CpG Oligodeoxyneucleotides as TLR9 Agonists

Murad, Yanal; Clay, Timothy M.

doi:10.2165/11316930-000000000-00000

Cited by 88 publications

(35 citation statements)

References 120 publications

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“…Except as a vaccine adjuvant, numerous studies established that systemic delivery of free CpG is ineffective in eliciting anti-tumor immunity (8, 10, 13, 14, 18). chTNT-3/CpG1585 and chTNT-3/1826 monotherapies likely delayed tumor growth and improved survival by delivering the CpG moiety to the tumor, and may have increased CpG half-life.…”

Section: Resultsmentioning

confidence: 99%

“…Intratumoral injections of CpG elicited immune responses against tumors in murine models of melanoma (7–10), fibrosarcoma (7), renal cell carcinoma (8), colon adenocarcinoma (8, 9, 11), pancreatic adenocarcinoma (11), neuroblastomas (12), and lymphoma (13). Following its success in preclinical models, CpG were used in clinical trials for a wide range of cancers (reviewed in (14, 15)). However, optimal therapeutic effects were generally limited to intratumoral injections.…”

Section: Introductionmentioning

confidence: 99%

“…However, optimal therapeutic effects were generally limited to intratumoral injections. Disappointing clinical results (16, 17) were in part due to its poor efficacy when given systemically or in non-tumor sites (8, 10, 13, 14, 18). In clinical trials where CpG resulted in systemic tumor regression, CpG were still given intratumorally (19, 20).…”

Section: Introductionmentioning

confidence: 99%

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Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models

Jang

Khawli

Canter

et al. 2016

Cancer Immunol Immunother

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CpG oligodeoxynucleotides (CpG) potently activate the immune system by mimicking microbial DNA. Conjugation of CpG to chTNT-3, an antibody targeting the necrotic centers of tumors, enabled CpG to accumulate in tumors after systemic delivery, where it can activate the immune system in the presence of tumor antigens. CpG chemically conjugated to chTNT-3 (chTNT-3/CpG) were compared to free CpG in their ability to stimulate the immune system in vitro and reduce tumor burden in vivo. In subcutaneous Colon 26 adenocarcinoma and B16-F10 melanoma models in BALB/c and C57BL/6 mice, respectively, chTNT-3/CpG, free CpG, or several different control constructs were administered systemically. Intraperitoneal injections of chTNT-3/CpG delayed tumor growth and improved survival, and were comparable to intratumorally administered CpG. Compared to saline-treated mice, chTNT-3/CpG-treated mice had smaller average tumor volumes by as much as 72% in Colon 26-bearing mice and 79% in B16-bearing mice. Systemically delivered free CpG and CpG conjugated to an isotype control antibody did not reduce tumor burden or improve survival. In this study, chTNT-3/CpG retained immunostimulatory activity of the CpG moiety and enabled delivery to tumors. Because systemically administered CpG rapidly clear the body and do not accumulate into tumors, chTNT-3/CpG provide a solution to the limitations observed in preclinical and clinical trials.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models

Jang

Khawli

Canter

et al. 2016

Cancer Immunol Immunother

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“…After this trial was initiated, Slingluff and colleagues reported that the inclusion of GM-CSF with Montanide may result in diminished peptide-induced T cell responses in a melanoma vaccine study [34]. The TLR agonists CpG 7909 and polyIC:LC have recently been explored and should continue to be investigated as a possible adjuvant [35]. The MAGE-3 protein-based vaccine from GSK-Bio utilizes a combination of the TLR9 agonist CpG7909 and the TLR4 agonist MPL [36].…”

