Randomized Phase II Trial of a Toll-Like Receptor 9 Agonist Oligodeoxynucleotide, PF-3512676, in Combination With First-Line Taxane Plus Platinum Chemotherapy for Advanced-Stage Non–Small-Cell Lung Cancer

Manegold, Christian; Gravenor, Donald S.; Woytowitz, Donald; Mezger, J.; Hirsh, Vera; Albert, Gary; Al‐Adhami, Mohammed; Readett, David; Krieg, Arthur Μ.; Leichman, Cynthia G.

doi:10.1200/jco.2007.12.5807

Cited by 154 publications

(105 citation statements)

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“…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 (26)(27)(28)(29)(30). In another phase II study of TLR9 agonist oligodeoxynucleotide in combination with first-line taxane plus platinum chemotherapy in the treatment of advanced-stage non-small-cell lung cancer, the author concluded that addition of PF-3512676, a TLR9 agonist, to taxane plus platinum chemotherapy for first-line treatment of NSCLC improves objective response and may improve even survival of patients (31). It may be only a result of the chemosensitization effect of TLR9 agonist by upregulating antitumor activity of immunocells.…”

Section: Discussionmentioning

confidence: 99%

Association of Toll like receptor 9 expression with lymph node metastasis in human breast cancer

Qiu¹,

Shao²,

Yang³

et al. 2011

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The toll like receptor 9(TLR9) has been suggested to play an important role in the invasion and metastasis of cancer cells in vitro. However, the expression of TLR9 in human cancer specimens has never been characterized. In this study, we investigated the expression of TLR9 in breast cancer specimens and determined the association between its expression and the clinicopathological features observed. We found that TLR9 expression was significantly higher in patients with breast cancers displaying large tumor size (P = 0.040), lymph node metastasis (P <0.001) or advanced pathological stage (P = 0.006). TLR9 expression was also increased in ER negative breast cancer specimens(P=0.043). Logistic regression analysis revealed that pathological stage(P = 0.007) and TLR9 (P = 0.001) expression were independent factors that influenced axillary lymph node metastasis of breast cancer. Patients with positive TLR9 expression had a higher progress free survival compared with the TLR9-negative cohort(P=0.037). Therefore we concluded that Lymph node metastasis more likely occur in breast cancer patients with a postive TLR9 status and its expression might serve as an indicator of poor prognosis in patients with breast cancer.

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Section: Discussionmentioning

confidence: 99%

Association of Toll like receptor 9 expression with lymph node metastasis in human breast cancer

Qiu¹,

Shao²,

Yang³

et al. 2011

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“…Although at least nine distinct TLRs have been discovered in mammals (62), drug development efforts have focused on targeting TLRs 3, 7, and 9, because they are thought to effectively integrate innate and adaptive immune responses (63). However, the promise of such TLR agonist-based therapies has not been borne out in the clinic, not only because little attention has been paid to identifying the most suitable target tumor types, but also because systemic administration of the pharmacologics used to engage these particular TLR pathways have led to "cytokine storm"-related dose-limiting toxicities (10)(11)(12). This led us to consider that the therapeutic value of the "TLR agonist concept" might be markedly improved by exploiting a TLR system intrinsic to the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

“…Although proof-ofprinciple for this concept has been demonstrated with agonists of several TLRs (TLR3, -7, and -9) (8), only one, the TLR7 agonist Imiquimod, has been approved for clinical use [however, this is limited to topical treatment of basal cell carcinoma (9)]. The major clinical limitations of many TLR agonists are the risk of dose-limiting toxicities associated with their systemic delivery (10)(11)(12) and metastasis stimulation (13)(14)(15). Furthermore, some previously investigated TLR agonists are restricted to injection directly into tumor tissue (3,(16)(17)(18), an approach that will likely have limited therapeutic value in cancer patients with metastatic disease.…”

