancer treatment
3-Strategies to counsel and assist patients to overcome barriers to therapy, including Treatment side effects to improve adherence to therapy
This intro is geared towards interested novices who wish to find a resource that can serve as a starting point for further self-study. This is not meant to replace a doctor's advice. Please approach a medical professional for any health condition.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
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
Oncogene
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
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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
Oncogene
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
6. References
Akira S, Uematsu S, Takeuchi O. (2006). Pathogen recognition
and innate immunity. Cell 124: 783–801.
Appay V, Jandus C, Voelter V, Reynard S, Coupland SE,
Rimoldi D et al. (2006). New generation vaccine induces
effective melanoma-specific CD8+ T cells in the circulation
but not in the tumor site. J Immunol 177: 1670–1678.
Baines J, Celis E. (2003). Immune-mediated tumor regression
induced by CpG-containing oligodeoxynucleotides. Clin
Cancer Res 9: 2693–2700.
Carpentier A, Laigle-Donadey F, Zohar S, Capelle L, Behin A,
Tibi A et al. (2006). Phase 1 trial of a CpG oligodeoxynu-
cleotide for patients with recurrent glioblastoma. Neuro
Oncol 8: 60–66.
Daftarian P, Song GY, Ali S, Faynsod M, Longmate J,
Diamond DJ et al. (2004). Two distinct pathways of
immuno-modulation improve potency of p53 immunization
in rejecting established tumors. Cancer Res 64: 5407–5414.
Damiano V, Caputo R, Bianco R, D’Armiento FP, Leonardi
A, De Placido S et al. (2006). Novel Toll-like receptor 9
agonist induces epidermal growth factor receptor (EGFR)
inhibition and synergistic antitumor activity with EGFR
inhibitors. Clin Cancer Res 12: 577–583.
Damiano V, Caputo R, Garofalo S, Bianco R, Rosa R,
Merola G et al. (2007). TLR9 agonist acts by different
mechanisms synergizing with bevacizumab in sensitive and
cetuximab-resistant colon cancer xenografts. Proc Natl Acad
Sci USA 104: 12468–12473.
Davila E, Kennedy R, Celis E. (2003). Generation of
antitumor immunity by cytotoxic T lymphocyte epitope
peptide vaccination, CpG-oligodeoxynucleotide adjuvant,
and CTLA-4 blockade. Cancer Res 63: 3281–3288.
Decker T, Schneller F, Sparwasser T, Tretter T, Lipford GB,
Wagner H et al. (2000). Immunostimulatory CpG-oligo-
nucleotides cause proliferation, cytokine production, and an
immunogenic phenotype in chronic lymphocytic leukemia B
cells. Blood 95: 999–1006.
Droemann D, Albrecht D, Gerdes J, Ulmer AJ, Branscheid D,
Vollmer E et al. (2005). Human lung cancer cells express
functionally active Toll-like receptor 9. Respir Res 6: 1.
Friedberg JW, Kim H, McCauley M, Hessel EM, Sims P,
Fisher DC et al. (2005). Combination immunotherapy with
a CpG oligonucleotide (1018 ISS) and rituximab in patients
with non-Hodgkin lymphoma: increased interferon-alpha/
beta-inducible gene expression, without significant toxicity.
Blood 105: 489–495.
Gelman AE, LaRosa DF, Zhang J, Walsh PT, Choi Y, Sunyer JO
et al. (2006). The adaptor molecule MyD88 activates PI-3 kinase
signaling in CD4+ T cells and enables CpG oligodeoxynucleo-
tide-mediated costimulation. Immunity 25: 783–793.
Hayashi F, Means TK, Luster AD. (2003). Toll-like receptors
stimulate human neutrophil function. Blood 102: 2660–2669.
Hofmann MA, Kors C, Audring H, Walden P, Sterry W,
Trefzer U. (2007). Safety and activity of intralesionally
injected TLR9 ligand CpG DNA in basal cell carcinoma and
melanoma (submitted).
Iwasaki A, Medzhitov R. (2004). Toll-like receptor control of
the adaptive immune responses. Nat Immunol 5: 987–995.
Jahrsdorfer B, Hartmann G, Racila E, Jackson W, Muhlenhoff
L, Meinhardt G et al. (2001). CpG DNA increases primary
malignant B cell expression of costimulatory molecules and
target antigens. J Leukoc Biol 69: 81–88.
