ArticleCancer immunology, immunotherapy : CII2018
Administration of low-dose combination anti-CTLA4, anti-CD137, and anti-OX40 into murine tumor or proximal to the tumor draining lymph node induces systemic tumor regression.
Article in Cancer immunology, immunotherapy : CII, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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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.
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Who cites it
20 citing papers in PubMed, 36 citations in OpenAlex.
- Innovative immunotherapy approaches: harnessing synergy of dual checkpoint blockade in oncology.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade.Journal for immunotherapy of cancer · 2025Article
- Vitamin D3 reduces the viability of cancer cells in vitro and retard the EAC tumors growth in mice.PloS one · 2025Article
- Therapeutic Immunomodulation of Tumor-Lymphatic Crosstalk via Intratumoral Immunotherapy.Molecular pharmaceutics · 2024Review
- Intratumoural immunotherapy plus focal thermal ablation for localized prostate cancer.Nature reviews. Urology · 2024Review
- Intratumor injected gold molecular clusters for NIR-II imaging and cancer therapy.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Tumor-draining lymph nodes: opportunities, challenges, and future directions in colorectal cancer immunotherapy.Journal for immunotherapy of cancer · 2024Review
- Optimization of whole-cell vaccines with CpG/αOX40/cGAMP to strengthen the anti-tumor response of CD4Journal of cancer research and clinical oncology · 2022Article
- The "Great Debate" at Immunotherapy Bridge 2021, December 1st-2nd, 2021.Journal of translational medicine · 2022Article
- Article
- Co-stimulatory agonists: An insight into the immunotherapy of cancer.EXCLI journal · 2021Review
- Expression of immune checkpoint regulators, cytotoxic T lymphocyte antigen 4 (CTLA-4), and CD137 in cervical carcinoma.International journal of clinical and experimental pathology · 2021Article
- Peri-tumor administration of controlled release anti-CTLA-4 synergizes with systemic anti-PD-1 to induce systemic antitumor immunity while sparing autoimmune toxicity.Cancer immunology, immunotherapy : CII · 2020Article
- DNA-Based Delivery of Checkpoint Inhibitors in Muscle and Tumor Enables Long-Term Responses with Distinct Exposure.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
- Oncolytic Viruses: Priming Time for Cancer Immunotherapy.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2019Review
- OX40 and OX40L protein expression of tumor infiltrating lymphocytes in non-small cell lung cancer and its role in clinical outcome and relationships with other immune biomarkers.Translational lung cancer research · 2019Article
- Molecular and metabolic pathways mediating curative treatment of a non-Hodgkin B cell lymphoma by Sindbis viral vectors and anti-4-1BB monoclonal antibody.Journal for immunotherapy of cancer · 2019Article
- An Update on Anti-CD137 Antibodies in Immunotherapies for Cancer.International journal of molecular sciences · 2019Review
- The Crohn's-Like Lymphoid Reaction to Colorectal Cancer-Tertiary Lymphoid Structures With Immunologic and Potentially Therapeutic Relevance in Colorectal Cancer.Frontiers in immunology · 2019Review
- Immunomodulation of the Tumor Microenvironment: Turn Foe Into Friend.Frontiers in immunology · 2018Review
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
The delivery of immunomodulators directly into the tumor potentially harnesses the existing antigen, tumor-specific infiltrating lymphocytes, and antigen presenting cells. This can confer specificity and generate a potent systemic anti-tumor immune response with lower doses and less toxicity compared to systemic administration, in effect an in situ vaccine. Here, we test this concept using the novel combination of immunomodulators anti-CTLA4, -CD137, and -OX40. The triple combination administered intratumorally at low doses to one tumor of a dual tumor mouse model had dramatic local and systemic anti-tumor efficacy in lymphoma (A20) and solid tumor (MC38) models, consistent with an abscopal effect. The minimal effective dose was 10 μg each. The effect was dependent on CD8 T-cells. Intratumoral administration resulted in superior local and distant tumor control compared to systemic routes, supporting the in situ vaccine concept. In a single tumor A20 model, injection close to the tDLN resulted in similar efficacy as intratumoral and significantly better than targeting a non-tDLN, supporting the role of the tDLN as a viable immunotherapy target in addition to the tumor itself. Distribution studies confirmed expected concentration of antibodies in tumor and tDLN, in keeping with the anti-tumor results. Overall intratumoral or peri-tDLN administration of the novel combination of anti-CTLA4, anti-CD137, and anti-OX40, all agents in the clinic or clinical trials, demonstrates potent systemic anti-tumor effects. This immunotherapeutic combination is promising for future clinical development via both these safe and highly efficacious routes of administration.
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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.