Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors

Isambert, Nicolás; Fumoleau, P.; Paul, Catherine; Ferrand, Christophe; Zanetta, Sylvie; Bauer, Jacques; Ragot, Kévin; Lizard, Gérard; Jeannin, Jean–François; Bardou, Marc

doi:10.1186/1471-2407-13-172

Cited by 39 publications

(33 citation statements)

References 33 publications

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“…The exacerabation of this weight loss in the mutant animals was unexpected. Activation of TLR4 has for example been associated with emetic activity in humans [38]. Other TLRs have been shown to play important roles in mediating bowel pathology and permeability [39].…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor signaling regulates cisplatin-induced mechanical allodynia in mice

Park

Stokes

Corr

et al. 2013

Cancer Chemother Pharmacol

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Purpose Cisplatin treated mice develop a persistent pain state and a condition wherein otherwise innocuous tactile stimuli evoke pain behavior, e.g. tactile allodynia. The allodynia is associated with an up-regulation of Activation Transcription Factor 3 (ATF3) in the dorsal root ganglia (DRG), a factor, which is activated by Toll-like receptors (TLR). Accordingly, we sought to examine the role of the TLR signaling cascade on allodynia, weight and changes in DRG ATF3 in cisplatin-treated mice. Methods Cisplatin (2.3 mg/kg/day × 6 injections every other day) or vehicle was administered to male wild type (WT) C57BL/6, Tlr3−/−, Tlr4−/−, Myd88−/−, Triflps2 and Myd88/Triflps2 mice. We examined allodynia and body weight at intervals over 30 days, when we measured DRG ATF3 by immunostaining. Results i) WT cisplatin-treated mice showed tactile allodynia from day 3 through day 30. ii) The Myd88/Triflps2, mice did not show allodynia. iii) In Tlr3−/−, Tlr4−/−, and Myd88−/− mice, withdrawal thresholds were elevated towards normal versus WT cisplatin treated mice, but remained decreased as compared to vehicle mice. iv) In Triflps2 mice, cisplatin allodynia showed a delayed onset, but persisted. v) In Tlr3−/−, Tlr4−/−, Myd88−/−, and Myd88/Triflps2 mice, the increase in DRG ATF3 was abolished. vi) Weight loss occurred during cisplatin administration, which was exacerbated in mutant as compared to WT mice. Conclusions Cisplatin evoked a persistent allodynia and DRG ATF3 expression in WT mice, but these effects were reduced in mice with TLR signaling deficiency. TLR signaling may thus be involved in the mechanisms leading to the cisplatin-polyneuropathy.

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Section: Discussionmentioning

confidence: 99%

Toll-like receptor signaling regulates cisplatin-induced mechanical allodynia in mice

Park

Stokes

Corr

et al. 2013

Cancer Chemother Pharmacol

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“…Moreover, silencing of TLR4 or MyD88 completely reversed the effects of LPS [72]. In contrast, the lipid A analogue (OM-174), with a dual stimulating effect on TLR2 and TLR4 receptors, induced regression of several tumor types in animal models [75–77]. Induction of MyD88 and TRIF, downstream of TLR pathways, perturbed cell cycle regulation in pancreatic cancer [70].…”

Section: Innate Antibacterial Signalingmentioning

confidence: 99%

Dysregulation of signaling pathways associated with innate antibacterial immunity in patients with pancreatic cancer

Słotwiński

Słotwińska

2016

cejoi

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Disorders of innate antibacterial response are of fundamental importance in the development of gastrointestinal cancers, including pancreatic cancer. Multi-regulatory properties of the Toll-like receptors (TLRs) (e.g., regulation of proliferation, the activity of NF-κB, gene transcription of apoptosis proteins, regulation of angiogenesis, HIF-1α protein expression) are used in experimental studies to better understand the pathogenesis of pancreatic cancer, for early diagnosis, and for more effective therapeutic intervention. There are known numerous examples of TLR agonists (e.g., TLR2/5 ligands, TLR6, TLR9) of antitumor effect. The direction of these studies is promising, but a small number of them does not allow for an accurate assessment of the impact of TLR expression disorders, proteins of these signaling pathways, or attempts to block or stimulate them, on the results of treatment of pancreatic cancer patients. It is known, however, that the expression disorders of proteins of innate antibacterial response signaling pathways occur not only in tumor tissue but also in peripheral blood leukocytes of pancreatic cancer patients (e.g., increased expression of TLR4, NOD1, TRAF6), which is one of the most important factors facilitating further tumor development. This review mainly focuses on the genetic aspects of signaling pathway disorders associated with innate antibacterial response in the pathogenesis and diagnosis of pancreatic cancer.