Jahrsdorfer B, Wooldridge JE, Blackwell SE, Taylor CM,
Griffith TS, Link BK et al. (2005). Immunostimulatory
oligodeoxynucleotides induce apoptosis of B cell chronic
lymphocytic leukemia cells. J Leukoc Biol 77: 378–387.
Kim Y, Girardi M, Duvic M, Kuzel T, Rook A, Link B et al.
(2004). TLR9 agonist immunomodulator treatment of cuta-
neous T-cell lymphoma (CTCL) with CPG7909 [abstract].
ASH Annual Meeting Abstracts 104, Abstract 743.
Krieg AM. (2004). Antitumor applications of stimulating Toll-
like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol
Rep 6: 88–95.
Krieg AM. (2006). Therapeutic potential of Toll-like receptor
9 activation. Nat Rev Drug Discov 5: 471–484.
Krieg AM. (2007). Development of TLR9 agonists for cancer
therapy. J Clin Invest 117: 1184–1194.
Latz E, Verma A, Visintin A, Gong M, Sirois CM, Klein DC
et al. (2007). Ligand-induced conformational changes
allosterically activate Toll-like receptor 9. Nat Immunol 8:
772–779.
Lebre MC, van der Aar AM, van Baarsen L, van Capel TM,
Schuitemaker JH, Kapsenberg ML et al. (2007). Human
keratinocytes express functional Toll-like receptor 3, 4, 5,
and 9. J Invest Dermatol 127: 331–341.
Lee J, Mo JH, Katakura K, Alkalay I, Rucker AN, Liu YT
et al. (2006). Maintenance of colonic homeostasis by
distinctive apical TLR9 signalling in intestinal epithelial
cells. Nat Cell Biol 8: 1327–1336.
Leonard JP, Link B, Emmanouilides C, Gregory SA, Weisdorf
D, Andrey J et al. (2007). Phase I trial of Toll-like receptor 9
agonist PF-3512676 (CpG 7909) with and following
rituximab in patients with recurrent indolent and aggressive
non-Hodgkin’s lymphoma. Clin Cancer Res. (in press).
Li J, Ma Z, Tang ZL, Stevens T, Pitt B, Li S. (2004). CpG
DNA-mediated immune response in pulmonary endothelial
cells. Am J Physiol Lung Cell Mol Physiol 287: L552–L558.
Link BK, Ballas ZK, Weisdorf D, Wooldridge JE, Bossler AD,
Shannon M et al. (2006). Oligodeoxynucleotide CpG 7909
delivered as intravenous infusion demonstrates immunologic
modulation in patients with previously treated non-Hodgkin
lymphoma. J Immunother 29: 558–568.
Manegold C, Gravenor D, Woytowitz D, Mezger J, Hirsh V,
Albert G et al. (2007). Randomized phase II trial of a Toll-
like receptor 9 (TLR9) agonist oligodeoxynucleotide, PF-
3512676 (CPG 7909), in combination with first-line taxane/
platinum chemotherapy for advanced-stage non-small-cell
lung cancer. J Clin Oncol. (in press).
Milas L, Mason KA, Ariga H, Hunter N, Neal R, Valdecanas D
et al. (2004). CpG oligodeoxynucleotide enhances tumor
response to radiation. Cancer Res 64: 5074–5077.
Molenkamp BG, van Leeuwen PA, Meijer S, Sluijter BJ,
Wijnands PG, Baars A et al. (2007). Intradermal CpG-B
activates both plasmacytoid and myeloid dendritic cells in
the sentinel lymph node of melanoma patients. Clin Cancer
Res 13: 2961–2969.
Pashenkov M, Goess G, Wagner C, Hormann M, Jandl T,
Moser A et al. (2006). Phase II trial of a Toll-like receptor
9-activating oligonucleotide in patients with metastatic
melanoma. J Clin Oncol 24: 5716–5724.
Pedersen G, Andresen L, Matthiessen MW, Rask-Madsen J,
Brynskov J. (2005). Expression of Toll-like receptor 9 and
response to bacterial CpG oligodeoxynucleotides in human
intestinal epithelium. Clin Exp Immunol 141: 298–306.
Platz J, Beisswenger C, Dalpke A, Koczulla R, Pinkenburg O,
Vogelmeier C et al. (2004). Microbial DNA induces a host
defense reaction of human respiratory epithelial cells.
