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 2nd 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.

Combination of CD40 Agonism and CSF-1R Blockade Reconditions Tumor-Associated Macrophages and Drives Potent Antitumor Immunity

“…CD40 ligation drives "licensing" (maturation and activation) of APCs, enabling effective antigen presentation and stimulation of CD4 þ Th1 and CD8 þ T cells. This is a key step in mounting antitumor responses, as supported by emerging preclinical and clinical data with agonist anti-CD40 in multiple tumor types (18,20,25). However, a number of studies have shown that potency of CD40 agonists can be enhanced by combinations with other immune modulatory therapies such as TLR agonists, cytokines including type I interferons and IL2, adoptive cell transfer, and chemotherapy (18,(26)(27)(28)(29)(30).…”

“…CD40 is a highly conserved costimulatory receptor expressed on antigen-presenting cells (APCs) including dendritic cells (DC), macrophages, monocytes, B cells, as well as a number of nonhematopoietic cell types and some tumor cells (18,19). The ligand for CD40 (CD40L) is expressed on activated T cells and B cells and, under inflammatory conditions, is upregulated on innate immune cells as well as endothelial and epithelial cells (20)(21)(22)(23)(24).…”

Immunotherapy in pancreatic adenocarcinoma—overcoming barriers to response

“…Of the strategies utilized to activate myeloid cells as a means of enhancing anti-tumor immunity, CD40 are the most extensively evaluated target. CD40 activates APCs and enhances immune responses (107). CD40 agonist monoclonal antibody, has demonstrated some responses in solid tumors (108), leading to interest in investigating this strategy in PAC.…”

Single Radiotherapy Fraction with Local Anti-CD40 Therapy Generates Effective Abscopal Responses in Mouse Models of Cervical Cancer

“…CD40 is costimulatory protein binding to CD154 (CD40L) on T H cells, which lead to the activation of APCs and a cascade of immune effects. Studies have reported on the overexpression of CD40 in human papilloma virus-infected lesions and advanced squamous carcinomas of the cervix, compared to very low levels in normal cervical epithelium [13,14]. CD40 ligation has resulted in a tumor growth-inhibitory effect, delivering potent apoptotic signals to carcinoma cells.…”

“…This provides a potential therapeutic target that could generate antigens for boosting the abscopal effect [13]. Second, independent of the need for expression of CD40 on cancer cells, agonistic anti-CD40 can be potent stimulants of the immune system, with significant potential synergy in combination with other treatments [14]. This is because of the ability of agonist CD40 to activate antigen presenting cells (APCs), for the priming of antigen specific T cells and its capacity to redirect tumor-infiltrating myeloid cells with anti-tumor and anti-fibrotic activity.…”