OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal

Recent studies have highlighted the therapeutic efficacy of immunotherapy, a class of cancer treatments that utilize the patient’s own immune system to destroy cancerous cells. Within a tumor the presence of a family of negative regulatory molecules, collectively known as “checkpoint inhibitors,” ca...

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Main Authors:	Linch, Stefanie N., McNamara, Michael J., Redmond, William L.
Format:	Online
Language:	English
Published:	Frontiers Media S.A. 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329814/

id	pubmed-4329814
recordtype	oai_dc
spelling	pubmed-43298142015-03-11 OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal Linch, Stefanie N. McNamara, Michael J. Redmond, William L. Oncology Recent studies have highlighted the therapeutic efficacy of immunotherapy, a class of cancer treatments that utilize the patient’s own immune system to destroy cancerous cells. Within a tumor the presence of a family of negative regulatory molecules, collectively known as “checkpoint inhibitors,” can inhibit T cell function to suppress anti-tumor immunity. Checkpoint inhibitors, such as CTLA-4 and PD-1, attenuate T cell proliferation and cytokine production. Targeted blockade of CTLA-4 or PD-1 with antagonist monoclonal antibodies (mAbs) releases the “brakes” on T cells to boost anti-tumor immunity. Generating optimal “killer” CD8 T cell responses also requires T cell receptor activation plus co-stimulation, which can be provided through ligation of tumor necrosis factor receptor family members, including OX40 (CD134) and 4-1BB (CD137). OX40 is of particular interest as treatment with an activating (agonist) anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity against a variety of tumors. When used as single agents, these drugs can induce potent clinical and immunologic responses in patients with metastatic disease. However, each of these agents only benefits a subset of patients, highlighting the critical need for more effective combinatorial therapeutic strategies. In this review, we will discuss our current understanding of the cellular and molecular mechanisms by which OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the potential opportunities for clinical translation of combinatorial immunotherapeutic strategies. Frontiers Media S.A. 2015-02-16 /pmc/articles/PMC4329814/ /pubmed/25763356 http://dx.doi.org/10.3389/fonc.2015.00034 Text en Copyright © 2015 Linch, McNamara and Redmond. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Linch, Stefanie N. McNamara, Michael J. Redmond, William L.
spellingShingle	Linch, Stefanie N. McNamara, Michael J. Redmond, William L. OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal
author_facet	Linch, Stefanie N. McNamara, Michael J. Redmond, William L.
author_sort	Linch, Stefanie N.
title	OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal
title_short	OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal
title_full	OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal
title_fullStr	OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal
title_full_unstemmed	OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal
title_sort	ox40 agonists and combination immunotherapy: putting the pedal to the metal
description	Recent studies have highlighted the therapeutic efficacy of immunotherapy, a class of cancer treatments that utilize the patient’s own immune system to destroy cancerous cells. Within a tumor the presence of a family of negative regulatory molecules, collectively known as “checkpoint inhibitors,” can inhibit T cell function to suppress anti-tumor immunity. Checkpoint inhibitors, such as CTLA-4 and PD-1, attenuate T cell proliferation and cytokine production. Targeted blockade of CTLA-4 or PD-1 with antagonist monoclonal antibodies (mAbs) releases the “brakes” on T cells to boost anti-tumor immunity. Generating optimal “killer” CD8 T cell responses also requires T cell receptor activation plus co-stimulation, which can be provided through ligation of tumor necrosis factor receptor family members, including OX40 (CD134) and 4-1BB (CD137). OX40 is of particular interest as treatment with an activating (agonist) anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity against a variety of tumors. When used as single agents, these drugs can induce potent clinical and immunologic responses in patients with metastatic disease. However, each of these agents only benefits a subset of patients, highlighting the critical need for more effective combinatorial therapeutic strategies. In this review, we will discuss our current understanding of the cellular and molecular mechanisms by which OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the potential opportunities for clinical translation of combinatorial immunotherapeutic strategies.
publisher	Frontiers Media S.A.
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329814/
_version_	1613188819094339584

OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal

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