Monotherapy with a Tumor-Targeting Mutant of S. typhimurium Inhibits Liver Metastasis in a Mouse Model of Pancreatic Cancer

Yam, Clinton; Zhao, Ming; Hayashi, Katsuhiro; Ma, Huaiyu; Kishimoto, Hiroyuki; McElroy, Michele; Bouvet, Michael; Hoffman, Robert M.

doi:10.1016/j.jss.2009.02.023

Cited by 125 publications

(81 citation statements)

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“…In fact, activation of TLR5 by commensal bacteria was shown to drive malignant progression at extramucosal locations through the promotion of inflammation, which dampened antitumor immunity by expanding immunosuppressive networks (65). In contrast, we and others have shown that TLR5 activation has tumor growth suppressive effects and stimulates antitumor immunity (19)(20)(21)(22)(23)(24)(25)(26)53). Earlier studies in our laboratory showed that entolimod displayed a growth-inhibitory effect on a TLR5-expressing mouse xenograft model of human lung adenocarcinoma A549 (23), supporting a direct effect of TLR5 stimulation on tumor growth suppression.…”

Section: Discussionmentioning

confidence: 98%

“…Studies have shown that the only known natural TLR5 agonist, flagellin, flagellin-expressing Salmonella bacteria, and a pharmacologically optimized flagellin derivative named entolimod (CBLB502) have antitumor effects in several tumor models (19)(20)(21)(22)(23), including mouse models of liver metastases (24)(25)(26). Moreover, systemic administration of TLR5 agonists is uniquely safe because of the restricted pattern of expression of TLR5 (primarily in the gut, liver, and bladder) and the nature of the cytokines induced following TLR5 stimulation.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 98%

mentioning

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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“…Second, the TLR5 agonist CBLB502 was shown to be effective as a tissue protectant in mouse models of renal ischemia-reperfusion injury (10). Third, bacterial flagellin and flagellin-expressing bacteria (Salmonella) have shown antitumor effects in mouse models of colon and liver metastasis of pancreatic cancer (11,12). Bacterial flagellin and its derivative, CBLB502, also demonstrated antitumor effects in several in vivo models (9,13,14).…”

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confidence: 99%

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

Burdelya

Brackett

Kojouharov

et al. 2013

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

111

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Vertebrate Toll-like receptor 5 (TLR5) recognizes bacterial flagellin proteins and activates innate immune responses to motile bacteria. In addition, activation of TLR5 signaling can inhibit growth of TLR5-expressing tumors and protect normal tissues from radiation and ischemia-reperfusion injuries. To understand the mechanisms behind these phenomena at the organismal level, we assessed nuclear factor kappa B (NF-κB) activation (indicative of TLR5 signaling) in tissues and cells of mice treated with CBLB502, a pharmacologically optimized flagellin derivative. This identified the liver and gastrointestinal tract as primary CBLB502 target organs. In particular, liver hepatocytes were the main cell type directly and specifically responding to systemic administration of CBLB502 but not to that of the TLR4 agonist LPS. To assess CBLB502 impact on other pathways, we created multireporter mice with hepatocytes transduced in vivo with reporters for 46 inducible transcription factor families and found that along with NF-κB, CBLB502 strongly activated STAT3-, phenobarbital-responsive enhancer module (PREM), and activator protein 1 (AP-1-) -driven pathways. Livers of CBLB502-treated mice displayed induction of numerous immunomodulatory factors and massive recruitment of various types of immune cells. This led to inhibition of growth of liver metastases of multiple tumors regardless of their TLR5 status. The changed liver microenvironment was not, however, hepatotoxic, because CBLB502 induced resistance to Fas-mediated apoptosis in normal liver cells. Temporary occlusion of liver blood circulation prevented CBLB502 from protecting hematopoietic progenitors in lethally irradiated mice, indicating involvement of a factor secreted by responding liver cells. These results define the liver as the key mediator of TLR5-dependent effects in vivo and suggest clinical applications for TLR5 agonists as hepatoprotective and antimetastatic agents.breast cancer | colon cancer | neutrophils | natural killer cells | Salmonella T oll-like receptors (TLRs) recognize and are activated by specific patterns in molecules that are produced by a broad range of microbial pathogens but are not present in host molecules. Activation of TLRs by these pathogen-associated molecular patterns leads to induction of infection-fighting innate immune responses (1). Various TLR agonists have been considered for multiple clinical applications, including cancer immunotherapy (2-4), and one, the TLR7 agonist imiquimod, is approved for topical treatment of basal cell carcinoma (5).Although signaling pathways induced by different TLRs all result in mobilization of an innate immune response and involve activation of nuclear factor kappa B (NF-κB), the key regulator of immunity (6, 7), TLR5 is a particularly attractive candidate for therapeutic targeting for several reasons. First, bacterial flagellin, the natural ligand of TLR5, was found to have strong radioprotective effects in rodents and nonhuman primates (8). CBLB502 is a rationally designed derivative of Salmon...

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“…28 Leschner et al have observed a large influx of blood into the tumors by vascular disruption after treatment with S. typhimurium. Blood influx was followed by necrosis formation.…”

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confidence: 99%

Vessel destruction by tumor-targetingSalmonella typhimuriumA1-R is enhanced by high tumor vascularity

et al. 2010

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Monotherapy with a Tumor-Targeting Mutant of S. typhimurium Inhibits Liver Metastasis in a Mouse Model of Pancreatic Cancer

Cited by 125 publications

References 20 publications

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

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

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

Vessel destruction by tumor-targetingSalmonella typhimuriumA1-R is enhanced by high tumor vascularity

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Monotherapy with a Tumor-Targeting Mutant of S. typhimurium Inhibits Liver Metastasis in a Mouse Model of Pancreatic Cancer

Cited by 125 publications

References 20 publications

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

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

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

Vessel destruction by tumor-targetingSalmonella typhimuriumA1-R is enhanced by high tumor vascularity

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

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