Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists

ABSTRACT

Introduction: CD40 is a promising therapeutic target for cancer immunotherapy. In patients with advanced solid malignancies, CD40 agonists have demonstrated some anti-tumor activity and a manageable toxicity profile. A 2^nd generation of CD40 agonists has now been designed with optimized Fc receptor (FcR) binding based on preclinical evidence suggesting a critical role for FcR engagement in defining the potency of CD40 agonists in vivo.

Areas covered: We provide a comprehensive review using PubMed and Google Patent databases on the current clinical status of CD40 agonists, strategies for applying CD40 agonists in cancer therapy, and the preclinical data that supports and is guiding the future development of CD40 agonists.

Expert commentary: There is a wealth of preclinical data that provide rationale on several distinct approaches for using CD40 agonists in cancer immunotherapy. This data illustrates the need to strategically combine CD40 agonists with other clinically active treatment regimens in order to realize the full potential of activating CD40 in vivo. Thus, critical to the success of this class of immune-oncology drugs, which have the potential to restore both innate and adaptive immunosurveillance, will be the identification of biomarkers for monitoring and predicting responses as well as informing mechanisms of treatment resistance.

KEYWORDS:

• CD40 agonists
• macrophages
• T cells
• chemotherapy
• cancer
• clinical trials

Declaration of interest

GL Beatty has received research funding from Novartis, Incyte, Halozyme and Biothera. The authors have 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.

Additional information

Funding

This work was supported by a National Institutes of Health grant K08 CA138907 (GL Beatty), by a National Institutes of Health grant R01 CA197916 (GL Beatty), by grant 2013107 from the Doris Duke Charitable Foundation (GL Beatty), and by NIH National Institute of General Medical Sciences K12GM081295 (KB Long).