Anti-CD40 Abs may therefore be able to turn ‘cold’ tumors into ‘hot’ tumors 11. An attractive aspect of agonist anti-CD40 Abs, which make these complementary to checkpoint inhibitors, is the capacity to enhance the priming of T cell responses through the activation of dendritic cells (DCs) 10. Agonist immunostimulatory antibodies (IS-Abs) targeting activatory receptors on immune cells are a potential alternative for immune checkpoint inhibitors and have demonstrated notable results in preclinical models 9. In order to build on the first promising results of ICB, there is a clear need to explore additional drugs and treatment regimens in clinical trials. Last but not least, immunosuppressive mechanisms in the tumor microenvironment (TME) other than the PD-L1/PD-1 and CTLA-4 pathways may render checkpoint blockade ineffective, such as inhibitory myeloid cell types and CD4+ T-regulatory cells 6, 7, 8. The immunogenicity of many tumors is further decreased by loss of surface MHC class I expression 3, suppression of the antigen-processing machinery 4, and defects in interferon signaling 5. A major hurdle in this respect is the lower intrinsic immunogenicity of ICB-resistant tumors, which is at least partly related to the number of somatic mutations encoding potential T cell epitopes 2. Nevertheless, sub-groups of patients with these indications do not respond to ICB, and the same applies to patients with other cancer types.
The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma.Ĭancer immunotherapy is beginning to realize its potential in the clinic with immune checkpoint blockade (ICB), eliciting durable responses in patients with immunogenic cancers such as melanoma and lung cancer 1. Detailed analysis of the mechanism of action of MEKi shows that this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and T-regulatory cells. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor results in potent synergistic antitumor efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy.
Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade.
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