J Immunol 173: 1219–1223.
Readett DRJ, Denis L, Krieg AM, Benner RJ, Hanson DC.
(2007). PF-3512676 (CPG 7909), a Toll-like receptor 9
agonist—status of development for non-small cell lung
Cancer therapy with TLR9 agonists
AM Krieg
166
Oncogene
7. cancer (NSCLC) [poster]. Presented at: 12th World Con-
gress on Lung Cancer; September 2–6; Seoul, Korea.
Abstract PD3-1-6.
Sabel MS, Sondak VK. (2003). Pros and cons of adjuvant
interferon in the treatment of melanoma. Oncologist 8:
451–458.
Saikh KU, Kissner TL, Sultana A, Ruthel G, Ulrich RG.
(2004). Human monocytes infected with Yersinia pestis
express cell surface TLR9 and differentiate into dendritic
cells. J Immunol 173: 7426–7434.
Siren J, Pirhonen J, Julkunen I, Matikainen S. (2005). IFN-alpha
regulates TLR-dependent gene expression of IFN-alpha, IFN-
beta, IL-28, and IL-29. J Immunol 174: 1932–1937.
Speiser DE, Lienard D, Rufer N, Rubio-Godoy V, Rimoldi D,
Lejeune F et al. (2005). Rapid and strong human CD8+ T
cell responses to vaccination with peptide, IFA, and CpG
oligodeoxynucleotide 7909. J Clin Invest 115: 739–746.
Thompson JA, Kuzel T, Bukowski R, Masciari F, Schmalbach
T. (2004). Phase Ib trial of a targeted TLR9 CpG
immunomodulator (CPG 7909) in advanced renal cell
carcinoma (RCC). J Clin Oncol 22(Suppl): 416. Abstract
4644.
Trefzer U, Kors C, Pelzer K, Walden P, Sterry W, O’Keefe E.
(2002). Preliminary results of a phase I trial of intralesional
injection of CPG 7909 in patients with basal cell carcinoma
or melanoma. Proc Am Soc Clin Oncol 21, Abstract: 1902.
Van Den Eertwegh AJ, Lensen RJ, Scheper RJ, Giaccone G,
Meijer CJ, Bontkes HJ et al. (2006). Autologous tumor cell
vaccination with PF-3512676 (CPG 7909) and GM-CSF
followed by subcutaneous PF-3512676 and IFN-alpha for
patients with metastatic renal cell carcinoma. J Clin Oncol
24(Suppl): 107s Abstract 2530.
van Ojik H, Kruit W, Portielje J, Brichard V, Verloes R, Delire M
et al. (2002). Phase I/II study with CPG 7909 as adjuvant to
vaccination with MAGE-3 protein in patients with MAGE-3
positive tumors. Ann Oncol 13(Suppl): 157–158. Abstract 579O.
Weeratna RD, Bourne LL, Sullivan SM, Davis HL, Krieg
AM. (2004). Combination of a new TLR9 agonist immu-
nomodulator (CpG 7909) and paclitaxel for treatment of
metastatic Lewis lung carcinoma (LLC). J Clin Oncol
22(Suppl): 699 Abstract 7346.
Weigel BJ, Rodeberg DA, Krieg AM, Blazar BR. (2003). CpG
oligodeoxynucleotides potentiate the antitumor effects of
chemotherapy or tumor resection in an orthotopic murine
model of rhabdomyosarcoma. Clin Cancer Res 9: 3105–3114.
Wooldridge JE, Weiner GJ. (2003). CpG DNA and cancer
immunotherapy: orchestrating the antitumor immune re-
sponse. Curr Opin Oncol 15: 440–445.
Wooldridge JE, Ballas Z, Krieg AM, Weiner GJ. (1997).
Immunostimulatory oligodeoxynucleotides containing CpG
motifs enhance the efficacy of monoclonal antibody therapy
of lymphoma. Blood 89: 2994–2998.
Wysocka M, Benoit BM, Newton S, Azzoni L, Montaner LJ,
Rook AH. (2004). Enhancement of the host immune
responses in cutaneous T-cell lymphoma by CpG oligodeox-
ynucleotides and IL-15. Blood 104: 4142–4149.
Cancer therapy with TLR9 agonists
AM Krieg
167
Oncogene