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“…During the last 13 mo, picibanil has been shown to be well tolerated and effective as an adjuvant (1) to immature DCs administered intratumorally to resectable pancreatic cancer patients; 139 (2) to cisplatin (a DNA-damaging agent frequently associated with chemoresistance) 140 and hyperthermotherapy, in a cohort of individuals with malignant pleural effusions; 141 and (3) to a NY-ESO-1-based vaccine, in a single lung cancer patient selected out of a previously completed clinical trial 142 for the study of multiple immunological parameters 143 . In the same period, additional TLR2/TLR4 agonists have been shown to be safe and to exert therapeutically relevant immunostimulatory effects in cancer patients, including OM-174 (also known as CRX-527), a water soluble, diphosphorylated and triacetylated form of lipid A from Escherichia coli , 144 which has been tested in patients with refractory solid tumors; 145 and IMM-101, a preparation of heat-killed Mycobacterium obuense 146 that has been investigated as a standalone therapeutic intervention against melanoma 147 . Moreover, recently completed trials have evaluated the safety and immunostimulatory profile of (1) the TLR3 agonist Hiltonol, a particular formulation of polyriboinosinic polyribocytidylic acid (polyI:C) that includes carboxymethylcellulose and poly- L -lysine as stabilizing agents, 148 employed as adjuvant of a peptide-derived vaccine against ovarian cancer; 149 (2) the imidazoquinoline 852A, a TLR7 agonist, administered subcutaneously for a prolonged period to patients with advanced hematologic malignancies; 150 (3) the TLR9 agonist IMO-2055 (an immunomodulatory oligonucleotide also known as EMD1201081), 151 , 152 given in combination with 5-fluorouracil, cisplatin, and cetuximab (an FDA-approved monoclonal antibody specific for the epidermal growth factor receptor, EGFR) 153 as a first-line palliative treatment to patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC); 154 and (4) Agatolimod (also known as CpG-7909, PF-3512676 and Promune ® ), an unmethylated CpG ODN that also activates TLR9, 155 given in combination with tremelimumab (an experimental monoclonal antibody targeting the immune checkpoint regulator cytotoxic T-lymphocyte-associated protein 4, CTLA4) 156 , 157 to patients affected by advanced solid tumors (including melanoma), 158 or combined with local irradiation in subjects bearing mycosis fungoides 159 …”

Section: Literature Updatementioning

confidence: 99%

Trial Watch

et al. 2013

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Toll-like receptors (TLRs) have long been known for their ability to initiate innate immune responses upon exposure to conserved microbial components such as lipopolysaccharide (LPS) and double-stranded RNA. More recently, this family of pattern recognition receptors has been attributed a critical role in the elicitation of anticancer immune responses, raising interest in the development of immunochemotherapeutic regimens based on natural or synthetic TLR agonists. In spite of such an intense wave of preclinical and clinical investigation, only three TLR agonists are currently licensed by FDA for use in cancer patients: bacillus Calmette–Guérin (BCG), an attenuated strain of Mycobacterium bovis that operates as a mixed TLR2/TLR4 agonist; monophosphoryl lipid A (MPL), a derivative of Salmonella minnesota that functions as a potent agonist of TLR4; and imiquimod, a synthetic imidazoquinoline that activates TLR7. One year ago, in the August and September issues of OncoImmunology, we described the main biological features of TLRs and discussed the progress of clinical studies evaluating the safety and therapeutic potential of TLR agonists in cancer patients. Here, we summarize the latest developments in this exciting area of research, focusing on preclinical studies that have been published during the last 13 mo and clinical trials launched in the same period to investigate the antineoplastic activity of TLR agonists.

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Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors

Cited by 39 publications

References 33 publications

Toll-like receptor signaling regulates cisplatin-induced mechanical allodynia in mice

Toll-like receptor signaling regulates cisplatin-induced mechanical allodynia in mice

Dysregulation of signaling pathways associated with innate antibacterial immunity in patients with pancreatic cancer

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