OX40 Is a Potent Immune-Stimulating Target in Late-Stage Cancer Patients
| Autor: | Walter J. Urba, Rachel E. Sanborn, Lana Chisholm, Nicholas P. Morris, Bernard A. Fox, Tarsem Moudgil, Kevin Floyd, Andrew D. Weinberg, Iliana Gonzalez, Joshua M. Walker, Brenda Fisher, Daniel Haley, Eric D. Bernstein, Edwin B. Walker, Nicole Rymarchyk, Tracy L Kelly, Tanisha Meeuwsen, Laurie Delanty-Miller, Todd S. Crocenzi, Magdalena Kovacsovics-Bankowski, Brendan D. Curti, Todd Coffey, William Miller |
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| Rok vydání: | 2013 |
| Předmět: |
CD4-Positive T-Lymphocytes
Cancer Research medicine.drug_class Dose-Response Relationship Immunologic CD8-Positive T-Lymphocytes Lymphocyte Activation Monoclonal antibody T-Lymphocytes Regulatory Article TCIRG1 Mice Immune system Antigen Antigens Neoplasm Neoplasms medicine Animals Humans Cytotoxic T cell B cell biology Antibodies Monoclonal FOXP3 Receptors OX40 medicine.anatomical_structure Oncology Immunology biology.protein Antibody |
| Zdroj: | Cancer Research. 73:7189-7198 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-12-4174 |
| Popis: | OX40 is a potent costimulatory receptor that can potentiate T-cell receptor signaling on the surface of T lymphocytes, leading to their activation by a specifically recognized antigen. In particular, OX40 engagement by ligands present on dendritic cells dramatically increases the proliferation, effector function, and survival of T cells. Preclinical studies have shown that OX40 agonists increase antitumor immunity and improve tumor-free survival. In this study, we performed a phase I clinical trial using a mouse monoclonal antibody (mAb) that agonizes human OX40 signaling in patients with advanced cancer. Patients treated with one course of the anti-OX40 mAb showed an acceptable toxicity profile and regression of at least one metastatic lesion in 12 of 30 patients. Mechanistically, this treatment increased T and B cell responses to reporter antigen immunizations, led to preferential upregulation of OX40 on CD4+ FoxP3+ regulatory T cells in tumor-infiltrating lymphocytes, and increased the antitumor reactivity of T and B cells in patients with melanoma. Our findings clinically validate OX40 as a potent immune-stimulating target for treatment in patients with cancer, providing a generalizable tool to favorably influence the antitumor properties of circulating T cells, B cells, and intratumoral regulatory T cells. Cancer Res; 73(24); 7189–98. ©2013 AACR. |
| Databáze: | OpenAIRE |
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