OX40 is a potent immune-stimulating target in late-stage cancer patients

Brendan D. Curti, Magdalena Kovacsovics-Bankowski, Nicholas Morris, Edwin Walker, Lana Chisholm, Kevin Floyd, Joshua Walker, Iliana Gonzalez, Tanisha Meeuwsen, Bernard A. Fox, Tarsem Moudgil, William Miller, Daniel Haley, Todd Coffey, Brenda Fisher, Laurie Delanty-Miller, Nicole Rymarchyk, Tracy Kelly, Todd Crocenzi, Eric BernsteinRachel Sanborn, Walter J. Urba, Andrew D. Weinberg

Research output: Contribution to journalArticlepeer-review

322 Scopus citations

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 tumorfree 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 tumorinfiltrating 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.

Original languageEnglish (US)
Pages (from-to)7189-7198
Number of pages10
JournalCancer Research
Volume73
Issue number24
DOIs
StatePublished - Dec 15 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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