Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists

Abstract

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; T cells; cancer; chemotherapy; clinical trials; macrophages.

Figure 1. Milestones in the history of CD40 as a target for cancer immunotherapy

The timeline depicts some of the pivotal milestones in the study of CD40 as a target for cancer immunotherapy. 1990 – CD40 discovered [93]. 1992 – CD40 ligand identified [94,95]. 1998 – CD40 ligation “licenses” dendritic cells [–9,16]. 1999 – CD40 agonists induce anti-tumor immunity [–19]. 2003 – CD40 synergizes with chemotherapy [77]. 2007 – First-in-human clinical trial of CD40 agonist [23]. 2011 – CD40 agonists induce macrophage-dependent anti-tumor immunity [25]. 2015 – Preclinical models show benefit of CD40 agonist with PD-1/PD-L1 blockade [87]. 2016 – CD40 agonists “condition” tumors for enhanced chemotherapy efficacy [26]. 2016 –Multiple clinical trials ongoing with CD40 agonists.

Figure 2. Strategies for applying CD40 agonists in cancer therapy

A. Stimulating T cell immunity. Treatment with chemotherapy (step 1) induces an immunogenic form of tumor cell death with the release of tumor cell antigens (step 2) that are phagocytosed by APCs, such as macrophages and dendritic cells. APCs are then “licensed” by a CD40 agonist (step 3) to present tumor antigen and stimulate tumor specific T cells (step 4). B. Activating innate immunity. Treatment with a CD40 agonist stimulates tumor-infiltrating myeloid cells (step 1) to induce degradation of tumor-associated fibrosis (step 2). Loss of fibrosis renders the tumor more susceptible to chemotherapy (step 3) resulting in tumor cell death (step 4).