ArticleProceedings of the National Academy of Sciences of the United States of America2007
TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
34 citing papers in PubMed, 70 citations in OpenAlex.
- Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial.Nature medicine · 2023Trial
- Phase 2, open-label, 1:1 randomized controlled trial exploring the efficacy of EMD 1201081 in combination with cetuximab in second-line cetuximab-naïve patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).Investigational new drugs · 2014Trial
- Multiomics identifies a cholesterol-TFEB-PLD3-TLR9 axis driving immunosuppressive tumor-associated macrophage polarization in esophageal squamous cell carcinoma.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Toll-like receptors: versatile players in tumor.Frontiers in immunology · 2026Review
- Arthrospira Platensis Attenuates Endothelial Inflammation and Monocyte Activation.International journal of molecular sciences · 2025Article
- Association between antibody-dependent cellular cytotoxicity activity of antitumor antibodies and infusion reactions: a pharmacovigilance analysis using the Japanese adverse drug event report database.Journal of pharmaceutical health care and sciences · 2025Article
- Comparative Characterization of Different Molecular Formats of Bispecific Antibodies Targeting EGFR and PD-L1.Pharmaceutics · 2022Article
- Review
- The association of immunosurveillance and distant metastases in colorectal cancer.Journal of cancer research and clinical oncology · 2021Article
- The First WHO International Standard for Harmonizing the Biological Activity of Bevacizumab.Biomolecules · 2021Article
- Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies.Journal of experimental & clinical cancer research : CR · 2021Review
- Intratumoral injection of TLR9 agonist promotes an immunopermissive microenvironment transition and causes cooperative antitumor activity in combination with anti-PD1 in pancreatic cancer.Journal for immunotherapy of cancer · 2021Article
- Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC).Scientific reports · 2021Article
- TLRs as a Promise Target Along With Immune Checkpoint Against Gastric Cancer.Frontiers in cell and developmental biology · 2020Review
- Pharmacological modulation of nucleic acid sensors - therapeutic potential and persisting obstacles.Nature reviews. Drug discovery · 2019Review
- Intratumoural immunotherapy: activation of nucleic acid sensing pattern recognition receptors.Immuno-oncology technology · 2019Review
- TLRs in pulmonary diseases.Life sciences · 2019Review
- Targeting Toll-Like Receptors for Cancer Therapy.Targeted oncology · 2018Article
- Article
- Anti-tumor Activity of Toll-Like Receptor 7 Agonists.Frontiers in pharmacology · 2017Review
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Synthetic agonists of Toll-like receptor 9 (TLR9), a class of agents that induce specific immune response, exhibit antitumor activity and are currently being investigated in cancer patients. Intriguingly, their mechanisms of action on tumor growth and angiogenesis are still incompletely understood. We recently discovered that a synthetic agonist of TLR9, immune modulatory oligonucleotide (IMO), acts by impairing epidermal growth factor receptor (EGFR) signaling and potently synergizes with anti-EGFR antibody cetuximab in GEO human colon cancer xenografts, whereas it is ineffective in VEGF-overexpressing cetuximab-resistant GEO cetuximab-resistant (GEO-CR) tumors. VEGF is activated by EGFR, and its overexpression causes resistance to EGFR inhibitors. Therefore, we used IMO and the anti-VEGF antibody bevacizumab as tools to study IMO's role on EGFR and angiogenesis and to explore its therapeutic potential in GEO, LS174T, and GEO-CR cancer xenografts. We found that IMO enhances the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of cetuximab, that bevacizumab has no ADCC, and IMO is unable to enhance it. Nevertheless, the IMO-plus-bevacizumab combination synergistically inhibits the growth of GEO and LS174T as well as of GEO-CR tumors, preceded by inhibition of signaling protein expression, microvessel formation, and human, but not murine, VEGF secretion. Moreover, IMO inhibited the growth, adhesion, migration, and capillary formation of VEGF-stimulated endothelial cells. The antitumor activity was irrespective of the TLR9 expression on tumor cells. These studies demonstrate that synthetic agonists of TLR9 interfere with growth and angiogenesis also by EGFR- and ADCC-independent mechanisms affecting endothelial cell functions and provide a strong rationale to combine IMO with bevacizumab and EGFR inhibitory drugs in colon cancer patients.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.