OX40 Is a Potent Immune-Stimulating Target in Late-Stage Cancer Patients

Abstract

OX40 is a potent co-stimulatory 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 anti-tumor 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 12/30 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 anti-tumor reactivity of T and B cells in patients with melanoma. Our findings clinically validate OX40 as a potent immune-stimulating target for treatment in cancer patients, providing a generalizable tool to favorably influence the antitumor properties of circulating T cells, B cells and intratumoral regulatory T cells.

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…55,56 A phase I study performed in melanoma patients with anti-OX40 mouse monoclonal antibody confirmed its potent antitumor property. 57 It is interesting to combine coinhibitory inhibitors and costimulatory factors to completely activate the anergic T cells in tumors. Previous studies showed that PD-1 blockade and OX40 agonist jointly yield tumor rejection 58 but no clinical trials are available in NSCLC so far.…”

Antigen-Specific Antitumor Responses Induced by OX40 Agonist Are Enhanced by the IDO Inhibitor Indoximod

“…The OX40 receptor is inducible on activated T cells (11-15) and its engagement with cognate ligand or agonistic antibody enhances T-cell proliferation, cytokine production, survival, and memory development (16,17). In animal models, anti-OX40 has shown favorable antitumor activities and in autoimmune models increases the severity of disease (18)(19)(20)(21)(22)(23).…”

Cancer Immunotherapy and Immunonutrition

“…OX40 is a receptor found on CD4+ and CD8+ T cells, and its engagement helps promote T cell activation, proliferation and cytokine production. These class of agents is still in its early stage, and needs more clinical investigation [12].…”