Section: Discussionmentioning

confidence: 99%

A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma

Geynisman¹,

Zha²,

Kunnavakkam³

et al. 2013

J Immunother Cancer

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BackgroundCEA is expressed in >90% of pancreatic cancers (PC) and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand can help bypass tolerance. We conducted a pilot randomized phase I trial in PC patients to determine the peptide dose required to induce an optimal CD8+ T cell response.MethodsPatients with a PS 0-1, HLA-A2+ and CEA-expressing, previously-treated PC were randomized to receive 10 μg (arm A), 100 μg (arm B) or 1000 μg (arm C) of CEA peptide emulsified in Montanide and GM-CSF, given every 2 weeks until disease progression.ResultsSixty-six patients were screened and 19 enrolled of whom 14 received at least 3 doses of the vaccine and thus evaluated for the primary immunologic endpoint. A median of 4 cycles (range 1-81) was delivered. Median and mean peak IFN-γ T cell response by ELISPOT (spots per 104 CD8+ cells, Arm A/B/C) was 11/52/271 (A vs. C, p = 0.028) for medians and 37/148/248 (A vs. C, p = 0.032) for means. T cell responses developed or increased in 20%/60%/100% of pts in Arms A/B/C. Seven of the 19 patients remain alive at a minimum 32 months from trial initiation, including three with unresectable disease.ConclusionsThe T cell response in this randomized phase I trial was dose-dependent with the 1 mg CEA peptide dose eliciting the most robust T cell responses. A signal of clinical benefit was observed and no significant toxicity was noted. Further evaluation of 1 mg CEA peptide with stronger adjuvants, and/or combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts.Trial registrationClinicalTrials.gov NCT00203892

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“…8,9 This mechanism further triggers cell signaling pathways, such as mitogen-activated protein kinases and NFκB, which induce multiple proinflammatory cytokines and chemokines Thus, CpG ODNs are promising immune adjuvants and immunotherapeutic agents against allergy/asthma, cancer, and infectious diseases. [11][12][13][14] Clinical studies suggest that CpG ODNs are safe and well tolerated when administered to humans; these molecules reportedly improve vaccineinduced immune responses. 2,15 However, the biologic activity of CpG ODNs is transient, and the extreme susceptibility to nuclease degradation in serum and poor cellular uptake of natural CpG ODNs severely limit the therapeutic applications of these molecules.…”

Section: Introductionmentioning

confidence: 99%

Polyethyleneimine-functionalized boron nitride nanospheres as efficient carriers for enhancing the immunostimulatory effect of CpG oligodeoxynucleotides

Zhang

Feng

Yan

et al. 2015

IJN

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CpG oligodeoxynucleotides (ODNs) stimulate innate and adaptive immune responses. Thus, these molecules are promising therapeutic agents and vaccine adjuvants against various diseases. In this study, we developed a novel CpG ODNs delivery system based on polyethyleneimine (PEI)-functionalized boron nitride nanospheres (BNNS). PEI was coated on the surface of BNNS via electrostatic interactions. The prepared BNNS–PEI complexes had positive zeta potential and exhibited enhanced dispersity and stability in aqueous solution. In vitro cytotoxicity assays revealed that the BNNS–PEI complexes with concentrations up to 100 μg/mL exhibited no obvious cytotoxicity. Furthermore, the positively charged surface of the BNNS–PEI complexes greatly improved the loading capacity and cellular uptake efficiency of CpG ODNs. Class B CpG ODNs loaded on the BNNS–PEI complexes enhanced the production of interleukin-6 and tumor necrosis factor-α from peripheral blood mononuclear cells compared with CpG ODNs directly loaded on BNNS. Contrary to the free CpG ODNs or CpG ODNs directly loaded on BNNS, class B CpG ODNs loaded on the BNNS–PEI complexes induced interferon-α simultaneously. PEI coating may have changed the physical form of class B CpG ODNs on BNNS, which further affected their interaction with Toll-like receptor 9 and induced interferon-α. Therefore, BNNS–PEI complexes can be used to enhance the immunostimulatory effect and therapeutic activity of CpG ODNs and the treatment of diseases requiring interleukin-6, tumor necrosis factor-α, and interferon-α.

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CpG Oligodeoxyneucleotides as TLR9 Agonists

Cited by 88 publications

References 120 publications

Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models

Systemic delivery of chTNT-3/CpG immunoconjugates for immunotherapy in murine solid tumor models

A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma

Polyethyleneimine-functionalized boron nitride nanospheres as efficient carriers for enhancing the immunostimulatory effect of CpG oligodeoxynucleotides

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