Uncovering the Potential of CD40 Agonism to Enhance Immune Checkpoint Blockade

Abstract

In this CCR Translations, we discuss the therapeutic potential of CD40 agonism, which stimulates antigen-presenting cells (APC) to activate effector T and NK cells. CD40 agonism may lead to development of an interferon-activated, T cell-inflamed tumor microenvironment and has the potential to facilitate long-term response with immune checkpoint blockade. See related article by Weiss et al., p. 74.

Figure 1:. Enhancement of anti-tumor activity with CD40 agonistic mAb.

Preclinical data from murine tumor models have indicated synergistic activity between CD40 agonism and chemotherapy, radiation therapy, immune checkpoint therapy, anti-angiogenic therapy, and tumor vaccine. The possible explanation for this synergism may be due to the killing of tumor cells leading to release of tumor neoantigens. Cancer cells may also undergo apoptosis after CD40 activation. The enhanced tumor neoantigen presentation by APCs (DCs, macrophages, B-cells) is augmented by activation of CD40 receptor by the agonistic anti-CD40 mAb, which leads to expression of other co-stimulatory receptors (ie 4-1BB, OX40, ICOS, GITR) and secretion of interleukin-12 (IL-12), which is important for T-cell and NK-cell mediated anti-tumor cytotoxicity. CD40-mediated activation on B cells also facilitates tumor neoantigen presentation to CD4⁺ and CD8 T⁺ effector cells, and production of anti-tumor antibodies. Overall, CD40 agonistic mAb modifies the tumor microenvironment with the potential to convert immunologically “cold” tumors to “hot” tumors and enhance the therapeutic activity of other treatment approaches.