Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma1

Carpentier, Alexandre; Laigle‐Donadey, Florence; Zohar, Sarah; Laurent, Césari; Béhin, Anthony; Tibi, Annick; Martin-Duverneuil, N; Sanson, Marc; Lacomblez, Lucette; Taillibert, Sophie; Louis, Guillaume; Effenterre, R. Van; Delattre, Jean‐Yves; Carpentier, Antoine F.

doi:10.1215/s1522851705000475

Cited by 196 publications

(138 citation statements)

References 14 publications

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“…A minor response was observed in 2 of 24 patients with recurrent (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).…”

Section: Other Solid Tumorsmentioning

confidence: 99%

Toll-like receptor 9 (TLR9) agonists in the treatment of cancer

2008

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Although still early in clinical development, agonists of Tolllike receptor 9 (TLR9) have demonstrated potential for the treatment of cancer. TLR9 agonists directly induce activation 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 immunotherapies, 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.

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Section: Other Solid Tumorsmentioning

confidence: 99%

Toll-like receptor 9 (TLR9) agonists in the treatment of cancer

2008

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“…Further studies have confirmed the antitumor effects of CpG-ODN in different intracranial models of syngeneic glioma (24,25). Moreover, a phase I trial utilizing convection-enhanced intratumoral delivery of CpG-28 has recently been completed in the setting of recurrent glioblastoma multiforme resulting in minor responses in two patients without displaying serious adverse events (26).…”

mentioning

confidence: 94%

TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas

Grauer

Molling

Bennink

et al. 2008

The Journal of Immunology

117

102

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Local TLR stimulation is an attractive approach to induce antitumor immunity. In this study, we compared various TLR ligands for their ability to affect murine GL261 cells in vitro and to eradicate established intracerebral murine gliomas in vivo. Our data show that GL261 cells express TLR2, TLR3, and TLR4 and respond to the corresponding TLR ligands with increasing MHC class I expression and inducing IL-6 secretion in vitro, while TLR5, TLR7, and TLR9 are essentially absent. Remarkably, CpG-oligonucleotides (CpG-ODN, TLR9) appeared to inhibit GL261 cell proliferation in a cell-type specific, but CpG-motif and TLR9-independent manner. A single intratumoral injection of CpG-ODN most effectively inhibited glioma growth in vivo and cured 80% of glioma-bearing C57BL/6 mice. Intratumoral injection of Pam3Cys-SK4 (TLR1/2) or R848 (TLR7) also produced a significant survival benefit, whereas poly(I:C) (TLR3) or purified LPS (TLR4) stimulation alone was not effective. Additional studies using TLR9+/+ wild-type and TLR9−/− knockout mice revealed that the efficacy of local CpG-ODN treatment in vivo required TLR9 expression on nontumor cells. Additional experiments demonstrated increased frequencies of tumor-infiltrating IFN-γ producing CD4+ and CD8+ effector T cells and a marked increase in the ratio of CD4+ effector T cells to CD4+FoxP3+ regulatory T cells upon CpG-ODN treatment. Surviving CpG-ODN treated mice were also protected from a subsequent tumor challenge without further addition of CpG-ODN. In summary, this study underlines the potency of local TLR treatment in antiglioma therapy and demonstrates that local CpG-ODN treatment most effectively restores antitumor immunity in a therapeutic murine glioma model.

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“…A phase 1 clinical trial was undertaken using intratumoral administration of CpG-28 in recurrent glioblastoma, which showed some response without adverse side effects. [75]. In a follow-up phase II study, again using CpG-28 in recurrent glioblastoma, some response in progression-free survival at 6 months was observed [76] (Table 3).…”

mentioning

confidence: 98%

Evaluating the role of Toll-like receptors in diseases of the central nervous system

Carty

Bowie

2011

Biochemical Pharmacology

132

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A key part of the innate immune system is a network of pattern recognition receptors (PRRs) and their associated intracellular signalling pathways. Toll-like receptors (TLRs) are one such group of PRRs that detect pathogen associated molecular patterns (PAMPs). Activation of the TLRs with their respective agonists results in the activation of intracellular signalling pathways leading to the expression of proinflammatory mediators and anti-microbial effector molecules. Activation of the innate immune system through TLRs also triggers the adaptive immune response, resulting in a comprehensive immune program to eradicate invading pathogens. It is now known that immune surveillance and inflammatory responses occur in the central nervous system (CNS). Furthermore it is becoming increasingly clear that TLRs have a role in such CNS responses andare also implicated in the pathogenesis of a number of conditions in the CNS, such as Alzheimer's, stroke and multiple sclerosis. This is likely due to the generation of endogenous TLR agonists in these conditions which amplifies a detrimental neurotoxic inflammatory response. However TLRs in some situations can be neuroprotective, if triggered in a favourable context. This review aims to examine the recent literature on TLRs in the CNS thus demonstrating their importance in a range of infectious and non-infectious diseases of the brain.

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Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma1

Cited by 196 publications

References 14 publications

Toll-like receptor 9 (TLR9) agonists in the treatment of cancer

Toll-like receptor 9 (TLR9) agonists in the treatment of cancer

TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas

Evaluating the role of Toll-like receptors in diseases of the central nervous system

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