Abstract
Simple SummaryCD40 is a costimulatory molecule that is key for the activation of antigen-presenting cells and other innate immune cells. It plays an important role in anti-tumor immunity, and agonists of CD40 have been shown to eliminate tumors in both pre-clinical and clinical settings, alone and in combination with other treatment modalities. Here we assess the expression of CD40 and associations with other mediators of immunity in a variety of tumor types and review the potential of CD40 agonists for cancer treatment, given the promise of enhancing the interplay between innate and adaptive immunity.CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased antigen presentation, maturation (licensing) of dendritic cells, and activation of CD8+ T cells. Here we analyzed gene expression data from The Cancer Genome Atlas in melanoma, renal cell carcinoma, and pancreatic adenocarcinoma and found correlations between CD40 and several genes involved in antigen presentation and T cell function, supporting further exploration of CD40 agonists to treat cancer. Agonist CD40 antibodies have induced anti-tumor effects in several tumor models and the effect has been more pronounced when used in combination with other treatments (immune checkpoint inhibition, chemotherapy, and colony-stimulating factor 1 receptor inhibition). The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies.
Highlights
In the past decade, oncologic care has changed dramatically as immunotherapies have been developed for multiple tumor types
20,501) in samples from 534 clear cell renal cell carcinomas, 456 cutaneous melap-value of
We found several genes that are involved in the cytotoxic activity of T cells and NK cells including granzymes GZMM, GZMA, GZMH, and natural killer cell granule protein 7 (NKG7), that were correlated with CD40 expression
Summary
Oncologic care has changed dramatically as immunotherapies have been developed for multiple tumor types. Combinations of PD-1/PD-L1 axis inhibitors with inhibitors of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have been studied, and are widely used for melanoma, renal cell carcinoma (RCC), and non-small cell lung cancer [3,4,5,6,7,8,9,10]. Even with this dual approach, the majority of tumors are either resistant up-front or acquire resistance. Agonistic CD40 antibodies can mimic the binding of CD40L to CD40 and initiate downstream signaling that induces anti-tumor immunity
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