CD40 immunotherapy for pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and lethal cancer which is poorly responsive to standard therapies. Although the PDA tumor microenvironment is considered especially immunosuppressive, recent data mostly from genetically engineered and other mouse models of the disease suggest that novel immunotherapeutic approaches hold promise. Here, we describe both laboratory and clinical efforts to target the CD40 pathway for immunotherapy in PDA. Findings suggest that CD40 agonists can mediate both T-cell-dependent and T-cell-independent immune mechanisms of tumor regression in mice and patients. T-cell-independent mechanisms are associated with macrophage activation and the destruction of PDA tumor stroma, supporting the concept that immune modulation of the tumor microenvironment represents a useful approach in cancer immunotherapy.

Fig. 1

CD40 agonists can mediate both T-cell-independent and T-cell-dependent immune mechanisms of tumor regression in pancreatic cancer. The former mechanism involves systemic activation of macrophages that infiltrate the tumor, become tumoricidal, and facilitate the depletion of tumor stroma. In combination with chemotherapy, CD40 agonists can also activate T-cell immunity and mediate major tumor regression; however, anti-tumor T-cell responses can be inhibited by suppressive elements in the tumor microenvironment. A scientific priority going forward is to understand whether blockade of these inhibitory micro-environmental mechanisms will enable adequate priming of an adaptive immune response in concert with CD40 activation in PDA