Challenges and opportunities in the development of combination immunotherapy with OX40 agonists

ABSTRACT

Introduction

Costimulatory members of the tumor necrosis factor receptor family, such as OX40 (CD134), provide essential survival and differentiation signals that enhance T cell function. Specifically, OX40 (CD134) agonists stimulate potent anti-tumor immunity in a variety of preclinical models but their therapeutic impact in patients with advanced malignancies has been limited thus far.

Areas covered

In this review, we discuss the current state of combination immunotherapy with OX40 agonists including preclinical studies and recent clinical trials. We also discuss the strengths and limitations of these approaches and provide insight into alternatives that may help enhance the efficacy of combination OX40 agonist immunotherapy.

Expert opinion

OX40 agonist immunotherapy has not yet demonstrated significant clinical activity as a monotherapy or in combination with immune checkpoint blockade (ICB), likely due to several factors including the timing of administration, drug potency, and selection of agents for combination therapy clinical trials. We believe that careful consideration of the biological mechanisms regulating OX40 expression and function may help inform new approaches, particularly in combination with novel agents, capable of increasing the therapeutic efficacy of this approach.

KEYWORDS:

• OX40
• costimulation
• immune checkpoint blockade
• CTLA-4
• PD-1
• PD-L1
• immunotherapy
• clinical trials

Article highlights

• OX40-mediated costimulation can induce potent T cell activation and differentiation.

• Combination therapy with OX40 agonists and immune checkpoint blockade (ICB) or other novel agents stimulates robust anti-tumor immunity in a variety of preclinical models.

• However, clinical translation of OX40 agonists alone or in combination with ICB has not yielded similar efficacy in patients. This may be due to suboptimal dosing or timing of drug administration, differences in the biological activity of various OX40 agonists, and/or the presence of other suppressive mechanisms within the tumor microenvironment.

• Novel approaches are needed to drive more effective responses and fully realize the therapeutic potential of combination immunotherapy with OX40 agonists.

Declaration of interest

W Redmond declares research support from Bristol-Myers Squibb, GlaxoSmithKline, MiNA Therapeutics, Inhibrx, Veana Therapeutics, Shimadzu, Galecto, Turn Bio, and CanWell Pharma. W Redmond declares patents/licensing fees from Galectin Therapeutics and has acted on advisory boards for Vesselon, Medicenna and Veana Therapeutics. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by NIH grants R01CA255650 and R21CA248904, and by Providence Portland Medical Foundation.