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confidence: 99%

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 ⁺ T-cell axis

Brackett

Kojouharov

Veith

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Activation of an anticancer innate immune response is highly desirable because of its inherent ability to generate an adaptive antitumor T-cell response. However, insufficient safety of innate immune modulators limits clinical use to topical applications. Tolllike receptor 5 (TLR5) agonists are favorably positioned as potential systemic immunotherapeutic agents because of unusual tissue specificity of expression, uniquely safe profile of induced cytokines, and antitumor efficacy demonstrated in a number of animal models. Here, we decipher the molecular and cellular events underlying the metastasis suppressive activity of entolimod, a clinical stage TLR5 agonist that activates NF-κB-, AP-1-, and STAT3-driven immunomodulatory signaling pathways specifically within the liver. Used as a single agent in murine colon and mammary metastatic cancer models, entolimod rapidly induces CXCL9 and -10 that support homing of blood-borne CXCR3-expressing NK cells to the liver predominantly through an IFN-γ signaling independent mechanism. NK cell-dependent activation of dendritic cells is followed by stimulation of a CD8 + T-cell response, which exert both antimetastatic effect of entolimod and establishment of tumor-specific and durable immune memory. These results define systemically administered TLR5 agonists as organ-specific immunoadjuvants, enabling efficient antitumor vaccination that does not depend on identification of tumor-specific antigens.cancer immunotherapy | liver | colorectal cancer | breast cancer | innate immunity R ecent advancements in the field of anticancer immunotherapy have been primarily focused on development of T-cellbased approaches because of recognition of the inherent ability of adaptive immunity to efficiently eradicate neoplastic disease (1, 2). Innate immune responses play important roles in T-cell activation, but their potential relevance for prevention and treatment of cancer remains underappreciated (3-5). Toll-like receptors (TLRs) are gaining attention as potential therapeutic targets capable of stimulating antitumor immunity by initiating innate responses (6) and subsequent adaptive T-cell-based immunity (7). Although proof-ofprinciple for this concept has been demonstrated with agonists of several TLRs (TLR3, -7, and -9) (8), only one, the TLR7 agonist Imiquimod, has been approved for clinical use [however, this is limited to topical treatment of basal cell carcinoma (9)]. The major clinical limitations of many TLR agonists are the risk of dose-limiting toxicities associated with their systemic delivery (10-12) and metastasis stimulation (13-15). Furthermore, some previously investigated TLR agonists are restricted to injection directly into tumor tissue (3,(16)(17)(18), an approach that will likely have limited therapeutic value in cancer patients with metastatic disease.TLR5 is unique among TLRs as a potential target for systemic anticancer immunotherapy. Studies have shown that the only known natural TLR5 agonist, flagellin, flagellin-expressing Salmonella bacteria, and a pharmacolog...

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“…Statistical analysis suggests a trend toward improved survival for patients treated with ODN plus chemotherapy. The median survival for patients in the ODN plus chemotherapy arm was 12.3 months compared with 6.8 months for patients in the chemotherapy-alone group [124].…”

Section: Tlrs In Clinical Trials Against Human Malignanciesmentioning

confidence: 99%

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

Wolska

Lech‐Marańda

Robak

2009

Cellular and Molecular Biology Letters

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Toll-like receptors (TLRs) have been described as major components of the innate immune system, recognizing the conserved molecular structures found in the large groups of pathogens called pathogen-associated molecular patterns (PAMPs). TLR expression is ubiquitous, from epithelial to immunocompetent cells. TLR ligation triggers several adapter proteins and downstream kinases, leading to the induction of key pro-inflammatory mediators but also anti-inflammatory and anti-tumor cytokines. The result of this activation goes beyond innate immunity to shape the adaptive responses against pathogens and tumor cells, and maintains host homeostasis via cell debris utilization. TLRs have already become potent targets in infectious disease treatment and vaccine therapy and in neoplastic disease treatment, due to their ability to enhance antigen presentation. However, some studies show the dual effect of TLR stimulation on malignant cells: they can be proapoptotic or promote survival under different conditions. It is therefore crucial to design further studies assessing the biology of these receptors in normal and transformed cells. The established role of TLRs in human disease therapy is based on TLR7 and TLR4 agonists, respectively for the novel treatment of some types of skin cancer and for the anti-hepatitis B virus vaccine. Some clinical trials involving TLR agonists as potent enhancers of the anti-tumor response in solid tumors have begun.

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Randomized Phase II Trial of a Toll-Like Receptor 9 Agonist Oligodeoxynucleotide, PF-3512676, in Combination With First-Line Taxane Plus Platinum Chemotherapy for Advanced-Stage Non–Small-Cell Lung Cancer

Abstract: The addition of PF-3512676 to taxane plus platinum chemotherapy for first-line treatment of NSCLC improves objective response and may improve survival. Confirmatory phase III trials are ongoing.

Cited by 154 publications

References 39 publications

Association of Toll like receptor 9 expression with lymph node metastasis in human breast cancer

Association of Toll like receptor 9 expression with lymph node metastasis in human breast cancer

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 ⁺ T-cell axis

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

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Randomized Phase II Trial of a Toll-Like Receptor 9 Agonist Oligodeoxynucleotide, PF-3512676, in Combination With First-Line Taxane Plus Platinum Chemotherapy for Advanced-Stage Non–Small-Cell Lung Cancer

Abstract: The addition of PF-3512676 to taxane plus platinum chemotherapy for first-line treatment of NSCLC improves objective response and may improve survival. Confirmatory phase III trials are ongoing.

Cited by 154 publications

References 39 publications

Association of Toll like receptor 9 expression with lymph node metastasis in human breast cancer

Association of Toll like receptor 9 expression with lymph node metastasis in human breast cancer

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 + T-cell axis

Toll-like receptors and their role in carcinogenesis and anti-tumor treatment

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Product

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Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 ⁺ T-cell axis