title: OX40 is a potent immune-stimulating target in late-stage cancer patients.
abstract: 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.
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Curti
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kovacsovics-Bankowski
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Morris
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Edwin
authors.initials: E
authors.lastname: Walker
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Lana
authors.initials: L
authors.lastname: Chisholm
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Kevin
authors.initials: K
authors.lastname: Floyd
authors.affiliation: Oregon Health and Science University, Vaccine and Gene Therapy Institute, Beaverton, OR 97006.
authors.forename: Joshua
authors.initials: J
authors.lastname: Walker
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Iliana
authors.initials: I
authors.lastname: Gonzalez
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Tanisha
authors.initials: T
authors.lastname: Meeuwsen
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Fox
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Tarsem
authors.initials: T
authors.lastname: Moudgil
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: William
authors.initials: W
authors.lastname: Miller
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Daniel
authors.initials: D
authors.lastname: Haley
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Todd
authors.initials: T
authors.lastname: Coffey
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Brenda
authors.initials: B
authors.lastname: Fisher
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Laurie
authors.initials: L
authors.lastname: Delanty-Miller
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Nicole
authors.initials: N
authors.lastname: Rymarchyk
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Tracy
authors.initials: T
authors.lastname: Kelly
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Todd
authors.initials: T
authors.lastname: Crocenzi
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Eric
authors.initials: E
authors.lastname: Bernstein
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Rachel
authors.initials: R
authors.lastname: Sanborn
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Urba
authors.affiliation: Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan St. Portland, OR 97213.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D053262:Receptors, OX40 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D053262:Receptors, OX40