TY - JOUR
T1 - OX40 is a potent immune-stimulating target in late-stage cancer patients
AU - Curti, Brendan D.
AU - Kovacsovics-Bankowski, Magdalena
AU - Morris, Nicholas
AU - Walker, Edwin
AU - Chisholm, Lana
AU - Floyd, Kevin
AU - Walker, Joshua
AU - Gonzalez, Iliana
AU - Meeuwsen, Tanisha
AU - Fox, Bernard A.
AU - Moudgil, Tarsem
AU - Miller, William
AU - Haley, Daniel
AU - Coffey, Todd
AU - Fisher, Brenda
AU - Delanty-Miller, Laurie
AU - Rymarchyk, Nicole
AU - Kelly, Tracy
AU - Crocenzi, Todd
AU - Bernstein, Eric
AU - Sanborn, Rachel
AU - Urba, Walter J.
AU - Weinberg, Andrew D.
PY - 2013/12/15
Y1 - 2013/12/15
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84891275907&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-12-4174
DO - 10.1158/0008-5472.CAN-12-4174
M3 - Article
C2 - 24177180
AN - SCOPUS:84891275907
SN - 0008-5472
VL - 73
SP - 7189
EP - 7198
JO - Cancer Research
JF - Cancer Research
IS - 24
ER -