ArticleJournal for immunotherapy of cancer2018
Agonist redirected checkpoint, PD1-Fc-OX40L, for cancer immunotherapy.
Article in Journal for immunotherapy of cancer, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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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
37 citing papers in PubMed, 49 citations in OpenAlex.
- Efficient discovery of an agonistic anti-OX40 nanobody by epitope-directed approach to address enrichment-driven epitope bias.Journal for immunotherapy of cancer · 2026Article
- Tumor-infiltrating lymphocytes demonstrate potent anti-tumor efficacy and synergize with PD-1 blockade in bladder cancer.Journal of translational medicine · 2026Article
- OX40 signaling in cancer immunotherapy: mechanisms of action, translational applications, and therapeutic perspectives.Frontiers in immunology · 2026Review
- Optimizing antibody stability and efficacy in CD47- SIRPα inhibition via computational approaches.Molecular diversity · 2025Article
- Multi-omics analysis of tumor necrosis factor superfamily 4 reveals its prognostic value with T cell exhaustion feature in cancer.Discover oncology · 2025Article
- Multispecific Antibodies Targeting PD-1/PD-L1 in Cancer.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2025Review
- First-in-human, phase 1 dose escalation study of SL-279252, a hexameric PD1-Fc-OX40L fusion protein, in patients with advanced solid tumors and lymphoma.Investigational new drugs · 2025Article
- Combining iRGD with HuFOLactis enhances antitumor potency by facilitating immune cell infiltration and activation.Human vaccines & immunotherapeutics · 2024Article
- OX40/OX40 ligand and its role in precision immune oncology.Cancer metastasis reviews · 2024Review
- Costimulatory and Coinhibitory Immune Checkpoints in Atherosclerosis: Therapeutic Targets in Atherosclerosis?JACC. Basic to translational science · 2024Review
- Lipid-Encapsulated mRNAs Encoding Complex Fusion Proteins Potentiate Antitumor Immune Responses.Cancer research · 2024Article
- Generation and characterization of OX40-ligand fusion protein that agonizes OX40 on T-Lymphocytes.Frontiers in immunology · 2024Article
- Engaging stimulatory immune checkpoint interactions in the tumour immune microenvironment of primary liver cancers - how to push the gas after having released the brake.Frontiers in immunology · 2024Review
- VISTA and its ligands: the next generation of promising therapeutic targets in immunotherapy.Cancer cell international · 2023Review
- First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1).Journal for immunotherapy of cancer · 2023Article
- Targeting Co-Stimulatory Receptors of the TNF Superfamily for Cancer Immunotherapy.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2023Review
- The benefits of clustering in TNF receptor superfamily signaling.Frontiers in immunology · 2023Review
- Reconciling intrinsic properties of activating TNF receptors by native ligands versus synthetic agonists.Frontiers in immunology · 2023Review
- Secreted heat shock protein gp96-Ig and OX40L-Fc combination vaccine enhances SARS-CoV-2 Spike (S) protein-specific B and T cell immune responses.Vaccine: X · 2022Article
- A novel oncolytic virus induces a regional cytokine storm and safely eliminates malignant ascites of colon cancer.Cancer medicine · 2022Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Simultaneous blockade of immune checkpoint molecules and co-stimulation of the TNF receptor superfamily (TNFRSF) is predicted to improve overall survival in human cancer. TNFRSF co-stimulation depends upon coordinated antigen recognition through the T cell receptor followed by homotrimerization of the TNFRSF, and is most effective when these functions occur simultaneously. To address this mechanism, we developed a two-sided human fusion protein incorporating the extracellular domains (ECD) of PD-1 and OX40L, adjoined by a central Fc domain, termed PD1-Fc-OX40L. The PD-1 end of the fusion protein binds PD-L1 and PD-L2 with affinities of 2.08 and 1.76 nM, respectively, and the OX40L end binds OX40 with an affinity of 246 pM. High binding affinity on both sides of the construct translated to potent stimulation of OX40 signaling and PD1:PD-L1/L2 blockade, in multiple in vitro assays, including improved potency as compared to pembrolizumab, nivolumab, tavolixizumab and combinations of those antibodies. Furthermore, when activated human T cells were co-cultured with PD-L1 positive human tumor cells, PD1-Fc-OX40L was observed to concentrate to the immune synapse, which enhanced proliferation of T cells and production of IL-2, IFNγ and TNFα, and led to efficient killing of tumor cells. The therapeutic activity of PD1-Fc-OX40L in established murine tumors was significantly superior to either PD1 blocking, OX40 agonist, or combination antibody therapy; and required CD4+ T cells for maximum response. Importantly, all agonist functions of PD1-Fc-OX40L are independent of Fc receptor cross-linking. Collectively, these data demonstrate a highly potent fusion protein that is part of a platform, capable of providing checkpoint blockade and TNFRSF costimulation in a single molecule, which uniquely localizes TNFRSF costimulation to checkpoint ligand positive tumor cells.
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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.